Next Article in Journal
Topical L-Ascorbic Acid Formulation for a Better Management of Non-Melanoma Skin Cancer: Perspective for Treatment Strategies
Next Article in Special Issue
Assessing Lymphatic Uptake of Lipids Using Magnetic Resonance Imaging: A Feasibility Study in Healthy Human Volunteers with Potential Application for Tracking Lymph Node Delivery of Drugs and Formulation Excipients
Previous Article in Journal
Lipid-Polymeric Films: Composition, Production and Applications in Wound Healing and Skin Repair
Previous Article in Special Issue
Lipid Nanoparticle-Mediated Lymphatic Delivery of Immunostimulatory Nucleic Acids
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Focus on the Lymphatic Route to Optimize Drug Delivery in Cardiovascular Medicine

Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
Montreal Heart Institute Research Center, Montreal, QC H1T 1C8, Canada
Faculty of Pharmacy, Université de Montréal, Montreal, QC H3T 1J4, Canada
Department of Pharmaceutics, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62511, Egypt
Authors to whom correspondence should be addressed.
These authors equally contributed to this work.
These authors equally supervised this work.
Pharmaceutics 2021, 13(8), 1200;
Submission received: 21 June 2021 / Revised: 27 July 2021 / Accepted: 29 July 2021 / Published: 4 August 2021
(This article belongs to the Special Issue Recent Approaches for Lymphatic Drug Delivery)


While oral agents have been the gold standard for cardiovascular disease therapy, the new generation of treatments is switching to other administration options that offer reduced dosing frequency and more efficacy. The lymphatic network is a unidirectional and low-pressure vascular system that is responsible for the absorption of interstitial fluids, molecules, and cells from the peripheral tissue, including the skin and the intestines. Targeting the lymphatic route for drug delivery employing traditional or new technologies and drug formulations is exponentially gaining attention in the quest to avoid the hepatic first-pass effect. The present review will give an overview of the current knowledge on the involvement of the lymphatic vessels in drug delivery in the context of cardiovascular disease.

Graphical Abstract

1. Introduction

Cardiovascular diseases (CVD) are one of the leading causes of death worldwide [1]. CVD include coronary heart disease, myocardial infarction (MI), heart failure (HF), stroke, and artery diseases [2]. Treatments for cardiovascular diseases are numerous, and the routes of administration are diverse. The chosen drug delivery route is a key determinant of the pharmacodynamics, pharmacokinetics, as well as toxicity of the delivered compounds. Yet, side effects or therapeutic failures are raising concerns, highlighting the need for new administration routes and improved formulation of molecules that reduce their degradation by hepatic metabolism. Drug delivery refers to the methods, approaches, or strategies employed for the transport of pharmaceutical compounds to an organism to achieve a desired therapeutic outcome. With this intent, various routes of administration are used to manage CVD and their risk factors, including parenteral (intravenous (IV), intradermal (ID), intramuscular (IM), subcutaneous (SC), and intraperitoneal (IP)), and transmucosal (oral, nasal, pulmonary, ocular, and genital) and transdermal route [3]. Drug absorption and transport through the lymphatic system makes it possible to avoid hepatic metabolism and is a privileged target in pathologies, such as particular types of cancer (chemotherapeutics [4]) or vaccines [5,6] (HIV [7]), but also for macromolecules [8], and the extensively hepatic-metabolized compounds [9,10].
Discovered in the 17th century [11], the lymphatic system is composed of lymphatic vessels (LV), lymph nodes (LN), and lymphoid organs. LV are organized as initial lymphatics, also called capillaries, localized in the interstitium (i.e., such as the skin, the intestines, and peripheral tissues), pre-collecting and collecting LV. Lymphatic capillaries take up the interstitial fluid that normally consists of immune cells, cellular debris, proteins, electrolytes, chylomicrons, and high-density lipoproteins (HDL) [12,13]. Then, lymph circulates in a unidirectional way due to the presence of valves and lymphatic muscle cells (LMC) surrounding a lymphatic endothelial cell (LEC) monolayer. Lymph passes through the LN and the efferent LV until it reaches the thoracic lymphatic duct and, finally, the bloodstream via the subclavian vein [12]. Given its role in the absorption of interstitial fluids, molecules, and cells from the peripheral tissue, a dual interplay of the lymphatic system in CVD was first brought up in the early 1980s [14] and has gained growing attention in the past few decades [13,15,16,17,18,19,20,21,22]. Atherosclerosis, the main cause of CVD, is characterized by lipid and immune cell accumulation within the artery wall [23]. LV present in the blood vessel walls are involved in the removal of cholesterol from the arterial intima [15]. Further, after an MI, the lymphatic system is involved in the reduction of edema, improvement of cardiac function, and reduction of hypertrophy and fibrosis [24,25,26,27]. Whereas there is an interest in improving lymphatic function to further control CVD onset and progression, targeting the lymphatic system for cardiovascular drug delivery is a promising strategy to limit CVD outcomes. Preferential uptake into the lymphatics is highly dependent on the route of administration and physicochemical properties of the compounds, including size, molecular weight, surface charge, and lipophilicity [28]. This review focuses on the potential key involvement of the lymphatic system in the optimization of drug delivery in CVD.

2. Conventional and Novel Therapies to Treat CVD

Historically, small molecules have been used for the treatment of CVD. However, these molecules improve the symptoms and slow down the disease progression without having an actual regenerative effect on the affected tissues or organs [29]. Thus, the remaining unmet clinical needs necessitated the urgent seek for other potential therapeutic options.
Gene therapy is one of the most promising treatment strategies for CVD [30,31,32,33,34], inherited or acquired, through targeting the causative genes engaged in the induction and progression of the disease. It works through replacing defective genes, silencing overexpressed ones or providing functional copies of specific therapeutic genes, thanks to DNA, RNA (siRNA, microRNA, mRNA), and antisense oligonucleotides (ASO) [35]. Back in the 1950s and 1960s, several attempts were made to directly transfect cells with DNA and RNA. Nevertheless, in vivo studies failed to show a noticeable success. Thus, selecting a suitable vector to deliver gene therapy is as important as selecting the agent itself [36,37]. Generally, vectors can be divided into viral and non-viral. The most commonly used viral vectors are retrovirus (RV), adenovirus (AV), adeno-associated virus (AAV), and lentivirus [38]. The most commonly used non-viral vectors include lipid-based vectors using cationic lipids and polymer-based vectors using cationic polymers [39]. Cationic lipids complex with the genetic materials to form lipoplexes or lipid nanoparticles (LNP), while cationic polymers form polyplexes [40]. In 2012, cardiovascular gene therapy was the third most common application for gene therapy (8.4% of the total gene therapy trials). However, clinically, it is still in the infancy stage, and a lot of effort is yet to be expended to correct the underlying basal molecular mechanisms behind different cardiovascular disorders [41,42].
On the other hand, vaccines, developed to produce a long-term immune response against specific antigens, are considered the most economic life-saving medical intervention so far. Previous studies have demonstrated that antigens are trafficked by immune cells from the administration site through the lymphatic network to activate the residing lymphocytes in the secondary lymphoid tissues to produce antibodies [6], a fundamental step for a successful vaccination process. Vaccination against infectious diseases depends on activating T cells and inducing antibody production, following antigen presentation by antigen presenting cells (APC) to T cells through major histocompatibility complex (MHC) molecules. This binding produces cytotoxic T cells that may trigger an autoimmune response. However, the success of vaccination against self-antigen in life-long diseases, such as hypertension, depends on the ability of the vaccine to produce antibodies without triggering a cytotoxic immune response, for safety issues [43]. For example, vaccination against influenza and pneumococcal infection, a potential risk factor for CVD, could have a protective role in populations with a high risk of CVD, including MI and HF [44,45].
Moreover, conventional orally-administered molecules failed to reach satisfaction owing to their poor aqueous solubility, lack of specificity, short half-life, and, hence, low therapeutic outcome and high systemic adverse events [46]. Driven by these facts, researchers have made great efforts to deliver these molecules in a more effective and safer way. One of the most important strategies used for this purpose is nanotechnology. Indeed, using nanotechnology in the chronic management of CVD could revolutionize the cardiovascular healthcare sector. Nanotechnology can serve as a drug delivery platform to improve the characteristics of the free drugs, e.g., solubility, stability, biodistribution, pharmacokinetics, and toxicity profile. Hence, the choice of a suitable carrier has a great impact on the therapeutic outcome [47].
Related to their administration route, the use of conventional cardiovascular therapy, gene-based therapy, vaccines, and nanotechnology to treat CVD is discussed in this review.

3. Treating CVD through Various Administration Routes

The following sections describe several routes of administration, with an overview on the lymphatic involvement and several conventional and novel therapies used to treat CVD (Table 1, Table 2, Table 3, Table 4, Table 5 and Table 6).

3.1. Oral Administration

Among the various routes of administration, the oral route is the most commonly employed. It exhibits many advantages, including pain avoidance, ease of administration, patient compliance, reduced care cost, and low incidence of cross-infection. Furthermore, it is amenable to various types and forms of pharmaceuticals [48] (Table 1). While some drugs are intended to target the gastrointestinal tract (GIT), the majority are employed to exert a systemic therapeutic effect. Nevertheless, the oral bioavailability of most pharmaceutical compounds depends mainly on their solubility, permeability, and stability in the GIT environment [49,50,51].
Orally-administered compounds enter the systemic circulation through either the portal vein or the intestinal lymphatics after being absorbed, respectively, by the blood or lymphatic vasculature, draining the interstitium. However, these compounds should initially be able to pass through the intestinal epithelium and reach the interstitium to be amenable for transport [10]. Once in the interstitium, two essential factors determine the predominant way of transport: size and lipophilicity. Small molecules/particles are predominantly transported by the blood due to the higher portal blood flow rate as compared to the intestinal lymph flow rate, although they have relatively free access to both blood and lymphatic capillaries. Conversely, large (>500 g/mole) [52] and highly lipophilic molecules (log P > 5, long-chain triglyceride (TG) solubility > 50 mg/g) and particles (up to 10 µm) [53] preferentially enter the highly permeable lymphatics to different extents [10,53,54]. Thus, in order to avoid the hepatic metabolism, the use of a lipophilic molecule is essential, allowing the drug to reach the mesenteric lymphatic vessels permitting the absorption of lipids [55]. The lymphatic system in the intestines is composed of capillaries in the microvilli (lacteals) and collecting lymphatic vessels in the mesentery [56].
  • Diabetes
Cardiovascular diseases are known as the leading cause of mortality in diabetes mellitus (DM) [57], a chronic debilitating metabolic disorder that spreads worldwide. As presented in Table 1, diabetes is commonly treated by conventional therapy (i.e., metformin, sulfonylureas), while gene therapy, vaccines, and nanotechnology are under intensive investigation [35,58,59,60,61,62,63,64,65,66].
Nanotechnology has attracted an increasing interest in the treatment and management of diabetes mellitus. Oral insulin delivery as a convenient and pain-free alternative to SC injection has been the focus of researchers over the last century [67]. Nanocarriers can be used to protect insulin and other hypoglycemic medications from enzymatic degradation [35]. Indeed, encapsulating insulin in nanoparticles in different studies has shown improved oral bioavailability [68,69,70]. However, the clinical translation of these studies has been so far negative [64]. Several approaches have been employed to improve the encapsulated insulin bioavailability through enhancing its absorption from the intestinal lumen. One of them is via promoting its lymphatic absorption. Indeed, complexing insulin with cationic liposomes has shown a gradual increase in insulin concentration in the lymphatic system over time, upon investigating the absorption pathway in lymph fistula- rat model, indicating a major involvement of the lymphatic system in the transport of these nanoparticles [64]. Similarly, lymphatic transport of insulin-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles was believed to be the reason, in part, beyond its improved bioavailability and sustained hypoglycemic effect [65]. The same approach was used to improve the oral bioavailability of exenatide, the glucagon-like peptide-1 (GLP-1) analogue that is primarily administered SC. Exenatide is injected frequently in high doses to overcome its short plasma half-life. Hence, oral delivery seems a favorable alternative; however, it limited by the poor bioavailability of the peptide drug. Nevertheless, using a phase-changeable nanoemulsion with medium-chain fatty acid has increased the relative bioavailability of exenatide by enhancing its intestinal absorption and lymphatic transport, bypassing the hepatic first-pass effect. Lymphatic involvement in exenatide transport was confirmed by inhibiting the lymphatic pathway using cycloheximide. Results confirmed the absence of nanoparticles in epithelial villi, Peyer’s patches, and major organs [66].
  • Hypertension
Hypertension is a major risk factor for several CVD. Conventional antihypertensive medications (Table 1) mostly suffer from certain challenges that limit their therapeutic outcome, including short half-life, poor water solubility, low bioavailability, and serious side effects, such as angioedema, bronchospasm, asthma, male breast hyperplasia, reflex tachycardia, and others [46,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87]. Formulating drugs, such as carvedilol, into nanoemulsion demonstrated a significant improvement in its absorption, permeability, and bioavailability following oral administration [88,89,90,91,92]. The enhanced bioavailability of these medications in nanoemulsion was attributed to their transport via lymphatics, in accordance with the previously established role of nanoemulsion in promoting lymphatic absorption of lipophilic molecules [88,89]. Besides nanoemulsion, other nanocarriers have been widely tested to improve the characteristics of the antihypertensive medications. For instance, felodipine-loaded PLGA were able to bypass the hepatic metabolism by absorption via M-cells of the Peyer’s patches and transport through the lymphatics, facilitated by the negative charges on the particles [93]. Other nanosystems that improved the oral bioavailability and efficacy of antihypertensive medications through promoting lymphatic uptake in preclinical studies include: solid lipid nanoparticles [94], nanostructured lipid carriers [95], proliposomes [96], and Eudragit nanoparticles [97].
  • Hypercholesterolemia and hyperlipidemia
Hyperlipidemia is a family of disorders characterized by elevated level of lipids in the blood and is a major risk factor for atherosclerosis and CVD. One of the most common hyperlipidemia is hypercholesterolemia [98].
Several medications intended for the treatment of hyperlipidemia and hypercholesterolemia have various constraints that affect their efficacy [99,100]. Nanoparticles promoting lymphatic uptake seems a good strategy to resolve these constraints. For instance, atorvastatin, the widely prescribed statin for the treatment of hyperlipidemia and hypercholesterolemia, has been formulated into several polymeric and lipid-based nanocarriers that enhanced its lymphatic absorption and its oral bioavailability, in consequence (Table 1) [101,102,103,104,105].
The same strategy has been used with other statins to improve their bioavailability through enhancing lymphatic uptake, such as simvastatin [106], rosuvastatin [107], and fluvastatin [108], as well as other agents, such as fibrates [109,110,111] and the cholesterol absorption inhibitor ezetimibe [112,113,114].
Table 1. Oral delivery of various treatments for CVD.
Table 1. Oral delivery of various treatments for CVD.
ConditionIntervention and IdentifierTargetDose and Outcome
DiabetesMetformin From 500 to 850 mg, 2–3 times a day, during the meal [58]
Dosage is very different from one class of medication to another [59]
Carbohydrate digesting enzymes in the brush border50 mg three times daily (up to 100 mg) [60]
PPAR-αRosiglitazone: 4 mg per day (up to 8 mg)
Pioglitazone: 15–30 mg per day [61]
DPP42.5–100 mg once daily depending on the inhibitor used [62]
SGLTP2Dapagliflozin: 2.5–10 mg daily
Canagliflozin: 100–300 mg
Empagliflozin: 5–25 mg daily [63]
(NCT03751007) or in combination with the anti-CD3 monoclonal antibody teplizumab
2 or 6 capsules per day for 8 weeks (repeated dose) or for one day (single dose)
DiabetesInsulin nanocarriers Protection of insulin from enzymatic degradation
Enhancement of stability, intestinal permeability, and bioavailability [35]
DiabetesElectrostatically-complexed insulin with partially uncapped cationic liposomes Improved insulin pharmacokinetic profile [64]
DiabetesInsulin-loaded PLGA Improved bioavailability and sustained hypoglycemic effect [65]
DiabetesExenatide combined to phase-changeable nanoemulsion with medium-chain fatty acid Enhancement of intestinal absorption and lymphatic transport [66]
HTNPrazosine Terazosine DoxazosineAlpha-adrenergic receptorPrazosine: 3–7.5 mg per day in two doses
Terazosine: 1–9 mg per day in the evening at bedtime
Doxazosine: 4 mg per day [71]
HTNClonidine MethyldopaAlpha-adrenergic receptor (agonists)Clonidine: 0.1 mg twice daily [72]
Methydopa: 250 mg two to three times daily [73]
HTNCarvedilol into nanoemulsionBeta-adrenergic receptorsSignificant improvement in its absorption, permeability, and bioavailability [88,89]
HTNValsartan, Ramipril and Amlodipine into nanoemulsion Enhanced solubility, oral bioavailability, and pharmacological outcome [90]
HTNFelodipine-loaded PLGA nanoparticlesCalcium-channelSustained drug release both in vitro and ex vivo [93]
ß-blockerBeta-adrenergic receptorsAcebutol: 200 mg twice daily [74]
Conversion enzyme
Conversion enzymeCaptopril: 100 mg per day [75]
Angiotensin II20 mg twice a day, up to 160 mg [76]
Angiotensin/neprilysin receptor49 mg/51 mg twice daily and doubled after 2–4 weeks [77]
Calcium channel5–10 mg daily [78]
60 mg three times daily [79]
Calcium channel5–10 mg daily [78]
60 mg three times daily [79]
HFIvabradine Bradycardic
5–7.5 mg twice a day [80]
Aldosterone50 mg once a day [81] and 12.5–25 mg with each intake [82]
Digoxin 0.25 mg once daily [83]
StatinHMG-CoA10 mg once daily [84]
MIAspirinPlatelets325 mg, then 81 mg per day [85]
Platelets300 mg, then 75 mg daily with aspirin
60 mg, then 10 mg daily
180 mg, then 90 mg twice a day [86,87]
HCLEzetimibeIntestinal cholesterol absorption 10 mg once daily [99]
Fenofibrates 100–300 mg per day [100]
Atorvastatin formulated into ethylcellulose nanoparticles Enhanced atorvastatin’s lymphatic absorption and oral bioavailability [101]
Atorvastatin formulated into nanocrystals prepared with poloxamer 188 Improved atorvastatin’s gastric solubility and bioavailability [102]
Reduced circulating cholesterol, TG and LDL
Atorvastatin formulated into polycaprolactone nanoparticles Enhanced atorvastatin’s bioavailability [103]
Nanostructured lipid carriers Enhanced atorvastatin bioavailability by 2.1 fold compared to the commercial product: lipitor®
Reduced the serum level of cholesterol, TG and LDL [104]
Nanoemulsion Increased the bioavailability of atorvastatin compared to the commercial tablet ozovasTM [105]
Improved bioavailability via lymphatic uptake [106,107,108,109,110,111,112,113,114]
PPAR- α: peroxisome proliferator-activated receptor- α; DPP4: dipeptidyl peptidase-4; SGLTP2: Sodium glucose co-transporter-2; PLGA: Poly lactic-co-glycolic acid; HTN: Hypertension; MI: Myocardial infarction; HF: Heart failure; HCL: Hypercholesterolemia; HMG-CoA reductase: Hydroxymethyl glutaryl coenzyme A reductase; HLD: Hyperlipidemia; TG: Triglycerides; LDL: Low density lipoprotein.

3.2. Subcutaneous Injection

Subcutaneous injections consist of injecting a molecule under the dermis, in the SC cell layer (interstitial space), and slightly before the muscle, mostly in the abdomen or thigh. The injected molecules will, therefore, either be degraded or phagocytized at the site of injection and join the lymphatic system or the bloodstream [115]. To target the lymphatic system exclusively, this type of injection must be combined with the use of macromolecules. As described in Table 2, subcutaneous injections are used as treatment for various conditions [116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143].
Table 2. Therapies targeting CVD using subcutaneous injection.
Table 2. Therapies targeting CVD using subcutaneous injection.
ConditionIntervention and IdentifierTherapyTargetStage and StatusDose and Outcome
DiabetesInsulin Different types of insulin
At least 3 injections per day
Dosage adapted to the patient [116]
Exenatide LAR
GLP-1 analogues [117]
Exenatide: 5–10 µg twice a day
Lixisenatide: 10–20 µg once daily
Liraglutide: 0.6–1.8 mg once daily
Exenatide LAR: 2 mg once a week
Albiglutide: 30–50 mg once a week
Dulaglutide: 0.75–1.5 mg once a week
DiabetesVaccine formed of virus-like particles coupled to IAPP Against the insoluble IAPP- derived amyloid aggregates Three doses—10 µg
Strong immune response against these aggregates and restored insulin production Diminished the amyloid deposits in the pancreatic islets, reduced the level of the pro-inflammatory cytokine IL-1β, and reprieved the onset of amyloid-induced hyperglycemia [118]
DiabetesIL-1β epitope peptide Against IL-1β Three doses—50 µg
Enhancement glucose tolerance, improved insulin sensitivity, restored β-cell mass, reduced β-cell apoptosis, and enhanced β-cell proliferation, as well as downregulation of IL-1β expression and inhibition of the inflammatory activity [119,120]
Against IL-1β Six doses—300 µg
Mediated a dose-dependent IL-1β-specific antibody response
More studies are required to precisely investigate the clinical efficiency of this vaccine [121]
antibodies against DPP4
The GLP-1 and GIP inhibitor, DPP4 Five doses—2–20 µg
Increased pancreatic and plasma insulin level and improved postprandial blood glucose level [122]
HTNhR32 vaccine Renin-derived peptide Five doses—500 µg
Reduced systolic blood pressure by 15 mmHg [123]
HTNAngiotensin I
vaccine (PMD3117)
Three or four doses—100 µg
The vaccine failed to reduce the blood pressure [124]
HTNAngI-R vaccine Modifiedendogenous angiotensin I peptide Four doses—50 µg
15 mmHg reduction in systolic blood pressure and reduced angiotensin I/II level [125]
HTNATRQβ-001 Angiotensin II type I receptors Two doses—100 µg
Protective role against target organ damage induced by hypertension [126]
HTNATR12181 vaccine Angiotensin II type I receptors Nine doses—0.1 mg
Attenuated the development of hemodynamic alterations of hypertension [127]
HTNCYT006-AngQb vaccine Against angiotensin II 100 or 300 µg
Reduction in blood pressure and reduced ambulatory daytime blood pressure [128]
Angiotensin II Three doses—5 µg
Suppressed post-MI cardiac remodeling and improved cardiac function [129]
MICelecoxib loaded in nanoparticles Promoted vascularization in the ischemic myocardium and delayed HF progression [130]
MIChitosan-hyaluronic acid based hydrogel containing deferoxamine-PLGA
Persistent neovascularization in mice [131]
PCSK9 One dose every two weeks [132,133]
HCLInclisiran PCSK9 Two doses per year [134]
severe HCL
ASOApoBApproved200 mg once/week.
Phase III: reduction in LDL-C [135]
ASCVD HCL HeFHInclisiran
siRNAPCSK9Approved284 mg inclisiran, injected on day 1, day 90 and then twice/year
Phase III: reduction in LDL-C level [134,136]
ASOApoC3Approved300 mg once/week
Phase III: reduction in mean plasma APOC3 and TG level [137]
Elevated LP(a)ISIS-APO(a)Rx
ASOAPO(a)Phase II (Complete)Multiple escalating (100–300 mg) doses, injected on a weekly interval for 4 weeks each
Phase I/II: reduction in plasma Lp(a) concentration [138]
Elevated LP(a)
APO(a)Phase III
80 mg administered monthly
Phase I/II: reduction in plasma Lp(a) [138]
Multiple dosing injected as once/4 weeks for up to 49 weeks
Phase II: reduction in ApoC3 and TG levels [139]
(Active, Not recruiting)
Multiple escalating dosing (60–160 mg, once/2 or 4 weeks)
Phase I: reduction in TG and LDL-C levels [140]
HCLNeutralizing antibodies against PCSK9 PCSK9 Three doses—5–50 µg
Long-lasting reduction in the level of total cholesterol, VLDL and
chylomicron [141]
HCLAT04A PCSK9 Five doses
Strong and persistent anti-PCSK9 antibody production, reduced plasma cholesterol level, attenuated progression of atherosclerosis and reduced vascular and systemic inflammation [142]
HCLAT04A PCSK9 Four doses—15 µg and 75 µg
Reduced serum LDL-C level and elevated anti-PCSK9 antibody titer [143]

A peptide representing the mouse ANGPTL3 Angiopoietin-like proteins 3 (ANGPTL3) Three doses—5 µg
Reduced steady-state plasma TGs and promoted LPL activity
GLP-1: glucagon-like peptide-1; IAPP: Islet amyloid polypeptide; DPP4: dipeptidyl peptidase-4; GIP: glucose-dependent insulinotropic polypeptide; HTN: Hypertension; HF: Heart failure; MI: Myocardial infarction; HCL: Hypercholesterolemia; HoFH: Homozygous familial hypercholesterolemia; HeFH: Heterozygous familial hypercholesterolemia; AngII-KLH: Angiotensin II—keyhole-limpet hemocyanin; PCSK9: Proprotein convertase subtilisin/kexin type 9; ASO: Antisense oligonucleotides; ApoB: Apolipoprotein B; LDL-C: low density lipoprotein cholesterol; ASCVD: Atherosclerotic cardiovascular disease; FCS: Familial chylomicronemia syndrome; TG: Triglycerides; LP(a): Lipoprotein(a); APO(a): Apolipoprotein (a); CVD: Cardiovascular diseases; GalNAc3: Triantennary N-acetyl galactosamine; HTG: Hypertriglyceridemia; FH: Familial hypercholesterolemia; HLP: Hyperlipoproteinemia; ANGPTL3: Angiopoietin-like proteins 3; VLDL: Very low density lipoprotein; LPL: Lipoprotein lipase.
  • Diabetes
The commonly used treatment for diabetes is insulin injections at least three times per day, and the dosage is adapted to the patient [116]. In addition, many vaccines showed significant protection against type 2 diabetes mellitus (T2DM) (Table 2).
Islet amyloid polypeptide (IAPP) is a normally secreted product by β-cells in the pancreas. However, their accumulation in the extracellular space as insoluble aggregates mediates β-cell toxicity and inflammation. Moreover, interleukin 1β (IL-1β) is a key proinflammatory cytokine implicated in pancreatic islets inflammation and insulin resistance in T2DM.
  • Hypertension
Angiotensinogen (AGT) represents an important target for gene therapy. Indeed, recent studies based on siRNA targeting hepatic AGT, through SC or IV administration, resulted in stable and durable antihypertensive and cardioprotective effect in spontaneously hypertensive rats [144].
On the other hand, three targets in the renin-angiotensin system that have been extensively studied in the preclinical and clinical studies for the treatment of hypertension with vaccines include: renin, angiotensin I, and angiotensin II and its receptors. Renin, as an initiator of the renin-angiotensin system, was the first reported target for vaccination. Furthermore, angiotensin I converts into angiotensin II, which causes dramatic changes in blood pressure. Not only does angiotensin II exert a direct effect on blood pressure, but it also induces the release of the potent vasoconstrictor aldosterone. Direct angiotensin II effect on blood pressure is mediated through stimulating angiotensin II type I receptors that enhance sodium retention and raise blood pressure [145,146]. Thus, blocking the effect of the renin-angiotensin system would have a beneficial role in the management of hypertension.
  • Myocardial infarction
The high mortality rate associated with MI requires urgent intervention and repair of the affected zones. Advances in this area mainly depend on restoring the blood supply. Angiogenesis is one of the most exciting therapeutic strategies in the management of CVD. Nanotechnology plays an important role in initiating and promoting angiogenesis (or lymphangiogenesis, thanks to VEGF receptor 3), as described in Table 2 [130,131].
  • Hypercholesterolemia and hyperlipidemia
The use of gene-therapy has also been investigated for the treatment of hypercholesterolemia and hyperlipidemia. Indeed, mipomersen (Kynamro; Kastle Therapeutics) is a second-generation antisense oligonucleotides (ASO) that targets apolipoprotein-B 100 (ApoB-100) and was approved for the treatment of Homozygous familial hypercholesterolemia (HoFH) [147]. It reduces lipoproteins containing the ApoB-100 (e.g., lipoprotein(a) and LDL) through targeting ApoB-100 mRNA in the liver [148]. HoFH is an inherited disorder characterized by low density lipoprotein-cholesterol (LDL-C) uptake and caused by mutations in the ldl-receptor (ldlr), apolipoprotein-b (apob), and proprotein convertase subtilisin/kexin type 9 (pcsk9). Following SC administration, mipomersen is rapidly absorbed and distributed, compared to a 2 h IV infusion. One of the major accumulation sites of the drug in animals is mesenteric lymph nodes, assuming a considerable absorption by the lymphatics [149]. Kynamro has been withdrawn from the market in 2019 due to safety issues represented in liver toxicity, injection-site reaction, and flu-like symptoms [32,150].
Likewise and for safety issues, represented in thrombocytopenia and bleeding risks, volanesorsen (Waylivra®; Akcea Therapeutics, Cambridge, MA, USA) has been denied FDA approval for the treatment of familial chylomicronemia syndrome (FCS), a rare genetic disorder caused mainly by mutations in lpl gene or encoding genes required for LPL function [151]. However, in 2019, the European Medicines Agency (EMA) granted it a conditional marketing authorization for genetically confirmed FCS cases with a high risk of pancreatitis and patients with inadequate response to TG-lowering therapy and low-fat diet [152]. FCS is characterized by accumulation of TG-rich lipoproteins in the blood. Apolipoprotein-C3 (ApoC3) plays a regulatory role in the determination of plasma TG level through inhibiting lipoprotein clearance via both LPL-dependent/independent pathways [153]. Thus, inhibiting ApoC3 activity could have a favorable impact on the lipid profile in FCS. Volanesorsen is an ASO that targets and inhibits ApoC3 production in the liver and enhances TG metabolism via the LPL-independent pathway. In rats, one of the main accumulation sites of volanesorsen following SC administration are mesenteric lymph nodes, indicating a reasonable uptake by the lymphatics [154].
Furthermore, inclisiran (Leqvio®; Novartis, Schaftenau, Austria), a short-chain, double-stranded siRNA, conjugated to triantennary N-acetylgalactosamine carbohydrates to target the hepatocytes, has been approved in the European Union for the treatment of primary hypercholesterolemia or mixed dyslipidemia in adults, as an adjunct to low-fat diet [155,156]. Inclisiran is injected SC twice a year to produce a long-term anti-hypercholesterolemic effect through targeting PCSK9 [155]. Following SC injection of 14C labeled inclisiran in monkeys, lymph nodes showed the third-highest exposure organ, after liver and kidney [157].
On the other hand, several studies reported beneficial effects of active vaccination on hypercholesterolemia. For instance, vaccines targeting angiopoietin-like proteins 3 (ANGPTL3) in mice has reduced the steady-state plasma TGs and promoted LPL activity (Table 2). ANGPTL3 has a key role in TG metabolism and plasma levels through inhibiting LPL activity. People with loss-of-function mutations in ANGPTL3-encoding genes exhibit reduced TG level and a low risk of CVD. Thus, vaccination against ANGPTL3 could serve as a promising strategy for protection against hypertriglyceridemia and relative CVD [158].

3.3. Intradermal Injection

Lymphatic capillaries are present in the dermis and, thus, preferentially take up the injected molecules. Unlike the blood capillaries, initial lymphatics lack the basement membrane underlying the endothelial layer. The distal part of initial LV is exclusively composed of LECs with button-like junctions [159], leading to capillaries that have inter-endothelial gaps with size ranges from a few nanometers to several microns [4,160]. Small particles (<10 nm) [4] and medium-sized macromolecules (up to 16 kDa) [161] are mainly transported away from the interstitial spaces by blood capillaries, thanks to mass transport [162,163]. In contrast, lymphatic access of large particles with diameters exceeding 100 nm is hindered by their restricted movement through the interstitium, via diffusion and convection [4]. In between, particles with a size of 10–100 nm [4] and macromolecules with a size of 20–30 kDa [161] show preferential uptake into the highly permeable lymphatic capillaries either passively (paracellular) or actively (transcellular) through the lymphatic endothelial cells [164]. Indeed, it has been shown that the optimal diameter to target the lymphatic vessels in the dermis is 5 to 50 nm in mice [165]. Macromolecules can enter into lymphatics through transcytosis via receptors localized on the surface of LECs, the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), and scavenger receptor class B member 1 (SRB1) or p32 [28].
Intradermal therapy, also known as mesotherapy, is used in dermatology and consists of a series of micro-injections of drugs that will slowly diffuse into the peripheral tissues. For cardiovascular diseases or to target the immune system, ID injection would be a privileged pathway to target the lymphatic system. In fact, the skin has a higher lymph flow rate, higher interstitial pressure, and an abundance of APCs (e.g., macrophages, dendritic cells (DCs), and T cells) compared to the other interstitial spaces [166,167]. Then, drugs will be found directly in the lymph and, ultimately, reach the lymph nodes [168]. The antigens present in the lymph will then activate the immune response of T and B lymphocytes [169]. This method is used to treat, for example, alopecia, cystic acne, and psoriasis [170], or for certain vaccines, such as Bacille Calmette-Guérin (BCG) for tuberculosis disease [171].
  • Diabetes
In type 1 diabetes mellitus (T1DM), the main goal of vaccination is to induce diabetes-specific immune tolerance via vaccination against autoantigens that induce β-cells destruction, through antigen-specific and non-antigen-specific pathways, to restore β cell tolerance and suppress disease progression at early stages [172]. Non-antigen-specific pathway include using antibodies to suppress T cell immune response. However, the limited specificity of this approach can result in serious systemic side effects.
Antigen-specific modulation has proved efficacy in T1DM murine models and, recently, in clinical studies. Vaccination leads to the establishment of a tolerance of effector T cells (Teff) to diabetes-specific autoantigens and induce/expand immunoregulatory T cells (Treg). Teff has an essential role in the development of β cells- specific immune response, while Treg help maintain peripheral tolerance [173,174]. Tolerizing Teff is usually attained via delivery of a high amount of autoantigen to induce exhaustion, clonal anergy or clonal deletion [175]. Proinsulin, among others, is a major B cell autoantigen peptide targeted by CD4+ and CD8+ Teff at the early stages of the disease. Thus, proinsulin vaccines seem a good option in recently diagnosed cases [176].
Table 3 presents several vaccines used for diabetes through intradermal injection [177,178,179].
Table 3. Intradermal administration as treatment for diabetes.
Table 3. Intradermal administration as treatment for diabetes.
ConditionIntervention and IdentifierTargetDose and Outcome
DiabetesProinsulin peptide vaccine C19-A3CD4 T cells Three equal doses—10–100 µg
Vaccine was well tolerated [177]
CD4 T cells Three doses—10 ug
In vitro and ex vivo studies of in human skin reported rapid diffusion of the injected particles through the skin layers and preferential uptake by Langerhans cells in the epidermis, which have a primary role in the tolerance mechanism [178]
DiabetesPIpepTolDC vaccine (NCT04590872)Tolerogenic DC VaccineOne dose and another after 28 days
No results yet, but, it is believed to be able to produce proinsulin-specific Treg [179]
DC: Dendritic cells; Treg: immunoregulatory T cells.

3.4. Intramuscular Injection

Intramuscular injections are used to target the deeper muscle tissue that is highly irrigated. This route of injection allows a rapid absorption and prolonged action. The medication would enter the bloodstream directly and, thus, allow the “bypass” of the hepatic metabolism. It is mainly used for the administration of vaccines [180] (hepatitis, flu virus, tetanus) or with specific pathologies, such as rheumatoid arthritis and multiple sclerosis. It is frequently performed in the upper arm [181] but also in the hip or thigh [182]. It is possible to administer up to 5 mL via this route, based on the site of injection [183]. As lymphatic vessels are present in the skeletal muscle and the connective tissue [184], this leads to the assumption the lymphatic system might be involved in the drug absorption following intramuscular administration. As presented in Table 4, several conditions are treated with this type of injection [185,186,187,188].
Table 4. CVD therapies using intramuscular administration.
Table 4. CVD therapies using intramuscular administration.
ConditionIntervention and IdentifierTargetDose and Outcome
DiabetesPreproinsulin-encoding plasmid DNAPancreatic islets40% higher survival rate as compared to the control group [185]
HTNCoVaccine HT
Against angiotensin IIThree doses
Terminated in 2016 due to dose-limiting adverse effects
Against angiotensin IIHigh or low dose (0.2 mg plasmid DNA and 0.5 or 0.25 mg Ang II-KLH conjugate) Ongoing
Inactivated influenza vaccine Less frequent hospitalization from ACS, hospitalization from HF and stroke [186]
MIInfluenza vaccine Risk of cardiovascular-related death was significantly lower [187]
Pneumococcal vaccines Reduced incidence of cardiovascular events and mortality
Reduced risk of MI in the elderly [188]
Influenza vaccine
The primary endpoints: death, new MI and stent thrombosis
Secondary endpoints: patients with hospitalization for HF
HTN: Hypertension; AngII-KLH: Angiotensin II—keyhole-limpet hemocyanin; ACS: Acute coronary syndrome; CVD: cardiovascular disease; HF: Heart failure; MI: Myocardial infarction.
  • Diabetes
In a study carried out by Abai et al., they found that streptozotocin (STZ)-induced diabetic mice injected IM with preproinsulin-encoding plasmid DNA showed a 40% higher survival rate as compared to the control group. Muscles of the treated group were able to produce insulin, to which the increased survival was attributed [185].
In addition, patients with T2DM could benefit from vaccination against obesity, being a leading risk factor for T2DM. The main targets for obesity vaccines include GIP, adipose tissue antigen, somatostatin, and ghrelin [189]. Other vaccines that showed considerable benefits and are recommended for patients with DM are influenza, pneumococcal, hepatitis A and B, varicella vaccines, and others [190].
  • Heart failure
The last few decades have witnessed several studies that target the major pathogenic pathways implicated in HF. Among these targets: cardiac muscle contractility, angiogenesis, cytoprotection, and stem cell homing [191]. For instance, the β-adrenergic system plays a major role in the regulation of cardiac contractility. Up-regulation of the myocardial G-protein-coupled receptor kinase 2 (GRK2) protein in failing hearts was found to desensitize and down-regulate β-adrenergic receptors by up to 50% [192], which lead to the hypothesis that cardiac function could be improved with the GRK2-inhibitor peptide beta adrenergic receptor kinase carboxyl-terminus (βARKct). Several studies in mice, rats, rabbits, and pigs showed that overexpressing βARKct helped to prevent the development and progression of HF, restored β-adrenergic receptor sensitization and prolonged the survival [193,194,195,196,197], and improved and sustained contractile function [198].
Furthermore, disrupted calcium (Ca2+) homeostasis in the cardiomyocytes was found to be a consistent feature in HF, which is linked to down-regulation in the expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) protein pump and reduced cardiac contractility. The prominent success of SERCA2a gene transfer in enhancing cardiac contractility has paved the way to launch the clinical trial CUPID “Ca2+ Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease” [199,200]. CUPID was the first gene therapy clinical trial for HF and used AAV1 vectors for SERCA2a gene delivery [201].
  • Hypercholesterolemia and hyperlipidemia
An AAV1-based therapy encoding LPL gene has been commercialized and approved since 2012 for the treatment of lipoprotein lipase deficiency (LPLD), alipogene tiparvovec (Glybera; uniQure Biopharma) [202]. LPLD, otherwise identified as chylomicronaemia syndrome, is a rare, hereditary autosomal disease resulting from loss-of-function mutations in LPL gene, which has a central role in the breakdown and clearance of triglyceride (TG)-rich lipoproteins (chylomicron and very low-density lipoprotein (VLDL)). As a result, patients with LPLD are prone to severe, recurrent attacks of pancreatitis, and they are at high risk of developing diabetes mellitus [203]. Although the highest level of vector DNA was observed at the injection site following IM injection of the drug in mice, a considerable amount was detected in the draining lymph nodes indicating the involvement of the lymphatic system in drug uptake [204]. Clinical trials reported immediate LPL expression following AAV1 injection and an associated long-term enhancement in chylomicron clearance. In addition, a retrospective study has documented a potential benefit of Glybera in reducing the frequency of pancreatitis episodes [205]. However, in 2017, the company declined Glybera’s marketing authorization renewal due to the unprofitability driven by the disease rarity [206].

3.5. Intramyocardial Injection

Direct intramyocardial injection is the most effective and commonly used way for gene delivery to the heart owing to its ability to achieve a high concentration of the injected compound at the injection site [207]. It is a preferential route to directly target lymphatic vessels due to their high density in the myocardium [159,208]. Various CVD and their treatments via intramyocardial injection are presented in Table 5 [201,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224].
  • Myocardial infarction
The use of nanotechnology as treatment demonstrated significant protection against post-reperfusion myocardial injury in ischemic hearts via reducing the elevated level of reactive oxygen species (ROS) and the intracellular Ca2+ (Table 5). These nanoparticles protected the cardiomyocytes in isolated hearts from damage and oxidative stress, an approach that could be very useful upon in vivo application [223]. Although two nanoparticle systems have received FDA approval for post-MI imaging, none was approved for therapeutic purposes [225].
On the other hand, modulating one or more of the following growth factors, vascular endothelial growth factor (VEGF) [226], fibroblast growth factor (FGF) [227], hepatocyte growth factor (HGF) [228], and platelet-derived growth factor (PDGF) [229] could have a repairing effect on the affected zones within the myocardium (Table 5).
Table 5. Use of intramyocardial injections in several therapies targeting CVD.
Table 5. Use of intramyocardial injections in several therapies targeting CVD.
ConditionIntervention and IdentifierTherapyTargetStage and StatusDose and Outcome
Ad5AC6Phase I/II
Single administration of escalating doses (3.2 × 109 vp to 1012 vp)
Phase II: Reduced HF admission rate. Enhanced left ventricular function beyond the optimal HF therapy following a single administration [209]
Ad5AC6Phase III
Phase III: withdrawn for re-evaluation
AAV1SERCA2aPhase I/II (Completed)Single administration of escalating doses (1.4 × 1011–1 × 1013 DRP of AAV1/SERCA2a)
Phase I/II (CUPID): high-dose treatment resulted in increased time and reduced frequency of cardiovascular events within a year and reduced cardiovascular hospitalizations [210]
Single infusion of 1 × 1013 DRP of AAV1/SERCA2a
Phase IIb (CUPID-2b): no improvement was observed at the tested dose in patients with HF during the follow-up period [201]
1 × 1013 DRP of AAV1/SERCA2a as a single intracoronary infusion
Phase II: no improvement observed in the ventricular remodeling.The study terminated driven by the CUPID-2 trial neutral outcome [211]
(Active, not recruiting)
Single administration of 3 × 1013 vg
CUPID-3: aims to investigate the safety and efficacy of SRD-001 in anti-AAV1 neutralizing antibody-negative subjects with HFrEF
Non-viral, triple effector plasmidSDF-1α,
Phase I
Single 80 mg dose, given in 40 mL or 80 mL at a rate of 20 mL/min
Phase I: an improvement in the quality of life in 50% of patients was reported [212]
Plasmid DNASDF-1Phase I
Single escalating doses, injected at multiple sites
Preclinical studies: enhanced vasculogenesis and improved cardiac function reported with all doses [213]
Plasmid DNASDF-1Phase II
Single injection of escalating doses (15 and 30 mg)
Phase II (STOP-HF): JVS-100 showed potential to improve cardiac function through reducing left ventricular remodeling and improving ejection fraction [214]
Plasmid DNASDF-1Phase I/II
Single injection of escalating doses (30 and 45 mg)
Phase I (RETRO-HF): JVS-100 showed promising signs of clinical efficacy [215]
mRNAVEGF-A165Phase IIa
(Active, not recruiting)
Single injection of escalating doses (3 mg and 30 mg)
Preclinical studies: promoted angiogenesis, improved cardiac function and enhanced survival were reported [216]
Phase I: ID injection of AZD8601 was well tolerated and enhanced the basal skin blood flow [217]
AAVI-1cPhase I
Single escalating doses (3 × 1013 vg–3 × 1014 vg) of NAN-101
Preclinical studies: enhancement in left ventricular ejection fraction and improved cardiac performance [218]
DNA plasmidHGF-X7Phase II
Single escalating (0.5–3 mg) doses, administered into multiple sites
Phase I: improved myocardial function and wall thickness
Angina pectoris
AdVEGF-D (NCT01002430)AVVEGF-D Phase I/IIa
Single escalating (1 × 109–1 × 1011 Vpu) doses, injected into multiple sites in the endocardium
Phase 1/IIa: AdVEGF-D improved myocardial perfusion reserve in the injected region [220]
AVHGFPhase I/II (Unknown)Single dose
Preclinical studies: Ad-HGF preserved cardiac function, reduced infarct size, and improved post-MI cardiac remodeling [221]; fractional repeated dosing significantly improved cardiac function compared with single injection [222]
MIL-type Ca2+ channels’ AID peptide and antioxidant molecule (curcumin) in poly nanoparticles Reduced the elevated level of ROS and the intracellular Ca2+ [223]
LPLDAlipogene tiparvovec
AAVLPLApproved 1 × 1012 GC/kg
Phase II/III: reduction in mean total plasma and chylomicron TG level [224]
HF: Heart failure; hAC6: Human adenylyl cyclase type 6; vp: Virus particles; AAV: Adeno-associated virus; SERCA2a: Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase; DRP: DNase-resistant particles; HFrEF: HF with reduced ejection fraction; CVD: Cardiovascular diseases; SDF-1a: stromal cell-derived factor 1; VEGF: Vascular endothelial growth factor; I-1c: Constitutively active inhibitor-1; vg: Viral genomes; AMI: Acute myocardial infarction; IDH: Ischemic heart disease; HGF-X7: Hepatocyte growth factor-X7; AV: Adenovirus; Vpu: Viral protein U; HGF: Hepatocyte growth factor; AID: alpha-interacting domain; ROS: reactive oxygen species; LPL: Lipoprotein lipase; TG: Triglycerides; GC: Genome copies.

3.6. Intravenous Injection

Intravenous injections are often used for rehydration, nutrition, and therapeutic treatments (for example, blood transfusion or chemotherapy), as well as to avoid hepatic metabolism [230]. The interest of this route of administration is the continuous treatment, or regular frequencies, by the installation of a catheter [231]. However, the lymphatic system is only scarcely involved following IV injections [232,233,234]. Table 6 presents several conditions treated with this type of injection [74,83,85,235,236,237,238,239,240,241,242,243,244,245,246,247,248].
Table 6. Intravenous administration of medication as treatment for CVD.
Table 6. Intravenous administration of medication as treatment for CVD.
ConditionIntervention and IdentifierTherapyTargetStage and StatusDose and Outcome
HTNNO-releasing nanoparticles Reduction in the mean arterial blood pressure [235]
Digoxin Dose: 0.25 mg once daily [83]
ß-blocker Beta-adrenergic receptors Acebutol: 200 mg twice daily [74]
HFMesoporous silicon vector (Nanoconstruct) Able to internalize, accumulate, and traffic within the cardiomyocytes [236]
HFCombination of biocompatible magnetic nanoparticles and low-frequency magnetic stimulation Cardio-myocytes Managed the drug release by controlling the applied frequencies [237]
HFS100A1-loaded nanoparticles, decorated with N-acetylglucosamine Regulated Ca2+ release and restored contractile function in the isolated failing cardiomyocytes [238]
HFBiodegradable nanoparticles conjugated with myocyte-targeting peptide and PDT-enabling photosensitizerPDTCardio-myocytes Induced cell-specific death upon application of laser light, leaving adjacent and surrounding cells completely intact [239]
60 IU/kg for initial bolus
12 IU/kg/h for maintenance [240]
MIAspirin Platelets 325 mg, then 81 mg per day [85]
MIHuman recombinant VEGF-165 Significant improvement in the infarcted zone perfusion and cardiac function for up to six weeks post-MI [241].
MINanoparticles containing siRNA Anti-inflammatory effect in the infarcted heart and reduction of the post-MI heart failure [242]
MIMagnetic nanoparticles-loaded cells Robust improvement in the left ventricular and cardiac function [243]
MIInsulin-like growth factor electrostatically-complexed with PLGA nanoparticles Higher incidence in preventing cardiomyocytes’ apoptosis, reducing infarct size, and enhancing left ventricular function [244]
MIPitavastatin in PLGA nanoparticles Cardioprotective effect against ischemia-reperfusion injury [245]
AAVhLDLRPhase I/II (Completed)Single dose
Preclinical studies: reduction in total cholesterol [246,247]
Elevated LDL-CALN-PCS02
Single escalating (15 and 400 μg/kg) doses
Phase I: reduction in the level of circulating PCSK9 protein and LDL-C [248]
HTN: Hypertension; NO: nitric oxide; HF: Heart failure; MI: Myocardial infarction; PDT: Photodynamic therapy; VEGF: Vascular endothelial growth factor; PLGA: Poly lactic-co-glycolic acid; AAV: Adeno-associated virus; HoFH: Homozygous familial hypercholesterolemia; hLDLR: Human low density lipoprotein receptor; TBG: Thyroxine-binding globulin; LDL-C: low density lipoprotein cholesterol.
  • Diabetes
The first successful in vivo gene therapy study was completed in the early 1980s, when Nicolau et al. administered rats IV with liposome encapsulating preproinsulin 1-encoding plasmid DNA and demonstrated a significant hypoglycemic effect as well as elevated insulin level in the blood [249]. Ever since, several studies have been published in an attempt to control diabetes through targeting different tissues, such as pancreas [250], muscle [251,252], liver [253,254,255], and K-enteroendocrine cells (K cells) [256]. For effective hypoglycemic therapy, these tissues should be able to produce or secrete insulin in a glucose-dependent manner [257,258].
As for vaccination, several preclinical [259,260] and clinical [261,262,263] studies have demonstrated the efficacy of IV administration of anti-CD3 monoclonal antibodies in restoring β cell tolerance and reversing diabetes in recent-onset T1DM, via targeting the autoreactive T cells.
  • Hypertension
Antisense oligonucleotides-mediated inhibition of β1-receptors expression in hypertensive rats has resulted in a durable antihypertensive effect for more than two weeks after a single IV dose [264]. Moreover, Huang et al. showed that targeting renal G protein-coupled receptor kinase type 4 (GRK4) with siRNA helped to reduce the blood pressure significantly in spontaneously hypertensive rats [265].
To the best of our knowledge, none of the gene therapy studies targeting hypertension have reached the clinical trials so far [266].
From another perspective, nanoparticles can be used for controlling blood pressure by the generation/release of the vasodilator molecule nitric oxide (NO). Indeed, Cabrales et al. reported a reduction in the mean arterial blood pressure by using NO-releasing nanoparticles. Upon administration, hydration of these nanoparticles resulted in the release of NO at a therapeutic level into the circulation. NO acts by inducing vasodilatation and promoting microvascular perfusion [235]. In this study, NO-releasing nanoparticles were delivered via IV infusion; however, they could be injected IP or IM [235].
  • Heart failure
So far, myocardial, intracoronary, and pericardial injections are the most commonly used to transduce the myocardium. IV injection offers a less invasive way; however, the low transduction efficiency limits its application [191]. A nanoconstruct called mesoporous silicon vector was able to internalize, accumulate, and traffic within the cardiomyocytes following IV administration in HF murine model, without significant toxicity. This nanoconstruct could serve as a platform for therapeutic and diagnostic purposes in HF [236]. Indeed, as described in Table 6, the use of nanotechnology in this pathology seems promising.
  • Myocardial infarction
Management of MI at the early stages is essential to avoid the development of irreversible HF, due to the poor cardiomyocytes turnover (Table 6) [267]. IV-injected human recombinant VEGF-165 (an important angiogenesis factor) has resulted in a significant improvement in the infarcted zone perfusion and cardiac function for up to six weeks post-MI [241]. Furthermore, post-MI extended inflammation is another potential target, being a risk factor for post-MI heart failure. Indeed, a study published in 2013 showed that IV administration of nanoparticles containing siRNA in atherosclerotic mice, with coronary ligation-induced MI, produced a significant anti-inflammatory effect in the infarcted heart and reduction of the post-MI heart failure. This effect reflected an improved inflammatory resolution and reduced monocyte numbers in the infarcted area [242].
On the other hand, liposomes, the most primitive form in nanomedicine, could have a great potential for targeting and accumulation in ischemic tissues, following the less invasive IV administration. This could be achieved through attaching targeting moieties and used for diagnosis or therapy [268]. These targeting nanoparticles were exploited to deliver different therapeutic products, e.g., proangiogenic factors [269], genetic materials [270], and cytokines [271]. Moreover, nanoparticles could be used in cell replacement therapy post-MI to restore cardiac function (Table 6).

3.7. Intraperitoneal Injection

Intraperitoneal administration, in which therapeutic compounds are injected directly into the peritoneal cavity, is another attractive approach of the parenteral extravascular strategies. It is used specifically for the local treatment of peritoneal cavity disorders, e.g., peritoneal malignancies and dialysis. The peritoneal cavity contains the abdominal organs and the peritoneal fluid, normally composed of water, proteins, electrolytes, immune cells, and other interstitial fluid substances [272]. The high absorption rate associated to IP administration is promoted by the vast blood supply to the peritoneal cavity, along with its large surface area, which is further increased by the microvilli covering the mesothelial layer [273]. Injected compounds can enter the circulatory system after IP injection via both blood and lymphatic capillaries draining the peritoneal submesothelial layer [273,274,275]. Besides, the peritoneal absorption of molecules is greatly affected by their physicochemical characteristics. This route of administration also allows for the injection of large volumes (up to 10 mL) [273]. Extensive experimental studies carried out on animals have revealed that the peritoneal cavity has favorable absorption of lipophilic and unionized compounds [276]. This type of injection is most exploited for preclinical studies, since it is the simplest to perform, especially in small animals and with little impact on the animals’ stress [273,277]. IP use in humans is limited, despite showing many benefits in previous studies and even being recommended, for certain types of chemotherapy, by the National Cancer Institute [278,279,280].
  • Diabetes
Cheung et al. were able to produce long-term protection against diabetes by using GIP promoters in transgenic mice treated with STZ to damage their pancreatic β cells [256].
  • Myocardial infarction
IP injection of methotrexate-loaded lipid core nanoparticle in MI rat model has mediated angiogenesis through enhancing the expression of myocardial VEGF. Importantly, it reduced myocytes’ hypertrophy, necrosis, and infarct size, effects that were not observed with the free methotrexate [281].

4. Conclusions

Treatments for cardiovascular diseases are numerous, and the routes of administration are diverse. However, side effects or therapeutic failures are also present. Therefore, improvement in therapeutic delivery is essential. This review highlights new administration routes and improved formulation of molecules that ameliorate their efficacy via lymphatic transport. Thus, ensuring an optimal lymphatic transport throughout the body would not only directly reduce CVD [16,25,164,217,220,282,283] but would also allow a proper drug delivery to the various targeted organs. Taken together, the combination of the use of nanotechnology, vaccination, and gene therapy, along with the appropriate administration route to target the lymphatic system, thus, seems to be a promising target for the prevention and treatment of cardiovascular diseases.

Author Contributions

D.B. and C.M.: manuscript conceptualization and revision; N.T., F.M. and N.A.: Literature search and manuscript drafting. All authors have read and agreed to the published version of the manuscript.


D.B. is supported by the Canadian Generic Pharmaceutical Association and Biosimilars Canada, the Fonds de Recherche du Québec Santé et Nature et Technologies, and the Natural Sciences and Engineering Research Council of Canada. CM is supported by the Natural Sciences and Engineering Research Council of Canada, the Canadian Institute of Health Research, the Heart and Stroke Foundation of Canada, and a Canada Research Chair in lymphatics and cardiovascular medicine.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Kaptoge, S.; Pennells, L.; De Bacquer, D.; Cooney, M.T.; Kavousi, M.; Stevens, G.; Riley, L.M.; Savin, S.; Khan, T.; Altay, S.; et al. World Health Organization cardiovascular disease risk charts: Revised models to estimate risk in 21 global regions. Lancet Glob. Health 2019, 7, e1332–e1345. [Google Scholar] [CrossRef] [Green Version]
  2. Virani, S.S.; Alonso, A.; Aparicio, H.J.; Benjamin, E.J.; Bittencourt, M.S.; Callaway, C.W.; Carson, A.P.; Chamberlain, A.M.; Cheng, S.; Delling, F.N. Heart disease and stroke statistics—2021 update: A report from the American Heart Association. Circulation 2021, 143, e254–e743. [Google Scholar] [CrossRef]
  3. Tiwari, G.; Tiwari, R.; Sriwastawa, B.; Bhati, L.; Pandey, S.; Pandey, P.; Bannerjee, S.K. Drug delivery systems: An updated review. Int. J. Pharm. Investig. 2012, 2, 2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Ryan, G.M.; Kaminskas, L.M.; Porter, C.J. Nano-chemotherapeutics: Maximising lymphatic drug exposure to improve the treatment of lymph-metastatic cancers. J. Control. Release 2014, 193, 241–256. [Google Scholar] [CrossRef]
  5. Maisel, K.; Sasso, M.S.; Potin, L.; Swartz, M.A. Exploiting lymphatic vessels for immunomodulation: Rationale, opportunities, and challenges. Adv. Drug Deliv. Rev. 2017, 114, 43–59. [Google Scholar] [CrossRef] [PubMed]
  6. Pal, I.; Ramsey, J.D. The role of the lymphatic system in vaccine trafficking and immune response. Adv. Drug Deliv. Rev. 2011, 63, 909–922. [Google Scholar] [CrossRef] [PubMed]
  7. Sleeman, J.P. The relationship between tumors and the lymphatics: What more is there to know? Lymphology 2006, 39, 62–68. [Google Scholar]
  8. Porter, C.J.; Charman, S.A. Lymphatic transport of proteins after subcutaneous administration. J. Pharm. Sci. 2000, 89, 297–310. [Google Scholar] [CrossRef]
  9. Zhang, X.-Y.; Lu, W.-Y. Recent advances in lymphatic targeted drug delivery system for tumor metastasis. Cancer Biol. Med. 2014, 11, 247–254. [Google Scholar] [CrossRef]
  10. Yáñez, J.A.; Wang, S.W.; Knemeyer, I.W.; Wirth, M.A.; Alton, K.B. Intestinal lymphatic transport for drug delivery. Adv. Drug Deliv. Rev. 2011, 63, 923–942. [Google Scholar] [CrossRef] [PubMed]
  11. Asellius, G. De Lactibus Sive Lacteis Venis; JB Bidellium: Milan, Italy, 1627. [Google Scholar]
  12. Cueni, L.N.; Detmar, M. The lymphatic system in health and disease. Lymphat. Res. Biol. 2008, 6, 109–122. [Google Scholar] [CrossRef]
  13. Milasan, A.; Farhat, M.; Martel, C. Extracellular Vesicles as Potential Prognostic Markers of Lymphatic Dysfunction. Front. Physiol. 2020, 11, 476. [Google Scholar] [CrossRef]
  14. Lemole, G.M. The role of lymphstasis in atherogenesis. Ann. Thorac. Surg. 1981, 31, 290–293. [Google Scholar] [CrossRef]
  15. Martel, C.; Li, W.; Fulp, B.; Platt, A.M.; Gautier, E.L.; Westerterp, M.; Bittman, R.; Tall, A.R.; Chen, S.-H.; Thomas, M.J. Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. J. Clin. Investig. 2013, 123, 1571–1579. [Google Scholar] [CrossRef] [Green Version]
  16. Milasan, A.; Smaani, A.; Martel, C. Early rescue of lymphatic function limits atherosclerosis progression in Ldlr−/− mice. Atherosclerosis 2019, 283, 106–119. [Google Scholar] [CrossRef] [Green Version]
  17. Yeo, K.P.; Lim, H.Y.; Thiam, C.H.; Azhar, S.H.; Tan, C.; Tang, Y.; See, W.Q.; Koh, X.H.; Zhao, M.H.; Phua, M.L.; et al. Efficient aortic lymphatic drainage is necessary for atherosclerosis regression induced by ezetimibe. Sci. Adv. 2020, 6, eabc2697. [Google Scholar] [CrossRef] [PubMed]
  18. Singla, B.; Lin, H.P.; Chen, A.; Ahn, W.; Ghoshal, P.; Cherian-Shaw, M.; White, J.; Stansfield, B.K.; Csányi, G. Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis. Cardiovasc. Res. 2021, 117, 1489–1509. [Google Scholar] [CrossRef] [PubMed]
  19. Milasan, A.; Jean, G.; Dallaire, F.; Tardif, J.C.; Merhi, Y.; Sorci-Thomas, M.; Martel, C. Apolipoprotein A-I Modulates Atherosclerosis Through Lymphatic Vessel-Dependent Mechanisms in Mice. J. Am. Heart Assoc. 2017, 6, e006892. [Google Scholar] [CrossRef] [PubMed]
  20. Milasan, A.; Ledoux, J.; Martel, C. Lymphatic network in atherosclerosis: The underestimated path. Future Sci. OA 2015, 1, fso 61. [Google Scholar] [CrossRef] [Green Version]
  21. Milasan, A.; Tessandier, N.; Tan, S.; Brisson, A.; Boilard, E.; Martel, C. Extracellular vesicles are present in mouse lymph and their level differs in atherosclerosis. J. Extracell. Vesicles 2016, 5, 31427. [Google Scholar] [CrossRef] [Green Version]
  22. Milasan, A.; Dallaire, F.; Mayer, G.; Martel, C. Effects of LDL Receptor Modulation on Lymphatic Function. Sci. Rep. 2016, 6, 27862. [Google Scholar] [CrossRef]
  23. Libby, P.; Ridker, P.M.; Hansson, G.K. Progress and challenges in translating the biology of atherosclerosis. Nature 2011, 473, 317–325. [Google Scholar] [CrossRef] [PubMed]
  24. Henri, O.; Pouehe, C.; Houssari, M.; Galas, L.; Nicol, L.; Edwards-Lévy, F.; Henry, J.-P.; Dumesnil, A.; Boukhalfa, I.; Banquet, S.; et al. Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction. Circulation 2016, 133, 1484–1497. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Klotz, L.; Norman, S.; Vieira, J.M.; Masters, M.; Rohling, M.; Dubé, K.N.; Bollini, S.; Matsuzaki, F.; Carr, C.A.; Riley, P.R. Cardiac lymphatics are heterogeneous in origin and respond to injury. Nature 2015, 522, 62–67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Vieira, J.M.; Norman, S.; Del Campo, C.V.; Cahill, T.J.; Barnette, D.N.; Gunadasa-Rohling, M.; Johnson, L.A.; Greaves, D.R.; Carr, C.A.; Jackson, D.G. The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. J. Clin. Investig. 2018, 128, 3402–3412. [Google Scholar] [CrossRef] [PubMed]
  27. Vuorio, T.; Ylä-Herttuala, E.; Laakkonen, J.P.; Laidinen, S.; Liimatainen, T.; Ylä-Herttuala, S. Downregulation of VEGFR3 signaling alters cardiac lymphatic vessel organization and leads to a higher mortality after acute myocardial infarction. Sci. Rep. 2018, 8, 1–13. [Google Scholar] [CrossRef]
  28. Trevaskis, N.L.; Kaminskas, L.M.; Porter, C.J.H. From sewer to saviour—targeting the lymphatic system to promote drug exposure and activity. Nat. Rev. Drug Discov. 2015, 14, 781–803. [Google Scholar] [CrossRef] [PubMed]
  29. Li, T.; Liang, W.; Xiao, X.; Qian, Y.J. Nanotechnology, an alternative with promising prospects and advantages for the treatment of cardiovascular diseases. Int. J. Nanomed. 2018, 13, 7349. [Google Scholar] [CrossRef] [Green Version]
  30. Wong, M.S.; Hawthorne, W.J.; Manolios, N. Gene therapy in diabetes. Self Nonself 2010, 1, 165–175. [Google Scholar] [CrossRef]
  31. Phillips, M.I. Gene therapy for hypertension: Sense and antisense strategies. Expert Opin. Biol. Ther. 2001, 1, 655–662. [Google Scholar] [CrossRef]
  32. Tromp, T.R.; Stroes, E.S.; Hovingh, G.K. Gene-based therapy in lipid management: The winding road from promise to practice. Expert Opin. Investig. Drugs 2020, 29, 483–493. [Google Scholar] [CrossRef] [PubMed]
  33. Kieserman, J.M.; Myers, V.D.; Dubey, P.; Cheung, J.Y.; Feldman, A.M. Current landscape of heart failure gene therapy. J. Am. Heart Assoc. 2019, 8, e012239. [Google Scholar] [CrossRef] [PubMed]
  34. Shimamura, M.; Nakagami, H.; Taniyama, Y.; Morishita, R. Gene therapy for peripheral arterial disease. Expert Opin. Biol. Ther. 2014, 14, 1175–1184. [Google Scholar] [CrossRef] [PubMed]
  35. Zhao, R.; Lu, Z.; Yang, J.; Zhang, L.; Li, Y.; Zhang, X. Drug Delivery System in the Treatment of Diabetes Mellitus. Front. Bioeng. Biotechnol. 2020, 8, 880. [Google Scholar] [CrossRef] [PubMed]
  36. Avery, O.T.; MacLeod, C.M.; McCarty, M. Studies on the chemical nature of the substance inducing transformation of pneumococcal types: Induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. J. Exp. Med. 1944, 79, 137–158. [Google Scholar] [CrossRef]
  37. Meyerson, S.L.; Skelly, C.L.; Curi, M.A.; Schwartz, L.B. Gene therapy for cardiovascular disease. Semin. Cardiothorac. Vasc. Anesth. 2000, 4, 289–300. [Google Scholar]
  38. Bulcha, J.T.; Wang, Y.; Ma, H.; Tai, P.W.; Gao, G. Viral vector platforms within the gene therapy landscape. Signal Transduct. Target. Ther. 2021, 6, 1–24. [Google Scholar] [CrossRef] [PubMed]
  39. Su, C.-H.; Wu, Y.-J.; Wang, H.-H.; Yeh, H.-I. Nonviral gene therapy targeting cardiovascular system. Am. J. Physiol. Heart Circ. Physiol. 2012, 303, H629–H638. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Hall, A.; Lächelt, U.; Bartek, J.; Wagner, E.; Moghimi, S.M. Polyplex Evolution: Understanding Biology, Optimizing Performance. Mol. Ther. 2017, 25, 1476–1490. [Google Scholar] [CrossRef] [Green Version]
  41. Scimia, M.C.; Gumpert, A.M.; Koch, W.J. Cardiovascular gene therapy for myocardial infarction. Expert Opin. Biol. Ther. 2014, 14, 183–195. [Google Scholar] [CrossRef] [Green Version]
  42. Cannatà, A.; Ali, H.; Sinagra, G.; Giacca, M. Gene therapy for the heart lessons learned and future perspectives. Circ. Res. 2020, 126, 1394–1414. [Google Scholar] [CrossRef]
  43. Nakagami, H.; Morishita, R. Recent advances in therapeutic vaccines to treat hypertension. Hypertension 2018, 72, 1031–1036. [Google Scholar] [CrossRef] [PubMed]
  44. Siriwardena, A.N. Increasing Evidence That Influenza Is a Trigger for Cardiovascular Disease; Oxford University Press: Oxford, UK, 2012. [Google Scholar]
  45. Singanayagam, A.; Elder, D.; Chalmers, J.D. Is community-acquired pneumonia an independent risk factor for cardiovascular disease? Eur. Respir. J. 2012, 39, 187–196. [Google Scholar] [CrossRef] [Green Version]
  46. Deng, Y.; Zhang, X.; Shen, H.; He, Q.; Wu, Z.; Liao, W.; Yuan, M. Application of the Nano-Drug Delivery System in Treatment of Cardiovascular Diseases. Front. Bioeng. Biotechnol. 2019, 7, 489. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Sezer, A.D. Application of Nanotechnology in Drug Delivery; BoD–Books on Demand: London, UK, 2014. [Google Scholar]
  48. Zhang, J.; Xie, Z.; Zhang, N.; Zhong, J. Nanosuspension drug delivery system: Preparation, characterization, postproduction processing, dosage form, and application. In Nanostructures for Drug Delivery; Elsevier: Amsterdam, The Netherlands, 2017; pp. 413–443. [Google Scholar]
  49. Fox, C.B.; Kim, J.; Le, L.V.; Nemeth, C.L.; Chirra, H.D.; Desai, T.A. Micro/nanofabricated platforms for oral drug delivery. J. Control. Release 2015, 219, 431–444. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Trevaskis, N.L.; McEvoy, C.L.; McIntosh, M.P.; Edwards, G.A.; Shanker, R.M.; Charman, W.N.; Porter, C.J. The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (CP524,515 and CP532,623). Pharm. Res. 2010, 27, 878–893. [Google Scholar] [CrossRef]
  51. Vinarov, Z.; Abdallah, M.; Agundez, J.A.G.; Allegaert, K.; Basit, A.W.; Braeckmans, M.; Ceulemans, J.; Corsetti, M.; Griffin, B.T.; Grimm, M.; et al. Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review. Eur. J. Pharm. Sci. 2021, 162, 105812. [Google Scholar] [CrossRef]
  52. Brocks, D.R.; Davies, N.M. Lymphatic drug absorption via the enterocytes: Pharmacokinetic simulation, modeling, and considerations for optimal drug development. J. Pharm. Pharm. Sci. 2018, 21, 254s–270s. [Google Scholar] [CrossRef] [Green Version]
  53. Jenkins, P.; Howard, K.; Blackball, N.; Thomas, N.; Davis, S.; O’hagan, D.T. Microparticulate absorption from the rat intestine. J. Control. Release 1994, 29, 339–350. [Google Scholar] [CrossRef]
  54. Charman, W.; Stella, V.J. Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules. Int. J. Pharm. 1986, 34, 175–178. [Google Scholar] [CrossRef]
  55. Cifarelli, V.; Eichmann, A. The Intestinal Lymphatic System: Functions and Metabolic Implications. Cell. Mol. Gastroenterol. Hepatol. 2019, 7, 503–513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Miller, M.J.; Newberry, R.D. Microanatomy of the intestinal lymphatic system. Ann. N. Y. Acad. Sci. 2010, 1207, E21–E28. [Google Scholar] [CrossRef] [Green Version]
  57. Baena-Díez, J.M.; Peñafiel, J.; Subirana, I.; Ramos, R.; Elosua, R.; Marín-Ibañez, A.; Guembe, M.J.; Rigo, F.; Tormo-Díaz, M.J.; Moreno-Iribas, C.; et al. Risk of Cause-Specific Death in Individuals With Diabetes: A Competing Risks Analysis. Diabetes Care 2016, 39, 1987–1995. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Sanchez-Rangel, E.; Inzucchi, S.E. Metformin: Clinical use in type 2 diabetes. Diabetologia 2017, 60, 1586–1593. [Google Scholar] [CrossRef]
  59. Sola, D.; Rossi, L.; Schianca, G.P.C.; Maffioli, P.; Bigliocca, M.; Mella, R.; Corlianò, F.; Fra, G.P.; Bartoli, E.; Derosa, G. Sulfonylureas and their use in clinical practice. Arch. Med. Sci. 2015, 11, 840–848. [Google Scholar] [CrossRef] [PubMed]
  60. van de Laar, F.A. Alpha-glucosidase inhibitors in the early treatment of type 2 diabetes. Vasc. Health Risk Manag. 2008, 4, 1189–1195. [Google Scholar] [CrossRef] [Green Version]
  61. Lebovitz, H.E. Thiazolidinediones: The Forgotten Diabetes Medications. Curr. Diabetes Rep. 2019, 19, 151. [Google Scholar] [CrossRef] [Green Version]
  62. Gallwitz, B. Clinical Use of DPP-4 Inhibitors. Front. Endocrinol. 2019, 10, 389. [Google Scholar] [CrossRef]
  63. Neuen, B.L.; Cherney, D.Z.; Jardine, M.J.; Perkovic, V. Sodium-glucose cotransporter inhibitors in type 2 diabetes: Thinking beyond glucose lowering. CMAJ 2019, 191, E1128–E1135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Kim, K.S.; Kwag, D.S.; Hwang, H.S.; Lee, E.S.; Bae, Y.H. Immense insulin intestinal uptake and lymphatic transport using bile acid conjugated partially uncapped liposome. Mol. Pharm. 2018, 15, 4756–4763. [Google Scholar] [CrossRef]
  65. Jain, S.; Rathi, V.V.; Jain, A.K.; Das, M.; Godugu, C. Folate-decorated PLGA nanoparticles as a rationally designed vehicle for the oral delivery of insulin. Nanomedicine 2012, 7, 1311–1337. [Google Scholar] [CrossRef] [PubMed]
  66. Lin, P.Y.; Chen, K.H.; Miao, Y.B.; Chen, H.L.; Lin, K.J.; Chen, C.T.; Yeh, C.N.; Chang, Y.; Sung, H.W. Phase-Changeable Nanoemulsions for Oral Delivery of a Therapeutic Peptide: Toward Targeting the Pancreas for Antidiabetic Treatments Using Lymphatic Transport. Adv. Funct. Mater. 2019, 29, 1809015. [Google Scholar] [CrossRef]
  67. Harrison, G.A. Insulin in alcoholic solution by the mouth. Br. Med. J. 1923, 2, 1204. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Sonaje, K.; Lin, Y.-H.; Juang, J.-H.; Wey, S.-P.; Chen, C.-T.; Sung, H.-W. In vivo evaluation of safety and efficacy of self-assembled nanoparticles for oral insulin delivery. Biomaterials 2009, 30, 2329–2339. [Google Scholar] [CrossRef]
  69. Wu, Z.M.; Zhou, L.; Guo, X.D.; Jiang, W.; Ling, L.; Qian, Y.; Luo, K.Q.; Zhang, L.J. HP55-coated capsule containing PLGA/RS nanoparticles for oral delivery of insulin. Int. J. Pharm. 2012, 425, 1–8. [Google Scholar] [CrossRef]
  70. Jin, Y.; Song, Y.; Zhu, X.; Zhou, D.; Chen, C.; Zhang, Z.; Huang, Y. Goblet cell-targeting nanoparticles for oral insulin delivery and the influence of mucus on insulin transport. Biomaterials 2012, 33, 1573–1582. [Google Scholar] [CrossRef] [PubMed]
  71. Cohn, J.N.; Archibald, D.G.; Ziesche, S.; Franciosa, J.A.; Harston, W.E.; Tristani, F.E.; Dunkman, W.B.; Jacobs, W.; Francis, G.S.; Flohr, K.H. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N. Engl. J. Med. 1986, 314, 1547–1552. [Google Scholar] [CrossRef]
  72. MacDougall, A.I.; Addis, G.J.; MacKay, N.; Dymock, I.W.; Turpie, A.G.; Ballingall, D.L.; MacLennan, W.J.; Whiting, B.; MacArthur, J.G. Treatment of hypertension with clonidine. Br. Med. J. 1970, 3, 440–442. [Google Scholar] [CrossRef] [Green Version]
  73. Mah, G.T.; Tejani, A.M.; Musini, V.M. Methyldopa for primary hypertension. Cochrane Database Syst. Rev. 2009, 4, CD003893. [Google Scholar] [CrossRef]
  74. Bangalore, S.; Steg, G.; Deedwania, P.; Crowley, K.; Eagle, K.A.; Goto, S.; Ohman, E.M.; Cannon, C.P.; Smith, S.C.; Zeymer, U.; et al. β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 2012, 308, 1340–1349. [Google Scholar] [CrossRef]
  75. Lazar, H.L. Role of angiotensin-converting enzyme inhibitors in the coronary artery bypass patient. Ann. Thorac. Surg. 2005, 79, 1081–1089. [Google Scholar] [CrossRef]
  76. Güleç, S. Valsartan after myocardial infarction. Anadolu Kardiyol. Derg. 2014, 14, S9–S13. [Google Scholar] [CrossRef] [PubMed]
  77. Hubers, S.A.; Brown, N.J. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. Circulation 2016, 133, 1115–1124. [Google Scholar] [CrossRef] [PubMed]
  78. Fares, H.; DiNicolantonio, J.J.; O’Keefe, J.H.; Lavie, C.J. Amlodipine in hypertension: A first-line agent with efficacy for improving blood pressure and patient outcomes. Open Heart 2016, 3, e000473. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Rodríguez Padial, L.; Barón-Esquivias, G.; Hernández Madrid, A.; Marzal Martín, D.; Pallarés-Carratalá, V.; de la Sierra, A. Clinical Experience with Diltiazem in the Treatment of Cardiovascular Diseases. Cardiol. Ther. 2016, 5, 75–82. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Badu-Boateng, C.; Jennings, R.; Hammersley, D. The therapeutic role of ivabradine in heart failure. Ther. Adv. Chronic Dis. 2018, 9, 199–207. [Google Scholar] [CrossRef]
  81. Pitt, B.; Remme, W.; Zannad, F.; Neaton, J.; Martinez, F.; Roniker, B.; Bittman, R.; Hurley, S.; Kleiman, J.; Gatlin, M.; et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 2003, 348, 1309–1321. [Google Scholar] [CrossRef]
  82. Pitt, B.; Zannad, F.; Remme, W.J.; Cody, R.; Castaigne, A.; Perez, A.; Palensky, J.; Wittes, J. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. N. Engl. J. Med. 1999, 341, 709–717. [Google Scholar] [CrossRef] [Green Version]
  83. Campbell, T.J.; MacDonald, P.S. Digoxin in heart failure and cardiac arrhythmias. Med. J. Aust. 2003, 179, 98–102. [Google Scholar] [CrossRef] [PubMed]
  84. Ramkumar, S.; Raghunath, A.; Raghunath, S. Statin Therapy: Review of Safety and Potential Side Effects. Acta Cardiol. Sin. 2016, 32, 631–639. [Google Scholar] [CrossRef]
  85. Jneid, H.; Bhatt, D.L.; Corti, R.; Badimon, J.J.; Fuster, V.; Francis, G.S. Aspirin and clopidogrel in acute coronary syndromes: Therapeutic insights from the CURE study. Arch. Intern. Med. 2003, 163, 1145–1153. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Tran, H.; Mehta, S.R.; Eikelboom, J.W. Clinical update on the therapeutic use of clopidogrel: Treatment of acute ST-segment elevation myocardial infarction (STEMI). Vasc. Health Risk Manag. 2006, 2, 379–387. [Google Scholar] [CrossRef] [Green Version]
  87. Welsh, R.C.; Sidhu, R.S.; Cairns, J.A.; Lavi, S.; Kedev, S.; Moreno, R.; Cantor, W.J.; Stankovic, G.; Meeks, B.; Yuan, F.; et al. Outcomes Among Clopidogrel, Prasugrel, and Ticagrelor in ST-Elevation Myocardial Infarction Patients Who Underwent Primary Percutaneous Coronary Intervention From the TOTAL Trial. Can. J. Cardiol. 2019, 35, 1377–1385. [Google Scholar] [CrossRef]
  88. Date, A.A.; Desai, N.; Dixit, R.; Nagarsenker, M. Self-nanoemulsifying drug delivery systems: Formulation insights, applications and advances. Nanomedicine 2010, 5, 1595–1616. [Google Scholar] [CrossRef] [PubMed]
  89. Sun, M.; Zhai, X.; Xue, K.; Hu, L.; Yang, X.; Li, G.; Si, L. Intestinal absorption and intestinal lymphatic transport of sirolimus from self-microemulsifying drug delivery systems assessed using the single-pass intestinal perfusion (SPIP) technique and a chylomicron flow blocking approach: Linear correlation with oral bioavailabilities in rats. Eur. J. Pharm. Sci. 2011, 43, 132–140. [Google Scholar]
  90. Nekkanti, V.; Wang, Z.; Betageri, G.V. Pharmacokinetic evaluation of improved oral bioavailability of valsartan: Proliposomes versus self-nanoemulsifying drug delivery system. AAPS PharmSciTech 2016, 17, 851–862. [Google Scholar] [CrossRef]
  91. Shafiq, S.; Shakeel, F.; Talegaonkar, S.; Ahmad, F.J.; Khar, R.K.; Ali, M. Development and bioavailability assessment of ramipril nanoemulsion formulation. Eur. J. Pharm. Biopharm. 2007, 66, 227–243. [Google Scholar] [CrossRef]
  92. Chhabra, G.; Chuttani, K.; Mishra, A.K.; Pathak, K. Design and development of nanoemulsion drug delivery system of amlodipine besilate for improvement of oral bioavailability. Drug Dev. Ind. Pharm. 2011, 37, 907–916. [Google Scholar] [CrossRef]
  93. Shah, U.; Joshi, G.; Sawant, K.J. Improvement in antihypertensive and antianginal effects of felodipine by enhanced absorption from PLGA nanoparticles optimized by factorial design. Mater. Sci. Eng. C 2014, 35, 153–163. [Google Scholar] [CrossRef] [PubMed]
  94. Dudhipala, N.; Veerabrahma, K. Pharmacokinetic and pharmacodynamic studies of nisoldipine-loaded solid lipid nanoparticles developed by central composite design. Drug Dev. Ind. Pharm. 2015, 41, 1968–1977. [Google Scholar] [CrossRef] [PubMed]
  95. Ranpise, N.S.; Korabu, S.S.; Ghodake, V.N. Second generation lipid nanoparticles (NLC) as an oral drug carrier for delivery of lercanidipine hydrochloride. Colloids Surf. B Biointerfaces 2014, 116, 81–87. [Google Scholar] [CrossRef] [PubMed]
  96. Deshpande, P.B.; Gurram, A.K.; Deshpande, A.; Shavi, G.V.; Musmade, P.; Arumugam, K.; Averineni, R.K.; Mutalik, S.; Reddy, M.S.; Udupa, N. A novel nanoproliposomes of lercanidipine: Development, in vitro and preclinical studies to support its effectiveness in hypertension therapy. Life Sci. 2016, 162, 125–137. [Google Scholar] [CrossRef]
  97. Kim, Y.I.; Fluckiger, L.; Hoffman, M.; Lartaud-Idjouadiene, I.; Atkinson, J.; Maincent, T. The antihypertensive effect of orally administered nifedipine-loaded nanoparticles in spontaneously hypertensive rats. Br. J. Pharmacol. 1997, 120, 399–404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Nelson, R.H. Hyperlipidemia as a risk factor for cardiovascular disease. Prim. Care Clin. Off. Pract. 2013, 40, 195–211. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Vavlukis, M.; Vavlukis, A. Adding ezetimibe to statin therapy: Latest evidence and clinical implications. Drugs Context 2018, 7, 212534. [Google Scholar] [CrossRef] [Green Version]
  100. Tziomalos, K.; Athyros, V.G. Fenofibrate: A novel formulation (Triglide) in the treatment of lipid disorders: A review. Int. J. Nanomed. 2006, 1, 129–147. [Google Scholar] [CrossRef]
  101. Shaker, M.A.; Elbadawy, H.M.; Al Thagfan, S.S.; Shaker, M.A. Enhancement of atorvastatin oral bioavailability via encapsulation in polymeric nanoparticles. Int. J. Pharm. 2021, 592, 120077. [Google Scholar] [CrossRef]
  102. Sharma, M.; Mehta, I. Surface stabilized atorvastatin nanocrystals with improved bioavailability, safety and antihyperlipidemic potential. Sci. Rep. 2019, 9, 16105. [Google Scholar] [CrossRef]
  103. Kumar, N.; Chaurasia, S.; Patel, R.R.; Khan, G.; Kumar, V.; Mishra, B. Atorvastatin calcium loaded PCL nanoparticles: Development, optimization, in vitro and in vivo assessments. RSC Adv. 2016, 6, 16520–16532. [Google Scholar] [CrossRef]
  104. Elmowafy, M.; Ibrahim, H.M.; Ahmed, M.A.; Shalaby, K.; Salama, A.; Hefesha, H. Atorvastatin-loaded nanostructured lipid carriers (NLCs): Strategy to overcome oral delivery drawbacks. Drug Deliv. 2017, 24, 932–941. [Google Scholar] [CrossRef] [Green Version]
  105. Jain, K.; Kumar, R.S.; Sood, S.; Gowthamarajan, K. Enhanced oral bioavailability of atorvastatin via oil-in-water nanoemulsion using aqueous titration method. J. Pharm. Sci. Res. 2013, 5, 18. [Google Scholar]
  106. Tiwari, R.; Pathak, K. Nanostructured lipid carrier versus solid lipid nanoparticles of simvastatin: Comparative analysis of characteristics, pharmacokinetics and tissue uptake. Int. J. Pharm. 2011, 415, 232–243. [Google Scholar] [CrossRef]
  107. Dudhipala, N.; Veerabrahma, K. Improved anti-hyperlipidemic activity of Rosuvastatin Calcium via lipid nanoparticles: Pharmacokinetic and pharmacodynamic evaluation. Eur. J. Pharm. Biopharm. 2017, 110, 47–57. [Google Scholar] [CrossRef]
  108. El-Helw, A.-R.M.; Fahmy, U.A. Improvement of fluvastatin bioavailability by loading on nanostructured lipid carriers. Int. J. Nanomed. 2015, 10, 5797. [Google Scholar] [CrossRef]
  109. Chen, Y.; Lu, Y.; Chen, J.; Lai, J.; Sun, J.; Hu, F.; Wu, W. Enhanced bioavailability of the poorly water-soluble drug fenofibrate by using liposomes containing a bile salt. Int. J. Pharm. 2009, 376, 153–160. [Google Scholar] [CrossRef] [PubMed]
  110. Mohsin, K.; Alamri, R.; Ahmad, A.; Raish, M.; Alanazi, F.K.; Hussain, M.D. Development of self-nanoemulsifying drug delivery systems for the enhancement of solubility and oral bioavailability of fenofibrate, a poorly water-soluble drug. Int. J. Nanomed. 2016, 11, 2829. [Google Scholar]
  111. Tran, T.H.; Ramasamy, T.; Truong, D.H.; Choi, H.-G.; Yong, C.S.; Kim, J.O. Preparation and characterization of fenofibrate-loaded nanostructured lipid carriers for oral bioavailability enhancement. AAPS Pharmscitech 2014, 15, 1509–1515. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Agrawal, Y.O.; Mahajan, U.B.; Agnihotri, V.V.; Nilange, M.S.; Mahajan, H.S.; Sharma, C.; Ojha, S.; Patil, C.R.; Goyal, S.N. Ezetimibe-Loaded Nanostructured Lipid Carrier Based Formulation Ameliorates Hyperlipidaemia in an Experimental Model of High Fat Diet. Molecules 2021, 26, 1485. [Google Scholar] [CrossRef]
  113. Bandyopadhyay, S.; Katare, O.; Singh, B. Optimized self nano-emulsifying systems of ezetimibe with enhanced bioavailability potential using long chain and medium chain triglycerides. Colloids Surf. B Biointerfaces 2012, 100, 50–61. [Google Scholar] [CrossRef] [PubMed]
  114. Shevalkar, G.; Vavia, P. Solidified nanostructured lipid carrier (S-NLC) for enhancing the oral bioavailability of ezetimibe. J. Drug Deliv. Sci. Technol. 2019, 53, 101211. [Google Scholar] [CrossRef]
  115. McLennan, D.N.; Porter, C.J.; Charman, S.A. Subcutaneous drug delivery and the role of the lymphatics. Drug Discov. Today Technol. 2005, 2, 89–96. [Google Scholar] [CrossRef] [PubMed]
  116. American Diabetes, A. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020, 43, S14–S31. [Google Scholar] [CrossRef] [Green Version]
  117. Hinnen, D. Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes. Diabetes Spectr. 2017, 30, 202–210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Roesti, E.S.; Boyle, C.N.; Zeman, D.T.; Sande-Melon, M.; Storni, F.; Cabral-Miranda, G.; Knuth, A.; Lutz, T.A.; Vogel, M.; Bachmann, M.F. Vaccination against amyloidogenic aggregates in pancreatic islets prevents development of type 2 diabetes mellitus. Vaccines 2020, 8, 116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Zhang, Y.; Yu, X.-L.; Zha, J.; Mao, L.-Z.; Chai, J.-Q.; Liu, R.-T. Therapeutic vaccine against IL-1β improved glucose control in a mouse model of type 2 diabetes. Life Sci. 2018, 192, 68–74. [Google Scholar] [CrossRef]
  120. Zha, J.; Chi, X.-W.; Yu, X.-L.; Liu, X.-M.; Liu, D.-Q.; Zhu, J.; Ji, H.; Liu, R.-T. Interleukin-1β-targeted vaccine improves glucose control and β-cell function in a diabetic KK-Ay mouse model. PLoS ONE 2016, 11, e0154298. [Google Scholar] [CrossRef] [PubMed]
  121. Cavelti-Weder, C.; Timper, K.; Seelig, E.; Keller, C.; Osranek, M.; Lässing, U.; Spohn, G.; Maurer, P.; Müller, P.; Jennings, G.T. Development of an interleukin-1β vaccine in patients with type 2 diabetes. Mol. Ther. 2016, 24, 1003–1012. [Google Scholar] [CrossRef] [Green Version]
  122. Pang, Z.; Nakagami, H.; Osako, M.K.; Koriyama, H.; Nakagami, F.; Tomioka, H.; Shimamura, M.; Kurinami, H.; Takami, Y.; Morishita, R. Therapeutic vaccine against DPP4 improves glucose metabolism in mice. Proc. Natl. Acad. Sci. USA 2014, 111, E1256–E1263. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Qiu, Z.; Chen, X.; Zhou, Y.; Lin, J.; Ding, D.; Yang, S.; Chen, F.; Wang, M.; Zhu, F.; Yu, X. Therapeutic vaccines against human and rat renin in spontaneously hypertensive rats. PLoS ONE 2013, 8, e66420. [Google Scholar]
  124. Brown, M.J.; Coltart, J.; Gunewardena, K.; Ritter, J.M.; Auton, T.R.; Glover, J.F. Randomized double-blind placebo-controlled study of an angiotensin immunotherapeutic vaccine (PMD3117) in hypertensive subjects. Clin. Sci. 2004, 107, 167–173. [Google Scholar] [CrossRef]
  125. Hong, F.; Quan, W.Y.; Pandey, R.; Yi, S.; Chi, L.; Xia, L.Z.; Yuan, M.; Ming, L.J. A vaccine for hypertension based on peptide AngI-R: A pilot study. Int. J. Cardiol. 2011, 148, 76–84. [Google Scholar] [CrossRef]
  126. Chen, X.; Qiu, Z.; Yang, S.; Ding, D.; Chen, F.; Zhou, Y.; Wang, M.; Lin, J.; Yu, X.; Zhou, Z. Effectiveness and safety of a therapeutic vaccine against angiotensin II receptor type 1 in hypertensive animals. Hypertension 2013, 61, 408–416. [Google Scholar] [CrossRef]
  127. Zhu, F.; Liao, Y.H.; Li, L.D.; Cheng, M.; Wei, F.; Wei, Y.M.; Wang, M. Target organ protection from a novel angiotensin II receptor (AT1) vaccine ATR12181 in spontaneously hypertensive rats. Cell. Mol. Immunol. 2006, 3, 107–114. [Google Scholar]
  128. Tissot, A.C.; Maurer, P.; Nussberger, J.; Sabat, R.; Pfister, T.; Ignatenko, S.; Volk, H.-D.; Stocker, H.; Müller, P.; Jennings, G.T. Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: A double-blind, randomised, placebo-controlled phase IIa study. Lancet 2008, 371, 821–827. [Google Scholar] [CrossRef]
  129. Watanabe, R.; Suzuki, J.-I.; Wakayama, K.; Maejima, Y.; Shimamura, M.; Koriyama, H.; Nakagami, H.; Kumagai, H.; Ikeda, Y.; Akazawa, H. A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction. Sci. Rep. 2017, 7, 43920. [Google Scholar] [CrossRef]
  130. Margulis, K.; Neofytou, E.A.; Beygui, R.E.; Zare, R.N. Celecoxib nanoparticles for therapeutic angiogenesis. ACS Nano 2015, 9, 9416–9426. [Google Scholar] [CrossRef]
  131. Vignesh, S.; Sivashanmugam, A.; Annapoorna, M.; Janarthanan, R.; Subramania, I.; Jayakumar, R. Injectable deferoxamine nanoparticles loaded chitosan-hyaluronic acid coacervate hydrogel for therapeutic angiogenesis. Colloids Surf. B Biointerfaces 2018, 161, 129–138. [Google Scholar]
  132. Tomlinson, B.; Hu, M.; Zhang, Y.; Chan, P.; Liu, Z.-M. Alirocumab for the treatment of hypercholesterolemia. Expert Opin. Biol. Ther. 2017, 17, 633–643. [Google Scholar] [CrossRef] [PubMed]
  133. Kasichayanula, S.; Grover, A.; Emery, M.G.; Gibbs, M.A.; Somaratne, R.; Wasserman, S.M.; Gibbs, J.P. Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor. Clin. Pharmacokinet. 2018, 57, 769–779. [Google Scholar] [CrossRef] [Green Version]
  134. Ray, K.K.; Wright, R.S.; Kallend, D.; Koenig, W.; Leiter, L.A.; Raal, F.J.; Bisch, J.A.; Richardson, T.; Jaros, M.; Wijngaard, P.L.J.; et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N. Engl. J. Med. 2020, 382, 1507–1519. [Google Scholar] [CrossRef] [PubMed]
  135. Santos, R.D.; Raal, F.J.; Catapano, A.L.; Witztum, J.L.; Steinhagen-Thiessen, E.; Tsimikas, S. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein (a) in various populations with hypercholesterolemia: Results of 4 phase III trials. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 689–699. [Google Scholar] [CrossRef] [Green Version]
  136. Raal, F.J.; Kallend, D.; Ray, K.K.; Turner, T.; Koenig, W.; Wright, R.S.; Wijngaard, P.L.; Curcio, D.; Jaros, M.J.; Leiter, L.A. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N. Engl. J. Med. 2020, 382, 1520–1530. [Google Scholar] [CrossRef]
  137. Witztum, J.L.; Gaudet, D.; Freedman, S.D.; Alexander, V.J.; Digenio, A.; Williams, K.R.; Yang, Q.; Hughes, S.G.; Geary, R.S.; Arca, M. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N. Engl. J. Med. 2019, 381, 531–542. [Google Scholar] [CrossRef]
  138. Viney, N.J.; van Capelleveen, J.C.; Geary, R.S.; Xia, S.; Tami, J.A.; Rosie, Z.Y.; Marcovina, S.M.; Hughes, S.G.; Graham, M.J.; Crooke, R.M. Antisense oligonucleotides targeting apolipoprotein (a) in people with raised lipoprotein (a): Two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016, 388, 2239–2253. [Google Scholar] [CrossRef]
  139. Pharma, I. Positive Phase 2 Clinical Data of AKCEA-APOCIII-L(Rx) at ESC Congress 2020; Ionis Pharma: Boston, MA, USA; Carlsbad, CA, USA, 2020. [Google Scholar]
  140. Graham, M.J.; Lee, R.G.; Brandt, T.A.; Tai, L.-J.; Fu, W.; Peralta, R.; Yu, R.; Hurh, E.; Paz, E.; McEvoy, B.W. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N. Engl. J. Med. 2017, 377, 222–232. [Google Scholar] [CrossRef]
  141. Kawakami, R.; Nozato, Y.; Nakagami, H.; Ikeda, Y.; Shimamura, M.; Yoshida, S.; Sun, J.; Kawano, T.; Takami, Y.; Noma, T. Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9) epitope in mice. PLoS ONE 2018, 13, e0191895. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Landlinger, C.; Pouwer, M.G.; Juno, C.; van der Hoorn, J.W.; Pieterman, E.J.; Jukema, J.W.; Staffler, G.; Princen, H.M.; Galabova, G. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE* 3Leiden. CETP mice. Eur. Heart J. 2017, 38, 2499–2507. [Google Scholar] [CrossRef] [Green Version]
  143. Crossey, E.; Amar, M.J.; Sampson, M.; Peabody, J.; Schiller, J.T.; Chackerian, B.; Remaley, A.T. A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine 2015, 33, 5747–5755. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Olearczyk, J.; Gao, S.; Eybye, M.; Yendluri, S.; Andrews, L.; Bartz, S.; Cully, D.; Tadin-Strapps, M. Targeting of hepatic angiotensinogen using chemically modified siRNAs results in significant and sustained blood pressure lowering in a rat model of hypertension. Hypertens. Res. 2014, 37, 405–412. [Google Scholar] [CrossRef] [PubMed]
  145. Hsu, C.-N.; Tain, Y.-L. Targeting the Renin–Angiotensin–Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins. Int. J. Mol. Sci. 2021, 22, 2298. [Google Scholar] [CrossRef]
  146. Ames, M.K.; Atkins, C.E.; Pitt, B. The renin-angiotensin-aldosterone system and its suppression. J. Vet. Intern. Med. 2019, 33, 363–382. [Google Scholar] [CrossRef] [Green Version]
  147. U.S. Food and Drug Administration. Kynamro (Mipomersen Sodium) Injection: Drug Approval Package. 2013. Available online: (accessed on 1 May 2021).
  148. Fogacci, F.; Ferri, N.; Toth, P.P.; Ruscica, M.; Corsini, A.; Cicero, A.F. Efficacy and safety of mipomersen: A systematic review and meta-analysis of randomized clinical trials. Drugs 2019, 79, 751–766. [Google Scholar] [CrossRef]
  149. Geary, R.S.; Baker, B.F.; Crooke, S.T. Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (Kynamro®): A second-generation antisense oligonucleotide inhibitor of apolipoprotein B. Clin. Pharmacokinet. 2015, 54, 133–146. [Google Scholar] [CrossRef] [Green Version]
  150. Santos, R.D.; Duell, P.B.; East, C.; Guyton, J.R.; Moriarty, P.M.; Chin, W.; Mittleman, R.S. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur. Heart J. 2015, 36, 566–575. [Google Scholar] [CrossRef] [PubMed]
  151. Esan, O.; Wierzbicki, A.S. Volanesorsen in the Treatment of Familial Chylomicronemia Syndrome or Hypertriglyceridaemia: Design, Development and Place in Therapy. Drug Des. Dev. Ther. 2020, 14, 2623. [Google Scholar] [CrossRef]
  152. European Medicines Agency. Waylivra (Volanesorsen): Public Assessment Report. 2019. Available online: (accessed on 1 April 2021).
  153. Gaudet, D.; Brisson, D.; Tremblay, K.; Alexander, V.J.; Singleton, W.; Hughes, S.G.; Geary, R.S.; Baker, B.F.; Graham, M.J.; Crooke, R.M. Targeting APOC3 in the familial chylomicronemia syndrome. N. Engl. J. Med. 2014, 371, 2200–2206. [Google Scholar] [CrossRef] [PubMed]
  154. European Medicines Agency. Waylivra, INN-Volanesorsen. 2019. Available online: (accessed on 1 May 2021).
  155. Dyrbuś, K.; Gąsior, M.; Penson, P.; Ray, K.K.; Banach, M. Inclisiran—New hope in the management of lipid disorders? J. Clin. Lipidol. 2020, 14, 16–27. [Google Scholar] [CrossRef] [PubMed]
  156. European Medicines Agency. Leqvio (Inclisiran): An Overview of Leqvio and Why It Is Authorised in the EU. 2020. Available online: (accessed on 1 May 2021).
  157. European Medicines Agency. Leqvio: Assessment Report. 2020. Available online: (accessed on 1 May 2021).
  158. Fowler, A.; Sampson, M.; Remaley, A.T.; Chackerian, B. A VLP-based vaccine targeting ANGPTL3 lowers plasma triglycerides in mice. bioRxiv 2021. [Google Scholar] [CrossRef]
  159. Brakenhielm, E.; Alitalo, K. Cardiac lymphatics in health and disease. Nat. Rev. Cardiol. 2019, 16, 56–68. [Google Scholar] [CrossRef] [Green Version]
  160. Ananthakrishnan, P.; Mariani, G.; Moresco, L.; Giuliano, A.E. The anatomy and physiology of lymphatic circulation. In Radioguided Surgery; Springer: New York, NY, USA, 2008; pp. 57–71. [Google Scholar]
  161. Supersaxo, A.; Hein, W.R.; Steffen, H. Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm. Res. 1990, 7, 167–169. [Google Scholar] [CrossRef]
  162. Hirano, K.; Hunt, C.A. Lymphatic transport of liposome-encapsulated agents: Effects of liposome size following intraperitoneal administration. J. Pharm. Sci. 1985, 74, 915–921. [Google Scholar] [CrossRef]
  163. Flessner, M.; Dedrick, R.; Schultz, J.S. Exchange of macromolecules between peritoneal cavity and plasma. Am. J. Physiol. Heart Circ. Physiol. 1985, 248, H15–H25. [Google Scholar] [CrossRef] [PubMed]
  164. Lim, H.Y.; Thiam, C.H.; Yeo, K.P.; Bisoendial, R.; Hii, C.S.; McGrath, K.C.; Tan, K.W.; Heather, A.; Alexander, J.S.J.; Angeli, V. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab. 2013, 17, 671–684. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Reddy, S.T.; Rehor, A.; Schmoekel, H.G.; Hubbell, J.A.; Swartz, M.A. In vivo targeting of dendritic cells in lymph nodes with poly (propylene sulfide) nanoparticles. J. Control. Release 2006, 112, 26–34. [Google Scholar] [CrossRef] [PubMed]
  166. Harvey, A.J.; Kaestner, S.A.; Sutter, D.E.; Harvey, N.G.; Mikszta, J.A.; Pettis, R.J. Microneedle-based intradermal delivery enables rapid lymphatic uptake and distribution of protein drugs. Pharm. Res. 2011, 28, 107–116. [Google Scholar] [CrossRef]
  167. Hettinga, J.; Carlisle, R. Vaccination into the Dermal Compartment: Techniques, Challenges, and Prospects. Vaccines 2020, 8, 534. [Google Scholar] [CrossRef] [PubMed]
  168. Moore, J.E.; Bertram, C.D. Lymphatic System Flows. Annu. Rev. Fluid Mech. 2018, 50, 459–482. [Google Scholar] [CrossRef]
  169. Liao, S.; Padera, T.P. Lymphatic Function and Immune Regulation in Health and Disease. Lymphat. Res. Biol. 2013, 11, 136–143. [Google Scholar] [CrossRef] [Green Version]
  170. Canzona, F.; Massimo, M.; Tuzi, A.; Maggiori, E.; Grosso, M.G.; Antonaci, L.; Santini, S.; Catizzone, A.R.; Troili, F.; Gallo, A.; et al. Intradermal Therapy (mesotherapy) in Dermatology. J. Dermatol. Ski. Sci. 2020, 2, 22–25. [Google Scholar]
  171. Hawkridge, A.; Hatherill, M.; Little, F.; Goetz, M.A.; Barker, L.; Mahomed, H.; Sadoff, J.; Hanekom, W.; Geiter, L.; Hussey, G. Efficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: Randomised trial. BMJ 2008, 337, a2052. [Google Scholar] [CrossRef] [Green Version]
  172. Kroger, C.J.; Clark, M.; Ke, Q.; Tisch, R.M. Therapies to suppress β cell autoimmunity in type 1 diabetes. Front. Immunol. 2018, 9, 1891. [Google Scholar] [CrossRef] [PubMed]
  173. Clark, M.; Kroger, C.J.; Tisch, R.M. Type 1 diabetes: A chronic anti-self-inflammatory response. Front. Immunol. 2017, 8, 1898. [Google Scholar] [CrossRef] [Green Version]
  174. Richardson, S.J.; Willcox, A.; Bone, A.J.; Morgan, N.G.; Foulis, A.K. Immunopathology of the human pancreas in type-I diabetes. In Seminars in Immunopathology; Springer: New York, NY, USA, 2011; pp. 9–21. [Google Scholar]
  175. Harrison, L.C. The prospect of vaccination to prevent type 1 diabetes. Hum. Vaccines 2005, 1, 143–150. [Google Scholar] [CrossRef] [Green Version]
  176. Smith, E.L.; Peakman, M. Peptide immunotherapy for type 1 diabetes—Clinical advances. Front. Immunol. 2018, 9, 392. [Google Scholar] [CrossRef] [PubMed]
  177. Thrower, S.L.; James, L.; Hall, W.; Green, K.M.; Arif, S.; Allen, J.S.; Van-Krinks, C.; Lozanoska-Ochser, B.; Marquesini, L.; Brown, S.; et al. Proinsulin peptide immunotherapy in type 1 diabetes: Report of a first-in-man Phase I safety study. Clin. Exp. Immunol. 2009, 155, 156–165. [Google Scholar] [CrossRef]
  178. Dul, M.; Nikolic, T.; Stefanidou, M.; McAteer, M.; Williams, P.; Mous, J.; Roep, B.; Kochba, E.; Levin, Y.; Peakman, M. Conjugation of a peptide autoantigen to gold nanoparticles for intradermally administered antigen specific immunotherapy. Int. J. Pharm. 2019, 562, 303–312. [Google Scholar] [CrossRef]
  179. Nikolic, T.; Zwaginga, J.J.; Uitbeijerse, B.S.; Woittiez, N.J.; de Koning, E.J.; Aanstoot, H.-J.; Roep, B.O. Safety and feasibility of intradermal injection with tolerogenic dendritic cells pulsed with proinsulin peptide—For type 1 diabetes. Lancet Diabetes Endocrinol. 2020, 8, 470–472. [Google Scholar] [CrossRef]
  180. Nicoll, L.H.; Hesby, A. Intramuscular injection: An integrative research review and guideline for evidence-based practice. Appl. Nurs. Res. 2002, 15, 149–162. [Google Scholar] [CrossRef] [PubMed]
  181. Nakajima, Y.; Mukai, K.; Takaoka, K.; Hirose, T.; Morishita, K.; Yamamoto, T.; Yoshida, Y.; Urai, T.; Nakatani, T. Establishing a new appropriate intramuscular injection site in the deltoid muscle. Hum. Vaccin. Immunother. 2017, 13, 2123–2129. [Google Scholar] [CrossRef] [Green Version]
  182. Ogston-Tuck, S. Intramuscular injection technique: An evidence-based approach. Nurs. Stand. 2014, 29, 52–59. [Google Scholar] [CrossRef]
  183. Rodger, M.A.; King, L. Drawing up and administering intramuscular injections: A review of the literature. J. Adv. Nurs. 2000, 31, 574–582. [Google Scholar] [CrossRef] [PubMed]
  184. Kivelä, R.; Havas, E.; Vihko, V. Localisation of lymphatic vessels and vascular endothelial growth factors-C and -D in human and mouse skeletal muscle with immunohistochemistry. Histochem. Cell Biol. 2007, 127, 31–40. [Google Scholar] [CrossRef] [PubMed]
  185. Abai, A.M.; Hobart, P.M.; Barnhart, K.M. Insulin delivery with plasmid DNA. Hum. Gene Ther. 1999, 10, 2637–2649. [Google Scholar] [CrossRef]
  186. Phrommintikul, A.; Kuanprasert, S.; Wongcharoen, W.; Kanjanavanit, R.; Chaiwarith, R.; Sukonthasarn, A. Influenza vaccination reduces cardiovascular events in patients with acute coronary syndrome. Eur. Heart J. 2011, 32, 1730–1735. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  187. Gurfinkel, E.P.; Mendiz, O.; Mautner, B. Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) study. Eur. Heart J. 2004, 25, 25–31. [Google Scholar] [CrossRef] [Green Version]
  188. Vlachopoulos, C.V.; Terentes-Printzios, D.G.; Aznaouridis, K.A.; Pietri, P.G.; Stefanadis, C.I. Association between pneumococcal vaccination and cardiovascular outcomes: A systematic review and meta-analysis of cohort studies. Eur. J. Prev. Cardiol. 2015, 22, 1185–1199. [Google Scholar] [CrossRef]
  189. Monteiro, M.P. Obesity vaccines. Hum. Vaccines Immunother. 2014, 10, 887–895. [Google Scholar] [CrossRef] [Green Version]
  190. Chawla, R.; Madhu, S.; Makkar, B.; Ghosh, S.; Saboo, B.; Kalra, S. RSSDI-ESI clinical practice recommendations for the management of type 2 diabetes mellitus 2020. Int. J. Diabetes Dev. Ctries. 2020, 40, 1–122. [Google Scholar]
  191. Hulot, J.-S.; Ishikawa, K.; Hajjar, R.J. Gene therapy for the treatment of heart failure: Promise postponed. Eur. Heart J. 2016, 37, 1651–1658. [Google Scholar] [CrossRef]
  192. El-Armouche, A.; Eschenhagen, T. β-Adrenergic stimulation and myocardial function in the failing heart. Heart Fail. Rev. 2009, 14, 225. [Google Scholar] [CrossRef] [PubMed]
  193. Rockman, H.A.; Chien, K.R.; Choi, D.-J.; Iaccarino, G.; Hunter, J.J.; Ross, J.; Lefkowitz, R.J.; Koch, W.J. Expression of a β-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc. Natl. Acad. Sci. USA 1998, 95, 7000–7005. [Google Scholar] [CrossRef] [Green Version]
  194. Harding, V.B.; Jones, L.R.; Lefkowitz, R.J.; Koch, W.J.; Rockman, H.A. Cardiac βARK1 inhibition prolongs survival and augments β blocker therapy in a mouse model of severe heart failure. Proc. Natl. Acad. Sci. USA 2001, 98, 5809–5814. [Google Scholar] [CrossRef] [Green Version]
  195. Shah, A.S.; White, D.C.; Emani, S.; Kypson, A.P.; Lilly, R.E.; Wilson, K.; Glower, D.D.; Lefkowitz, R.J.; Koch, W.J. In vivo ventricular gene delivery of a β-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation 2001, 103, 1311–1316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  196. Rengo, G.; Lymperopoulos, A.; Zincarelli, C.; Donniacuo, M.; Soltys, S.; Rabinowitz, J.E.; Koch, W.J. Clinical Perspective. Circulation 2009, 119, 89–98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  197. Tevaearai, H.T.; Eckhart, A.D.; Shotwell, K.F.; Wilson, K.; Koch, W.J. Ventricular dysfunction after cardioplegic arrest is improved after myocardial gene transfer of a β-adrenergic receptor kinase inhibitor. Circulation 2001, 104, 2069–2074. [Google Scholar] [CrossRef]
  198. Raake, P.W.; Schlegel, P.; Ksienzyk, J.; Reinkober, J.; Barthelmes, J.; Schinkel, S.; Pleger, S.; Mier, W.; Haberkorn, U.; Koch, W.J. βARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model. Eur. Heart J. 2013, 34, 1437–1447. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  199. Kawase, Y.; Ly, H.Q.; Prunier, F.; Lebeche, D.; Shi, Y.; Jin, H.; Hadri, L.; Yoneyama, R.; Hoshino, K.; Takewa, Y. Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure. J. Am. Coll. Cardiol. 2008, 51, 1112–1119. [Google Scholar] [CrossRef] [Green Version]
  200. Lyon, A.R.; Bannister, M.L.; Collins, T.; Pearce, E.; Sepehripour, A.H.; Dubb, S.S.; Garcia, E.; O’Gara, P.; Liang, L.; Kohlbrenner, E.; et al. SERCA2a gene transfer decreases sarcoplasmic reticulum calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure. Circulation 2011, 4, 362–372. [Google Scholar] [CrossRef] [Green Version]
  201. Greenberg, B.; Butler, J.; Felker, G.M.; Ponikowski, P.; Voors, A.A.; Desai, A.S.; Barnard, D.; Bouchard, A.; Jaski, B.; Lyon, A.R. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): A randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet 2016, 387, 1178–1186. [Google Scholar] [CrossRef]
  202. Ylä-Herttuala, S. Endgame: Glybera finally recommended for approval as the first gene therapy drug in the European union. Mol. Ther. 2012, 20, 1831–1832. [Google Scholar] [CrossRef] [Green Version]
  203. Burnett, J.R.; Hooper, A.J.; Hegele, R.A. Familial Lipoprotein Lipase Deficiency; GeneReviews®: Seattle, WA, USA, 2017.
  204. Rip, J.; Nierman, M.C.; Sierts, J.A.; Petersen, W.; Den Oever, K.V.; Raalte, D.V.; Ross, C.J.; Hayden, M.R.; Bakker, A.C.; Dijkhuizen, P. Gene therapy for lipoprotein lipase deficiency: Working toward clinical application. Hum. Gene Ther. 2005, 16, 1276–1286. [Google Scholar] [CrossRef]
  205. Bryant, L.M.; Christopher, D.M.; Giles, A.R.; Hinderer, C.; Rodriguez, J.L.; Smith, J.B.; Traxler, E.A.; Tycko, J.; Wojno, A.P.; Wilson, J.M. Lessons learned from the clinical development and market authorization of Glybera. Hum. Gene Ther. Clin. Dev. 2013, 24, 55–64. [Google Scholar] [CrossRef]
  206. Senior, M. After Glybera’s Withdrawal, What’s Next for Gene Therapy? Nature Publishing Group: Berlin, Germany, 2017. [Google Scholar]
  207. Tilemann, L.; Ishikawa, K.; Weber, T.; Hajjar, R.J. Gene therapy for heart failure. Circ. Res. 2012, 110, 777–793. [Google Scholar] [CrossRef] [Green Version]
  208. Huang, L.-H.; Lavine, K.J.; Randolph, G.J. Cardiac Lymphatic Vessels, Transport, and Healing of the Infarcted Heart. JACC Basic Transl. Sci. 2017, 2, 477–483. [Google Scholar] [CrossRef] [PubMed]
  209. Hammond, H.K.; Penny, W.F.; Traverse, J.H.; Henry, T.D.; Watkins, M.W.; Yancy, C.W.; Sweis, R.N.; Adler, E.D.; Patel, A.N.; Murray, D.R. Intracoronary gene transfer of adenylyl cyclase 6 in patients with heart failure: A randomized clinical trial. JAMA Cardiol. 2016, 1, 163–171. [Google Scholar] [CrossRef] [Green Version]
  210. Jessup, M.; Greenberg, B.; Mancini, D.; Cappola, T.; Pauly, D.F.; Jaski, B.; Yaroshinsky, A.; Zsebo, K.M.; Dittrich, H.; Hajjar, R.J. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID) a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation 2011, 124, 304–313. [Google Scholar] [CrossRef] [Green Version]
  211. Hulot, J.S.; Salem, J.E.; Redheuil, A.; Collet, J.P.; Varnous, S.; Jourdain, P.; Logeart, D.; Gandjbakhch, E.; Bernard, C.; Hatem, S.N. Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: Results from the AGENT-HF randomized phase 2 trial. Eur. J. Heart Fail. 2017, 19, 1534–1541. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  212. Precigen Triple-Gene. Precigen Triple-Gene Provides Six-Month Follow-Up Data from Phase I Study of INXN-4001, a Multigenic Investigational Therapeutic Candidate for Heart Failure. 2020. Available online: (accessed on 1 April 2021).
  213. Model, M.I. 425. Arginine and Tetrahydrobiopterin Synergistically Potentiate the Antirestenotic Effect of Vascular Gene Therapy with Inducible Nitric Oxide Synthase. Mol. Ther. 2010, 18, 1. [Google Scholar]
  214. Chung, E.S.; Miller, L.; Patel, A.N.; Anderson, R.D.; Mendelsohn, F.O.; Traverse, J.; Silver, K.H.; Shin, J.; Ewald, G.; Farr, M.J. Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: The STOP-HF randomized Phase II trial. Eur. Heart J. 2015, 36, 2228–2238. [Google Scholar] [CrossRef]
  215. Juventas Therapeutics. Juventas Therapeutics Completes Enrollment of Phase I/II RETRO-HF Trial and Demonstrates Safety for Retrograde Infusion of JVS-100 in Patients with Heart Failure. 2014. Available online: (accessed on 1 May 2021).
  216. Anttila, V.; Saraste, A.; Knuuti, J.; Jaakkola, P.; Hedman, M.; Svedlund, S.; Lagerström-Fermér, M.; Kjaer, M.; Jeppsson, A.; Gan, L.-M.; et al. Synthetic mRNA encoding VEGF-A in patients undergoing coronary artery bypass grafting: Design of a phase 2a clinical trial. Mol. Ther. Methods Clin. Dev. 2020, 18, 464–472. [Google Scholar] [CrossRef]
  217. Gan, L.-M.; Lagerström-Fermér, M.; Carlsson, L.G.; Arfvidsson, C.; Egnell, A.-C.; Rudvik, A.; Kjaer, M.; Collén, A.; Thompson, J.D.; Joyal, J.; et al. Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes. Nat. Commun. 2019, 10, 871. [Google Scholar] [CrossRef]
  218. Ishikawa, K.; Fish, K.M.; Tilemann, L.; Rapti, K.; Aguero, J.; Santos-Gallego, C.G.; Lee, A.; Karakikes, I.; Xie, C.; Akar, F.G. Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure. Mol. Ther. 2014, 22, 2038–2045. [Google Scholar] [CrossRef] [Green Version]
  219. Kim, J.S.; Hwang, H.; Cho, K.; Park, E.; Lee, W.; Paeng, J.; Lee, D.; Kim, H.; Sohn, D.; Kim, K. Intramyocardial transfer of hepatocyte growth factor as an adjunct to CABG: Phase I clinical study. Gene Ther. 2013, 20, 717–722. [Google Scholar] [CrossRef] [Green Version]
  220. Hartikainen, J.; Hassinen, I.; Hedman, A.; Kivelä, A.; Saraste, A.; Knuuti, J.; Husso, M.; Mussalo, H.; Hedman, M.; Rissanen, T.T.; et al. Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: A phase I/IIa study with 1-year follow-up. Eur. Heart J. 2017, 38, 2547–2555. [Google Scholar] [CrossRef] [Green Version]
  221. Liu, J.; Wu, P.; Wang, Y.; Du, Y. Ad-HGF improves the cardiac remodeling of rat following myocardial infarction by upregulating autophagy and necroptosis and inhibiting apoptosis. Am. J. Transl. Res. 2016, 8, 4605. [Google Scholar]
  222. Wang, W.; Wang, M.-Q.; Wang, H.; Gao, W.; Zhang, Z.; Zhao, S.; Xu, H.-Z.; Chen, B.; Zhu, M.-X.; Wu, Z.-Z. Effects of adenovirus-mediated hepatocyte growth factor gene therapy on postinfarct heart function: Comparison of single and repeated injections. Hum. Gene Ther. 2016, 27, 643–651. [Google Scholar] [CrossRef]
  223. Hardy, N.; Viola, H.M.; Johnstone, V.P.; Clemons, T.D.; Cserne Szappanos, H.; Singh, R.; Smith, N.M.; Iyer, K.S.; Hool, L.C. Nanoparticle-mediated dual delivery of an antioxidant and a peptide against the L-Type Ca2+ channel enables simultaneous reduction of cardiac ischemia-reperfusion injury. ACS Nano 2015, 9, 279–289. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  224. Carpentier, A.C.; Frisch, F.; Labbe, S.M.; Gagnon, R.; de Wal, J.; Greentree, S.; Petry, H.; Twisk, J.; Brisson, D.; Gaudet, D. Effect of alipogene tiparvovec (AAV1-LPLS447X) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J. Clin. Endocrinol. 2012, 97, 1635–1644. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  225. Anselmo, A.C.; Mitragotri, S. Nanoparticles in the clinic: An update. Bioeng. Transl. Med. 2019, 4, e10143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  226. Kobayashi, K.; Maeda, K.; Takefuji, M.; Kikuchi, R.; Morishita, Y.; Hirashima, M.; Murohara, T. Dynamics of angiogenesis in ischemic areas of the infarcted heart. Sci. Rep. 2017, 7, 7156. [Google Scholar] [CrossRef] [Green Version]
  227. Post, M.J.; Sato, K.; Murakami, M.; Bao, J.; Tirziu, D.; Pearlman, J.D.; Simons, M. Adenoviral PR39 improves blood flow and myocardial function in a pig model of chronic myocardial ischemia by enhancing collateral formation. Am. J. Physiol. -Regul. Integr. Comp. Physiol. 2006, 290, R494–R500. [Google Scholar] [CrossRef]
  228. Du, C.; Chen, X.-W.; Wang, Z.-M.; Meng, H.-Y.; Li, Y.-F.; Wei, T.-W.; Wang, L.-S. HGF Treatment Promotes Cardiac Function and Cardiac Repair: Meta-analysis of Pig Models with Myocardial Infarction. Res. Sq. 2020. preprint. [Google Scholar] [CrossRef]
  229. Korpisalo, P.; Karvinen, H.; Rissanen, T.T.; Kilpijoki, J.; Marjomäki, V.; Baluk, P.; McDonald, D.M.; Cao, Y.; Eriksson, U.; Alitalo, K. VEGF-A and PDGF-B combination gene therapy prolongs angiogenic effects via recruitment of interstitial mononuclear cells and paracrine effects rather than improved pericyte coverage of angiogenic vessels. Circ. Res. 2008, 103, 1092. [Google Scholar] [CrossRef]
  230. Jin, J.-F.; Zhu, L.-L.; Chen, M.; Xu, H.-M.; Wang, H.-F.; Feng, X.-Q.; Zhu, X.-P.; Zhou, Q. The optimal choice of medication administration route regarding intravenous, intramuscular, and subcutaneous injection. Patient Prefer. Adherence 2015, 9, 923–942. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  231. 2—Intravenous Drug Administration. In Techniques in the Behavioral and Neural Sciences; Claassen, V. (Ed.) Elsevier: Amsterdam, The Netherlands, 1994; Volume 12, pp. 5–22. [Google Scholar]
  232. Xie, Y.; Bagby, T.R.; Cohen, M.S.; Forrest, M.L. Drug delivery to the lymphatic system: Importance in future cancer diagnosis and therapies. Expert Opin. Drug Deliv. 2009, 6, 785–792. [Google Scholar] [CrossRef]
  233. Caliph, S.M.; Trevaskis, N.L.; Charman, W.N.; Porter, C.J. Intravenous dosing conditions may affect systemic clearance for highly lipophilic drugs: Implications for lymphatic transport and absolute bioavailability studies. J. Pharm. Sci. 2012, 101, 3540–3546. [Google Scholar] [CrossRef]
  234. Yadav, P.; McLeod, V.M.; Nowell, C.J.; Selby, L.I.; Johnston, A.P.R.; Kaminskas, L.M.; Trevaskis, N.L. Distribution of therapeutic proteins into thoracic lymph after intravenous administration is protein size-dependent and primarily occurs within the liver and mesentery. J. Control. Release 2018, 272, 17–28. [Google Scholar] [CrossRef]
  235. Cabrales, P.; Han, G.; Roche, C.; Nacharaju, P.; Friedman, A.J.; Friedman, J.M. Sustained release nitric oxide from long-lived circulating nanoparticles. Free Radic. Biol. Med. 2010, 49, 530–538. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  236. Ruiz-Esparza, G.U.; Segura-Ibarra, V.; Cordero-Reyes, A.M.; Youker, K.A.; Serda, R.E.; Cruz-Solbes, A.S.; Amione-Guerra, J.; Yokoi, K.; Kirui, D.K.; Cara, F.E. A specifically designed nanoconstruct associates, internalizes, traffics in cardiovascular cells, and accumulates in failing myocardium: A new strategy for heart failure diagnostics and therapeutics. Eur. J. Heart Fail. 2016, 18, 169–178. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  237. Marrella, A.; Iafisco, M.; Adamiano, A.; Rossi, S.; Aiello, M.; Barandalla-Sobrados, M.; Carullo, P.; Miragoli, M.; Tampieri, A.; Scaglione, S. A combined low-frequency electromagnetic and fluidic stimulation for a controlled drug release from superparamagnetic calcium phosphate nanoparticles: Potential application for cardiovascular diseases. J. R. Soc. Interface 2018, 15, 20180236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  238. Maxwell, J.T.; Somasuntharam, I.; Gray, W.D.; Shen, M.; Singer, J.M.; Wang, B.; Saafir, T.; Crawford, B.H.; Jiang, R.; Murthy, N. Bioactive nanoparticles improve calcium handling in failing cardiac myocytes. Nanomedicine 2015, 10, 3343–3357. [Google Scholar] [CrossRef]
  239. Avula, U.M.R.; Kim, G.; Lee, Y.-E.K.; Morady, F.; Kopelman, R.; Kalifa, J. Cell-specific nanoplatform-enabled photodynamic therapy for cardiac cells. Heart Rhythm. 2012, 9, 1504–1509. [Google Scholar] [CrossRef] [Green Version]
  240. Onwordi, E.N.; Gamal, A.; Zaman, A. Anticoagulant Therapy for Acute Coronary Syndromes. Interv. Cardiol. 2018, 13, 87–92. [Google Scholar] [CrossRef] [Green Version]
  241. Liu, G.; Li, L.; Huo, D.; Li, Y.; Wu, Y.; Zeng, L.; Cheng, P.; Xing, M.; Zeng, W.; Zhu, C. A VEGF delivery system targeting MI improves angiogenesis and cardiac function based on the tropism of MSCs and layer-by-layer self-assembly. Biomaterials 2017, 127, 117–131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  242. Majmudar, M.D.; Keliher, E.J.; Heidt, T.; Leuschner, F.; Truelove, J.; Sena, B.F.; Gorbatov, R.; Iwamoto, Y.; Dutta, P.; Wojtkiewicz, G. Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice. Circulation 2013, 127, 2038–2046. [Google Scholar] [CrossRef] [Green Version]
  243. Ottersbach, A.; Mykhaylyk, O.; Heidsieck, A.; Eberbeck, D.; Rieck, S.; Zimmermann, K.; Breitbach, M.; Engelbrecht, B.; Brügmann, T.; Hesse, M. Improved heart repair upon myocardial infarction: Combination of magnetic nanoparticles and tailored magnets strongly increases engraftment of myocytes. Biomaterials 2018, 155, 176–190. [Google Scholar] [CrossRef] [PubMed]
  244. Chang, M.-Y.; Yang, Y.-J.; Chang, C.-H.; Tang, A.C.; Liao, W.-Y.; Cheng, F.-Y.; Yeh, C.-S.; Lai, J.J.; Stayton, P.S.; Hsieh, P.C. Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction. J. Control. Release 2013, 170, 287–294. [Google Scholar] [CrossRef]
  245. Nagaoka, K.; Matoba, T.; Mao, Y.; Nakano, Y.; Ikeda, G.; Egusa, S.; Tokutome, M.; Nagahama, R.; Nakano, K.; Sunagawa, K. A new therapeutic modality for acute myocardial infarction: Nanoparticle-mediated delivery of pitavastatin induces cardioprotection from ischemia-reperfusion injury via activation of PI3K/Akt pathway and anti-inflammation in a rat model. PLoS ONE 2015, 10, e0132451. [Google Scholar] [CrossRef]
  246. Kassim, S.H.; Li, H.; Bell, P.; Somanathan, S.; Lagor, W.; Jacobs, F.; Billheimer, J.; Wilson, J.M.; Rader, D.J. Adeno-associated virus serotype 8 gene therapy leads to significant lowering of plasma cholesterol levels in humanized mouse models of homozygous and heterozygous familial hypercholesterolemia. Hum. Gene Ther. 2013, 24, 19–26. [Google Scholar] [CrossRef] [Green Version]
  247. Greig, J.A.; Limberis, M.P.; Bell, P.; Chen, S.-J.; Calcedo, R.; Rader, D.J.; Wilson, J.M. Nonclinical pharmacology/toxicology study of AAV8. TBG. mLDLR and AAV8. TBG. hLDLR in a mouse model of homozygous familial hypercholesterolemia. Hum. Gene Ther. Clin. Dev. 2017, 28, 28–38. [Google Scholar] [CrossRef]
  248. Fitzgerald, K.; Frank-Kamenetsky, M.; Shulga-Morskaya, S.; Liebow, A.; Bettencourt, B.R.; Sutherland, J.E.; Hutabarat, R.M.; Clausen, V.A.; Karsten, V.; Cehelsky, J. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: A randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 2014, 383, 60–68. [Google Scholar] [CrossRef] [Green Version]
  249. Nicolau, C.; Le Pape, A.; Soriano, P.; Fargette, F.; Juhel, M.-F. In vivo expression of rat insulin after intravenous administration of the liposome-entrapped gene for rat insulin I. Proc. Natl. Acad. Sci. USA 1983, 80, 1068–1072. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  250. Shifrin, A.; Auricchio, A.; Yu, Q.; Wilson, J.; Raper, S. Adenoviral vector-mediated insulin gene transfer in the mouse pancreas corrects streptozotocin-induced hyperglycemia. Gene Ther. 2001, 8, 1480–1489. [Google Scholar] [CrossRef] [Green Version]
  251. Mas, A.; Montané, J.; Anguela, X.M.; Muñoz, S.; Douar, A.M.; Riu, E.; Otaegui, P.; Bosch, F. Reversal of type 1 diabetes by engineering a glucose sensor in skeletal muscle. Diabetes 2006, 55, 1546–1553. [Google Scholar] [CrossRef] [Green Version]
  252. Oh, T.K.; Li, M.Z.; Kim, S.T. Gene therapy for diabetes mellitus in rats by intramuscular injection of lentivirus containing insulin gene. Diabetes Res. Clin. Pract. 2006, 71, 233–240. [Google Scholar] [CrossRef] [PubMed]
  253. Muzzin, P.; Eisensmith, R.C.; Copeland, K.C.; Woo, S.L. Hepatic insulin gene expression as treatment for type 1 diabetes mellitus in rats. Mol. Endocrinol. 1997, 11, 833–837. [Google Scholar] [CrossRef]
  254. Thule, P.; Liu, J. Regulated hepatic insulin gene therapy of STZ-diabetic rats. Gene Ther. 2000, 7, 1744–1752. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  255. Park, Y.M.; Woo, S.; Lee, G.T.; Ko, J.Y.; Lee, Y.; Zhao, Z.S.; Kim, H.J.; Ahn, C.W.; Cha, B.S.; Kim, K.S.; et al. Safety and efficacy of adeno-associated viral vector-mediated insulin gene transfer via portal vein to the livers of streptozotocin-induced diabetic Sprague-Dawley rats. J. Gene Med. 2005, 7, 621–629. [Google Scholar] [CrossRef]
  256. Cheung, A.T.; Dayanandan, B.; Lewis, J.T.; Korbutt, G.S.; Rajotte, R.V.; Bryer-Ash, M.; Boylan, M.O.; Wolfe, M.M.; Kieffer, T.J. Glucose-dependent insulin release from genetically engineered K cells. Science 2000, 290, 1959–1962. [Google Scholar] [CrossRef]
  257. Encina, G.; Ezquer, F.; Conget, P.; Israel, Y. Insulin is secreted upon glucose stimulation by both gastrointestinal enteroendocrine K-cells and L-cells engineered with the preproinsulin gene. Biol. Res. 2011, 44, 301–305. [Google Scholar] [CrossRef] [Green Version]
  258. Thulé, P.M.; Campbell, A.G.; Jia, D.; Lin, Y.; You, S.; Paveglio, S.; Olson, D.E.; Kozlowski, M. Long-term glycemic control with hepatic insulin gene therapy in streptozotocin-diabetic mice. J. Gene Med. 2015, 17, 141–152. [Google Scholar] [CrossRef]
  259. Chatenoud, L.; Primo, J.; Bach, J.-F. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J. Immunol. 1997, 158, 2947–2954. [Google Scholar] [PubMed]
  260. von Herrath, M.G.; Coon, B.; Wolfe, T.; Chatenoud, L. Nonmitogenic CD3 antibody reverses virally induced (rat insulin promoter-lymphocytic choriomeningitis virus) autoimmune diabetes without impeding viral clearance. J. Immunol. 2002, 168, 933–941. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  261. Herold, K.C.; Hagopian, W.; Auger, J.A.; Poumian-Ruiz, E.; Taylor, L.; Donaldson, D.; Gitelman, S.E.; Harlan, D.M.; Xu, D.; Zivin, R.A. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 2002, 346, 1692–1698. [Google Scholar] [CrossRef] [Green Version]
  262. Herold, K.C.; Gitelman, S.E.; Ehlers, M.R.; Gottlieb, P.A.; Greenbaum, C.J.; Hagopian, W.; Boyle, K.D.; Keyes-Elstein, L.; Aggarwal, S.; Phippard, D. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: Metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes 2013, 62, 3766–3774. [Google Scholar] [CrossRef] [Green Version]
  263. Herold, K.C.; Gitelman, S.E.; Masharani, U.; Hagopian, W.; Bisikirska, B.; Donaldson, D.; Rother, K.; Diamond, B.; Harlan, D.M.; Bluestone, J.A. A single course of anti-CD3 monoclonal antibody hOKT3γ1 (Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005, 54, 1763–1769. [Google Scholar] [CrossRef] [Green Version]
  264. Zhang, Y.C.; Bui, J.D.; Shen, L.; Phillips, M.I. Antisense inhibition of β1-adrenergic receptor mRNA in a single dose produces a profound and prolonged reduction in high blood pressure in spontaneously hypertensive rats. Circulation 2000, 101, 682–688. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  265. Huang, H.; Li, X.; Zheng, S.; Chen, Y.; Chen, C.; Wang, J.; Tong, H.; Zhou, L.; Yang, J.; Zeng, C. Downregulation of Renal G Protein–Coupled Receptor Kinase Type 4 Expression via Ultrasound-Targeted Microbubble Destruction Lowers Blood Pressure in Spontaneously Hypertensive Rats. J. Am. Heart Assoc. 2016, 5, e004028. [Google Scholar] [CrossRef]
  266. Paulis, L.; Franke, H.; Simko, F. Gene therapy for hypertension. Expert Opin. Biol. Ther. 2017, 17, 1345–1361. [Google Scholar] [CrossRef] [PubMed]
  267. Lázár, E.; Sadek, H.A.; Bergmann, O. Cardiomyocyte renewal in the human heart: Insights from the fall-out. Eur. Heart J. 2017, 38, 2333–2342. [Google Scholar] [CrossRef] [Green Version]
  268. Torchilin, V.; Klibanov, A.; Huang, L.; O’Donnell, S.; Nossiff, N.; Khaw, B. Targeted accumulation of polyethylene glycol-coated immunoliposomes in infarcted rabbit myocardium. FASEB J. 1992, 6, 2716–2719. [Google Scholar] [CrossRef]
  269. Scott, R.C.; Rosano, J.M.; Ivanov, Z.; Wang, B.; Chong, P.L.-G.; Issekutz, A.C.; Crabbe, D.L.; Kiani, M.F. Targeting VEGF-encapsulated immunoliposomes to MI heart improves vascularity and cardiac function. FASEB J. 2009, 23, 3361–3367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  270. Ko, Y.; Hartner, W.; Kale, A.; Torchilin, V. Gene delivery into ischemic myocardium by double-targeted lipoplexes with anti-myosin antibody and TAT peptide. Gene Ther. 2009, 16, 52–59. [Google Scholar] [CrossRef]
  271. Dvir, T.; Bauer, M.; Schroeder, A.; Tsui, J.H.; Anderson, D.G.; Langer, R.; Liao, R.; Kohane, D.S. Nanoparticles targeting the infarcted heart. Nano Lett. 2011, 11, 4411–4414. [Google Scholar] [CrossRef] [Green Version]
  272. Pannu, H.K.; Oliphant, M. The subperitoneal space and peritoneal cavity: Basic concepts. Abdom. Imaging 2015, 40, 2710–2722. [Google Scholar] [CrossRef] [Green Version]
  273. Al Shoyaib, A.; Archie, S.R.; Karamyan, V.T. Intraperitoneal Route of Drug Administration: Should it Be Used in Experimental Animal Studies? Pharm. Res. 2020, 37, 12. [Google Scholar] [CrossRef] [PubMed]
  274. Michailova, K.N.; Usunoff, K.G. Serosal Membranes (Pleura, Pericardium, Peritoneum): Normal Structure, Development and Experimental Pathology; Springer Science & Business Media: Berlin/Heidelberg, Germany, 2006; Volume 183. [Google Scholar]
  275. Lee, G.; Han, S.; Inocencio, I.; Cao, E.; Hong, J.; Phillips, A.R.J.; Windsor, J.A.; Porter, C.J.H.; Trevaskis, N.L. Lymphatic Uptake of Liposomes after Intraperitoneal Administration Primarily Occurs via the Diaphragmatic Lymphatics and is Dependent on Liposome Surface Properties. Mol. Pharm. 2019, 16, 4987–4999. [Google Scholar] [CrossRef]
  276. Torres, I.; Litterst, C.; Guarino, A. Transport of model compounds across the peritoneal membrane in the rat. Pharmacology 1978, 17, 330–340. [Google Scholar] [CrossRef]
  277. Turner, P.V.; Brabb, T.; Pekow, C.; Vasbinder, M.A. Administration of substances to laboratory animals: Routes of administration and factors to consider. J. Am. Assoc. Lab. Anim. Sci. 2011, 50, 600–613. [Google Scholar] [PubMed]
  278. Alberts, D.S.; Liu, P.; Hannigan, E.V.; O’Toole, R.; Williams, S.D.; Young, J.A.; Franklin, E.W.; Clarke-Pearson, D.L.; Malviya, V.K.; DuBeshter, B. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N. Engl. J. Med. 1996, 335, 1950–1955. [Google Scholar] [CrossRef]
  279. Armstrong, D.K.; Bundy, B.; Wenzel, L.; Huang, H.Q.; Baergen, R.; Lele, S.; Copeland, L.J.; Walker, J.L.; Burger, R.A. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N. Engl. J. Med. 2006, 354, 34–43. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  280. National Cancer Institute. NCI Clinical Announcement on Intraperitoneal Chemotherapy for Ovarian Cancer. 2006. Available online: (accessed on 1 May 2021).
  281. Maranhão, R.C.; Guido, M.C.; de Lima, A.D.; Tavares, E.R.; Marques, A.F.; de Melo, M.D.T.; Nicolau, J.C.; Salemi, V.M.; Kalil-Filho, R. Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats. Int. J. Nanomed. 2017, 12, 3767. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  282. Losordo, D.W.; Vale, P.R.; Hendel, R.C.; Milliken, C.E.; Fortuin, F.D.; Cummings, N.; Schatz, R.A.; Asahara, T.; Isner, J.M.; Kuntz, R.E. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation 2002, 105, 2012–2018. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  283. Reilly, J.P.; Grise, M.A.; Fortuin, F.D.; Vale, P.R.; Schaer, G.L.; Lopez, J.; Van Camp, J.R.; Henry, T.; Richenbacher, W.E.; Losordo, D.W.; et al. Long-term (2-year) clinical events following transthoracic intramyocardial gene transfer of VEGF-2 in no-option patients. J. Interv. Cardiol. 2005, 18, 27–31. [Google Scholar] [CrossRef]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Tessier, N.; Moawad, F.; Amri, N.; Brambilla, D.; Martel, C. Focus on the Lymphatic Route to Optimize Drug Delivery in Cardiovascular Medicine. Pharmaceutics 2021, 13, 1200.

AMA Style

Tessier N, Moawad F, Amri N, Brambilla D, Martel C. Focus on the Lymphatic Route to Optimize Drug Delivery in Cardiovascular Medicine. Pharmaceutics. 2021; 13(8):1200.

Chicago/Turabian Style

Tessier, Nolwenn, Fatma Moawad, Nada Amri, Davide Brambilla, and Catherine Martel. 2021. "Focus on the Lymphatic Route to Optimize Drug Delivery in Cardiovascular Medicine" Pharmaceutics 13, no. 8: 1200.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop