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Pharmaceutics, Volume 15, Issue 3 (March 2023) – 316 articles

Cover Story (view full-size image): The delivery of many drugs to the brain is limited by the blood–brain barrier (BBB). Nanoparticle (NP) technologies may be developed to provide targeted drug delivery with controlled release. Polymeric and lipid-based NPs have emerged as versatile and biocompatible materials that provide requisite protection for drugs and improve drug entry to the brain at the BBB. Intranasal drug delivery has been found to bypass the BBB. The details of the pharmacokinetic and pharmacodynamics of drugs associated with drug delivery via intranasal drug-loaded polymeric and lipid-based NPs are emerging from preclinical studies. A combinatory approach of nose-to-brain administration and drug-loaded polymeric and lipid-based NPs is a promising strategy for enhancing drug targeting to the brain. View this paper
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15 pages, 8021 KiB  
Article
Block Copolymer Micelles Encapsulating Au(III) Bis(Dithiolene) Complexes as Promising Nanostructures with Antiplasmodial Activity
by Joana F. Santos, Raquel Azevedo, Miguel Prudêncio, Fernanda Marques, Yann Le Gal, Dominique Lorcy and Célia Fernandes
Pharmaceutics 2023, 15(3), 1030; https://doi.org/10.3390/pharmaceutics15031030 - 22 Mar 2023
Cited by 3 | Viewed by 1649
Abstract
Block copolymer micelles (BCMs) can be used to improve the solubility of lipophilic drugs and increase their circulation half-life. Hence, BCMs assembled from MePEG-b-PCL were evaluated as drug delivery systems of gold(III) bis(dithiolene) complexes (herein AuS and AuSe) to be employed [...] Read more.
Block copolymer micelles (BCMs) can be used to improve the solubility of lipophilic drugs and increase their circulation half-life. Hence, BCMs assembled from MePEG-b-PCL were evaluated as drug delivery systems of gold(III) bis(dithiolene) complexes (herein AuS and AuSe) to be employed as antiplasmodial drugs. These complexes exhibited remarkable antiplasmodial activity against liver stages of the Plasmodium berghei parasite, and low toxicity in a model of zebrafish embryos. To improve the complexes’ solubility, BCMs were loaded with AuS, AuSe, and the reference drug primaquine (PQ). PQ-BCMs (Dh = 50.9 ± 2.8 nm), AuSe-BCMs (Dh = 87.1 ± 9.7 nm), and AuS-BCMs (Dh = 72.8 ± 3.1 nm) were obtained with a loading efficiency of 82.5%, 55.5%, and 77.4%, respectively. HPLC analysis and UV–Vis spectrophotometry showed that the compounds did not suffer degradation after encapsulation in BCMs. In vitro release studies suggest that AuS/AuSe-BCMs present a more controlled release compared with PQ-loaded BCMs. The antiplasmodial hepatic activity of the drugs was assessed in vitro and results indicate that both complexes present higher inhibitory activity than PQ, although encapsulated AuS and AuSe presented lower activity than their non-encapsulated counterparts. Nevertheless, these results suggest that the use of BCMs as delivery vehicles for lipophilic metallodrugs, particularly AuS and AuSe, could enable the controlled release of complexes and improve their biocompatibility, constituting a promising alternative to conventional antimalarial treatments. Full article
(This article belongs to the Special Issue Functional Polymers for Drug and Gene Delivery)
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16 pages, 1225 KiB  
Review
Apelin Is a Prototype of Novel Drugs for the Treatment of Acute Myocardial Infarction and Adverse Myocardial Remodeling
by Sergey V. Popov, Leonid N. Maslov, Alexandr V. Mukhomedzyanov, Boris K. Kurbatov, Alexandr S. Gorbunov, Michail Kilin, Viacheslav N. Azev, Maria S. Khlestkina and Galina Z. Sufianova
Pharmaceutics 2023, 15(3), 1029; https://doi.org/10.3390/pharmaceutics15031029 - 22 Mar 2023
Cited by 5 | Viewed by 2135
Abstract
In-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) is 5–6%. Consequently, it is necessary to develop fundamentally novel drugs capable of reducing mortality in patients with acute myocardial infarction. Apelins could be the prototype for such drugs. Chronic administration of apelins [...] Read more.
In-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) is 5–6%. Consequently, it is necessary to develop fundamentally novel drugs capable of reducing mortality in patients with acute myocardial infarction. Apelins could be the prototype for such drugs. Chronic administration of apelins mitigates adverse myocardial remodeling in animals with myocardial infarction or pressure overload. The cardioprotective effect of apelins is accompanied by blockage of the MPT pore, GSK-3β, and the activation of PI3-kinase, Akt, ERK1/2, NO-synthase, superoxide dismutase, glutathione peroxidase, matrix metalloproteinase, the epidermal growth factor receptor, Src kinase, the mitoKATP channel, guanylyl cyclase, phospholipase C, protein kinase C, the Na+/H+ exchanger, and the Na+/Ca2+ exchanger. The cardioprotective effect of apelins is associated with the inhibition of apoptosis and ferroptosis. Apelins stimulate the autophagy of cardiomyocytes. Synthetic apelin analogues are prospective compounds for the development of novel cardioprotective drugs. Full article
(This article belongs to the Section Biologics and Biosimilars)
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14 pages, 6350 KiB  
Article
Antiviral Mechanisms of N-Phenyl Benzamides on Coxsackie Virus A9
by Mira Laajala, Kerttu Kalander, Sara Consalvi, Olivier Sheik Amamuddy, Özlem Tastan Bishop, Mariangela Biava, Giovanna Poce and Varpu Marjomäki
Pharmaceutics 2023, 15(3), 1028; https://doi.org/10.3390/pharmaceutics15031028 - 22 Mar 2023
Cited by 2 | Viewed by 1967
Abstract
Enteroviruses are one of the most abundant groups of viruses infecting humans, and yet there are no approved antivirals against them. To find effective antiviral compounds against enterovirus B group viruses, an in-house chemical library was screened. The most effective compounds against Coxsackieviruses [...] Read more.
Enteroviruses are one of the most abundant groups of viruses infecting humans, and yet there are no approved antivirals against them. To find effective antiviral compounds against enterovirus B group viruses, an in-house chemical library was screened. The most effective compounds against Coxsackieviruses B3 (CVB3) and A9 (CVA9) were CL212 and CL213, two N-phenyl benzamides. Both compounds were more effective against CVA9 and CL213 gave a better EC50 value of 1 µM with high a specificity index of 140. Both drugs were most effective when incubated directly with viruses suggesting that they mainly bound to the virions. A real-time uncoating assay showed that the compounds stabilized the virions and radioactive sucrose gradient as well as TEM confirmed that the viruses stayed intact. A docking assay, taking into account larger areas around the 2-and 3-fold axes of CVA9 and CVB3, suggested that the hydrophobic pocket gives the strongest binding to CVA9 but revealed another binding site around the 3-fold axis which could contribute to the binding of the compounds. Together, our data support a direct antiviral mechanism against the virus capsid and suggest that the compounds bind to the hydrophobic pocket and 3-fold axis area resulting in the stabilization of the virion. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)
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17 pages, 4721 KiB  
Article
Development and Characterization of Pullulan-Based Orodispersible Films of Iron
by Maram Suresh Gupta, Tegginamath Pramod Kumar, Dinesh Reddy, Kamla Pathak, Devegowda Vishakante Gowda, A. V. Naresh Babu, Alhussain H. Aodah, El-Sayed Khafagy, Hadil Faris Alotaibi, Amr Selim Abu Lila, Afrasim Moin and Talib Hussin
Pharmaceutics 2023, 15(3), 1027; https://doi.org/10.3390/pharmaceutics15031027 - 22 Mar 2023
Cited by 4 | Viewed by 2606
Abstract
Iron deficiency is the principal cause of nutritional anemia and it constitutes a major health problem, especially during pregnancy. Despite the availability of various non-invasive traditional oral dosage forms such as tablets, capsules, and liquid preparations of iron, they are hard to consume [...] Read more.
Iron deficiency is the principal cause of nutritional anemia and it constitutes a major health problem, especially during pregnancy. Despite the availability of various non-invasive traditional oral dosage forms such as tablets, capsules, and liquid preparations of iron, they are hard to consume for special populations such as pregnant women, pediatric, and geriatric patients with dysphagia and vomiting tendency. The objective of the present study was to develop and characterize pullulan-based iron-loaded orodispersible films (i-ODFs). Microparticles of iron were formulated by a microencapsulation technique, to mask the bitter taste of iron, and ODFs were fabricated by a modified solvent casting method. Morphological characteristics of the microparticles were identified by optical microscopy and the percentage of iron loading was evaluated by inductively coupled plasma optical emission spectroscopy (ICP-OES). The fabricated i-ODFs were evaluated for their morphology by scanning electron microscopy. Other parameters including thickness, folding endurance, tensile strength, weight variation, disintegration time, percentage moisture loss, surface pH, and in vivo animal safety were evaluated. Lastly, stability studies were carried out at a temperature of 25 °C/60% RH. The results of the study confirmed that pullulan-based i-ODFs had good physicochemical properties, excellent disintegration time, and optimal stability at specified storage conditions. Most importantly, the i-ODFs were free from irritation when administered to the tongue as confirmed by the hamster cheek pouch model and surface pH determination. Collectively, the present study suggests that the film-forming agent, pullulan, could be successfully employed on a lab scale to formulate orodispersible films of iron. In addition, i-ODFs can be processed easily on a large scale for commercial use. Full article
(This article belongs to the Special Issue Dosage Form Design for Oral Drug Delivery)
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16 pages, 2022 KiB  
Article
Caveolin-Mediated Internalization of Fmoc-FF Nanogels in Breast Cancer Cell Lines
by Giovanni Smaldone, Elisabetta Rosa, Enrico Gallo, Carlo Diaferia, Giancarlo Morelli, Mariano Stornaiuolo and Antonella Accardo
Pharmaceutics 2023, 15(3), 1026; https://doi.org/10.3390/pharmaceutics15031026 - 22 Mar 2023
Cited by 6 | Viewed by 2033
Abstract
Introduction: Hydrogel nanoparticles, also known as nanogels (NGs), have been recently proposed as alternative supramolecular vehicles for the delivery of biologically relevant molecules like anticancer drugs and contrast agents. The inner compartment of peptide based NGs can be opportunely modified according to the [...] Read more.
Introduction: Hydrogel nanoparticles, also known as nanogels (NGs), have been recently proposed as alternative supramolecular vehicles for the delivery of biologically relevant molecules like anticancer drugs and contrast agents. The inner compartment of peptide based NGs can be opportunely modified according to the chemical features of the cargo, thus improving its loading and release. A full understanding of the intracellular mechanism involved in nanogel uptake by cancer cells and tissues would further contribute to the potential diagnostic and clinical applications of these nanocarriers, allowing the fine tuning of their selectivity, potency, and activity. The structural characterization of nanogels were assessed by Dynamic Light Scattering (DLS) and Nanoparticles Tracking Analysis (NTA) analysis. Cells viability of Fmoc-FF nanogels was evaluated by MTT assay on six breast cancer cell lines at different incubation times (24, 48, and 72 h) and peptide concentrations (in the range 6.25 × 10−4 ÷ 5·10−3 × wt%). The cell cycle and mechanisms involved in Fmoc-FF nanogels intracellular uptake were evaluated using flow cytometry and confocal analysis, respectively. Fmoc-FF nanogels, endowed with a diameter of ~130 nm and a zeta potential of ~−20.0/−25.0 mV, enter cancer cells via caveolae, mostly those responsible for albumin uptake. The specificity of the machinery used by Fmoc-FF nanogels confers a selectivity toward cancer cell lines overexpressing the protein caveolin1 and efficiently performing caveolae-mediated endocytosis. Full article
(This article belongs to the Special Issue Nanotechnology-Based Drug Delivery Systems)
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22 pages, 2890 KiB  
Review
Nanotechnology in Cancer Diagnosis and Treatment
by Noor Alrushaid, Firdos Alam Khan, Ebtesam Abdullah Al-Suhaimi and Abdelhamid Elaissari
Pharmaceutics 2023, 15(3), 1025; https://doi.org/10.3390/pharmaceutics15031025 - 22 Mar 2023
Cited by 29 | Viewed by 14841
Abstract
Traditional cancer diagnosis has been aided by the application of nanoparticles (NPs), which have made the process easier and faster. NPs possess exceptional properties such as a larger surface area, higher volume proportion, and better targeting capabilities. Additionally, their low toxic effect on [...] Read more.
Traditional cancer diagnosis has been aided by the application of nanoparticles (NPs), which have made the process easier and faster. NPs possess exceptional properties such as a larger surface area, higher volume proportion, and better targeting capabilities. Additionally, their low toxic effect on healthy cells enhances their bioavailability and t-half by allowing them to functionally penetrate the fenestration of epithelium and tissues. These particles have attracted attention in multidisciplinary areas, making them the most promising materials in many biomedical applications, especially in the treatment and diagnosis of various diseases. Today, many drugs are presented or coated with nanoparticles for the direct targeting of tumors or diseased organs without harming normal tissues/cells. Many types of nanoparticles, such as metallic, magnetic, polymeric, metal oxide, quantum dots, graphene, fullerene, liposomes, carbon nanotubes, and dendrimers, have potential applications in cancer treatment and diagnosis. In many studies, nanoparticles have been reported to show intrinsic anticancer activity due to their antioxidant action and cause an inhibitory effect on the growth of tumors. Moreover, nanoparticles can facilitate the controlled release of drugs and increase drug release efficiency with fewer side effects. Nanomaterials such as microbubbles are used as molecular imaging agents for ultrasound imaging. This review discusses the various types of nanoparticles that are commonly used in cancer diagnosis and treatment. Full article
(This article belongs to the Special Issue Study of Nanoparticles for Photodynamic Therapy and Imaging)
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18 pages, 1015 KiB  
Review
The Potential Use of Exosomes in Anti-Cancer Effect Induced by Polarized Macrophages
by Chizumi Abe, Maharshi Bhaswant, Teruo Miyazawa and Taiki Miyazawa
Pharmaceutics 2023, 15(3), 1024; https://doi.org/10.3390/pharmaceutics15031024 - 22 Mar 2023
Cited by 3 | Viewed by 2269
Abstract
The rapid development of aberrant cells outgrowing their normal bounds, which can subsequently infect other body parts and spread to other organs—a process known as metastasis—is one of the significant characteristics of cancer. The main reason why cancer patients die is because of [...] Read more.
The rapid development of aberrant cells outgrowing their normal bounds, which can subsequently infect other body parts and spread to other organs—a process known as metastasis—is one of the significant characteristics of cancer. The main reason why cancer patients die is because of widespread metastases. This abnormal cell proliferation varies in cancers of over a hundred types, and their response to treatment can vary substantially. Several anti-cancer drugs have been discovered to treat various tumors, yet they still have harmful side-effects. Finding novel, highly efficient targeted therapies based on modifications in the molecular biology of tumor cells is essential to reduce the indiscriminate destruction of healthy cells. Exosomes, an extracellular vesicle, are promising as a drug carrier for cancer therapy due to their good tolerance in the body. In addition, the tumor microenvironment is a potential target to regulate in cancer treatment. Therefore, macrophages are polarized toward M1 and M2 phenotypes, which are involved in cancer proliferation and are malignant. It is evident from recent studies that controlled macrophage polarization might contribute to cancer treatment, by the direct way of using miRNA. This review provides an insight into the potential use of exosomes to develop an ‘indirect’, more natural, and harmless cancer treatment through regulating macrophage polarization. Full article
(This article belongs to the Special Issue Nanomedicine to Enhance Innate and Adaptive Anticancer Immunity)
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18 pages, 3096 KiB  
Article
An Enhanced Dissolving Cyclosporin-A Inhalable Powder Efficiently Reduces SARS-CoV-2 Infection In Vitro
by Davide D’Angelo, Eride Quarta, Stefania Glieca, Giada Varacca, Lisa Flammini, Simona Bertoni, Martina Brandolini, Vittorio Sambri, Laura Grumiro, Giulia Gatti, Giorgio Dirani, Francesca Taddei, Annalisa Bianchera, Fabio Sonvico, Ruggero Bettini and Francesca Buttini
Pharmaceutics 2023, 15(3), 1023; https://doi.org/10.3390/pharmaceutics15031023 - 22 Mar 2023
Viewed by 1782
Abstract
This work illustrates the development of a dry inhalation powder of cyclosporine-A for the prevention of rejection after lung transplantation and for the treatment of COVID-19. The influence of excipients on the spray-dried powder’s critical quality attributes was explored. The best-performing powder in [...] Read more.
This work illustrates the development of a dry inhalation powder of cyclosporine-A for the prevention of rejection after lung transplantation and for the treatment of COVID-19. The influence of excipients on the spray-dried powder’s critical quality attributes was explored. The best-performing powder in terms of dissolution time and respirability was obtained starting from a concentration of ethanol of 45% (v/v) in the feedstock solution and 20% (w/w) of mannitol. This powder showed a faster dissolution profile (Weibull dissolution time of 59.5 min) than the poorly soluble raw material (169.0 min). The powder exhibited a fine particle fraction of 66.5% and an MMAD of 2.97 µm. The inhalable powder, when tested on A549 and THP-1, did not show cytotoxic effects up to a concentration of 10 µg/mL. Furthermore, the CsA inhalation powder showed efficiency in reducing IL-6 when tested on A549/THP-1 co-culture. A reduction in the replication of SARS-CoV-2 on Vero E6 cells was observed when the CsA powder was tested adopting the post-infection or simultaneous treatment. This formulation could represent a therapeutic strategy for the prevention of lung rejection, but is also a viable approach for the inhibition of SARS-CoV-2 replication and the COVID-19 pulmonary inflammatory process. Full article
(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)
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13 pages, 1130 KiB  
Article
Does Cytokine-Release Syndrome Induced by CAR T-Cell Treatment Have an Impact on the Pharmacokinetics of Meropenem and Piperacillin/Tazobactam in Patients with Hematological Malignancies? Findings from an Observational Case-Control Study
by Chun Liu, Pier Giorgio Cojutti, Maddalena Giannella, Marcello Roberto, Beatrice Casadei, Gianluca Cristiano, Cristina Papayannidis, Nicola Vianelli, Pier Luigi Zinzani, Pierluigi Viale, Francesca Bonifazi and Federico Pea
Pharmaceutics 2023, 15(3), 1022; https://doi.org/10.3390/pharmaceutics15031022 - 22 Mar 2023
Viewed by 1942
Abstract
Chimeric antigen receptor (CAR) T-cell therapy is a promising approach for some relapse/refractory hematological B-cell malignancies; however, in most patients, cytokine release syndrome (CRS) may occur. CRS is associated with acute kidney injury (AKI) that may affect the pharmacokinetics of some beta-lactams. The [...] Read more.
Chimeric antigen receptor (CAR) T-cell therapy is a promising approach for some relapse/refractory hematological B-cell malignancies; however, in most patients, cytokine release syndrome (CRS) may occur. CRS is associated with acute kidney injury (AKI) that may affect the pharmacokinetics of some beta-lactams. The aim of this study was to assess whether the pharmacokinetics of meropenem and piperacillin may be affected by CAR T-cell treatment. The study included CAR T-cell treated patients (cases) and oncohematological patients (controls), who were administered 24-h continuous infusion (CI) meropenem or piperacillin/tazobactam, optimized by therapeutic drug monitoring, over a 2-year period. Patient data were retrospectively retrieved and matched on a 1:2 ratio. Beta-lactam clearance (CL) was calculated as CL = daily dose/infusion rate. A total of 38 cases (of whom 14 and 24 were treated with meropenem and piperacillin/tazobactam, respectively) was matched with 76 controls. CRS occurred in 85.7% (12/14) and 95.8% (23/24) of patients treated with meropenem and piperacillin/tazobactam, respectively. CRS-induced AKI was observed in only 1 patient. CL did not differ between cases and controls for both meropenem (11.1 vs. 11.7 L/h, p = 0.835) and piperacillin (14.0 vs. 10.4 L/h, p = 0.074). Our findings suggest that 24-h CI meropenem and piperacillin dosages should not be reduced a priori in CAR T-cell patients experiencing CRS. Full article
(This article belongs to the Special Issue Dosing Strategies for Protecting the Vulnerable)
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14 pages, 3065 KiB  
Article
Design, Synthesis, Characterization, and Evaluation of the Anti-HT-29 Colorectal Cell Line Activity of Novel 8-Oxyquinolinate-Platinum(II)-Loaded Nanostructured Lipid Carriers Targeted with Riboflavin
by Tugce Boztepe, Sebastián Scioli-Montoto, Rocio C. Gambaro, María Esperanza Ruiz, Silvia Cabrera, José Alemán, Germán A. Islan, Guillermo R. Castro and Ignacio E. León
Pharmaceutics 2023, 15(3), 1021; https://doi.org/10.3390/pharmaceutics15031021 - 22 Mar 2023
Cited by 4 | Viewed by 2023
Abstract
Colorectal cancer is occasionally called colon or rectal cancer, depending on where cancer begins to form, and is the second leading cause of cancer death among both men and women. The platinum-based [PtCl(8-O-quinolinate)(dmso)] (8-QO-Pt) compound has demonstrated encouraging anticancer activity. Three different systems [...] Read more.
Colorectal cancer is occasionally called colon or rectal cancer, depending on where cancer begins to form, and is the second leading cause of cancer death among both men and women. The platinum-based [PtCl(8-O-quinolinate)(dmso)] (8-QO-Pt) compound has demonstrated encouraging anticancer activity. Three different systems of 8-QO-Pt-encapsulated nanostructured lipid carriers (NLCs) with riboflavin (RFV) were investigated. NLCs of myristyl myristate were synthesized by ultrasonication in the presence of RFV. RFV-decorated nanoparticles displayed a spherical shape and a narrow size dispersion in the range of 144–175 nm mean particle diameter. The 8-QO-Pt-loaded formulations of NLC/RFV with more than 70% encapsulation efficiency showed sustained in vitro release for 24 h. Cytotoxicity, cell uptake, and apoptosis were evaluated in the HT-29 human colorectal adenocarcinoma cell line. The results revealed that 8-QO-Pt-loaded formulations of NLC/RFV showed higher cytotoxicity than the free 8-QO-Pt compound at 5.0 µM. All three systems exhibited different levels of cellular internalization. Moreover, the hemotoxicity assay showed the safety profile of the formulations (less than 3.7%). Taken together, RFV-targeted NLC systems for drug delivery have been investigated for the first time in our study and the results are promising for the future of chemotherapy in colon cancer treatment. Full article
(This article belongs to the Special Issue Recent Developments of Nanovaccine Candidates on Immunology)
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13 pages, 1240 KiB  
Article
Differential Preincubation Effects of Nicardipine on OATP1B1- and OATP1B3-Mediated Transport in the Presence and Absence of Protein: Implications in Assessing OATP1B1- and OATP1B3-Mediated Drug–Drug Interactions
by Ruhul Kayesh, Vishakha Tambe, Chao Xu and Wei Yue
Pharmaceutics 2023, 15(3), 1020; https://doi.org/10.3390/pharmaceutics15031020 - 22 Mar 2023
Cited by 1 | Viewed by 2040
Abstract
Impaired transport activity of hepatic OATP1B1 and OATP1B3 due to drug–drug interactions (DDIs) often leads to increased systemic exposure to substrate drugs (e.g., lipid-lowering statins). Since dyslipidemia and hypertension frequently coexist, statins are often concurrently used with antihypertensives, including calcium channel blockers (CCBs). [...] Read more.
Impaired transport activity of hepatic OATP1B1 and OATP1B3 due to drug–drug interactions (DDIs) often leads to increased systemic exposure to substrate drugs (e.g., lipid-lowering statins). Since dyslipidemia and hypertension frequently coexist, statins are often concurrently used with antihypertensives, including calcium channel blockers (CCBs). OATP1B1/1B3-related DDIs in humans have been reported for several CCBs. To date, the OATP1B1/1B3-mediated DDI potential of CCB nicardipine has not been assessed. The current study was designed to assess the OATP1B1- and OATP1B3-mediated DDI potential of nicardipine using the R-value model, following the US-FDA guidance. IC50 values of nicardipine against OATP1B1 and OATP1B3 were determined in transporter-overexpressing human embryonic kidney 293 cells using [3H]-estradiol 17β-D-glucuronide and [3H]-cholecystokinin-8 as substrates, respectively, with or without nicardipine-preincubation in protein-free Hanks’ Balanced Salt Solution (HBSS) or in fetal bovine serum (FBS)-containing culture medium. Preincubation with nicardipine for 30 min in protein-free HBSS buffer produced lower IC50 and higher R-values for both OATP1B1 and OATP1B3 compared to in FBS-containing medium, yielding IC50 values of 0.98 and 1.63 µM and R-values of 1.4 and 1.3 for OATP1B1 and OATP1B3, respectively. The R-values were higher than the US-FDA cut-off value of 1.1, supporting that nicardipine has the potential to cause OATP1B1/3-mediated DDIs. Current studies provide insight into the consideration of optimal preincubation conditions when assessing the OATP1B1/3-mediated DDIs in vitro. Full article
(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)
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22 pages, 1997 KiB  
Review
Carbon Dots: Opportunities and Challenges in Cancer Therapy
by Tanima Bhattacharya, Gye Hwa Shin and Jun Tae Kim
Pharmaceutics 2023, 15(3), 1019; https://doi.org/10.3390/pharmaceutics15031019 - 22 Mar 2023
Cited by 19 | Viewed by 3483
Abstract
Recently, carbon dots (CDs) have been actively studied and reported for their various properties. In particular, the specific characteristics of carbon dots have been considered as a possible technique for cancer diagnosis and therapy. This is also a cutting-edge technology that offers fresh [...] Read more.
Recently, carbon dots (CDs) have been actively studied and reported for their various properties. In particular, the specific characteristics of carbon dots have been considered as a possible technique for cancer diagnosis and therapy. This is also a cutting-edge technology that offers fresh ideas for treating various disorders. Though carbon dots are still in their infancy and have not yet shown their value to society, their discovery has already resulted in some noteworthy advancements. The application of CDs indicates conversion in natural imaging. Photography using CDs has demonstrated extraordinary appropriateness in bio-imaging, the discovery of novel drugs, the delivery of targeted genes, bio-sensing, photodynamic therapy, and diagnosis. This review seeks to provide a comprehensive understanding of CDs, including their benefits, characteristics, applications, and mode of action. In this overview, many CD design strategies will be highlighted. In addition, we will discuss numerous studies on cytotoxic testing to demonstrate the safety of CDs. The current study will address the production method, mechanism, ongoing research, and application of CDs in cancer diagnosis and therapy. Full article
(This article belongs to the Special Issue Multifunctional Nanoparticles for Cancer Therapy and Imaging)
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17 pages, 4624 KiB  
Article
Bacterial Lectin FimH and Its Aggregation Hot-Spots: An Alternative Strategy against Uropathogenic Escherichia coli
by Georgia I. Nasi, Konstantina I. Georgakopoulou, Marilena K. Theodoropoulou, Nikos C. Papandreou, Evangelia D. Chrysina, Paraskevi L. Tsiolaki and Vassiliki A. Iconomidou
Pharmaceutics 2023, 15(3), 1018; https://doi.org/10.3390/pharmaceutics15031018 - 22 Mar 2023
Viewed by 1807
Abstract
Type I fimbriae are the main adhesive organelles of uropathogenic Escherichia coli (UPEC), consisting of four different subunits. Their component with the most important role in establishing bacterial infections is the FimH adhesin located at the fimbrial tip. This two-domain protein mediates adhesion [...] Read more.
Type I fimbriae are the main adhesive organelles of uropathogenic Escherichia coli (UPEC), consisting of four different subunits. Their component with the most important role in establishing bacterial infections is the FimH adhesin located at the fimbrial tip. This two-domain protein mediates adhesion to host epithelial cells through interaction with terminal mannoses on epithelial glycoproteins. Here, we propose that the amyloidogenic potential of FimH can be exploited for the development of therapeutic agents against Urinary Tract Infections (UTIs). Aggregation-prone regions (APRs) were identified via computational methods, and peptide-analogues corresponding to FimH lectin domain APRs were chemically synthesized and studied with the aid of both biophysical experimental techniques and molecular dynamic simulations. Our findings indicate that these peptide-analogues offer a promising set of antimicrobial candidate molecules since they can either interfere with the folding process of FimH or compete for the mannose-binding pocket. Full article
(This article belongs to the Section Biologics and Biosimilars)
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24 pages, 5116 KiB  
Review
The Delivery and Activation of Growth Factors Using Nanomaterials for Bone Repair
by Yiwei Li, Chun Xu and Chang Lei
Pharmaceutics 2023, 15(3), 1017; https://doi.org/10.3390/pharmaceutics15031017 - 22 Mar 2023
Cited by 2 | Viewed by 2382
Abstract
Bone regeneration is a comprehensive process that involves different stages, and various growth factors (GFs) play crucial roles in the entire process. GFs are currently widely used in clinical settings to promote bone repair; however, the direct application of GFs is often limited [...] Read more.
Bone regeneration is a comprehensive process that involves different stages, and various growth factors (GFs) play crucial roles in the entire process. GFs are currently widely used in clinical settings to promote bone repair; however, the direct application of GFs is often limited by their fast degradation and short local residual time. Additionally, GFs are expensive, and their use may carry risks of ectopic osteogenesis and potential tumor formation. Nanomaterials have recently shown great promise in delivering GFs for bone regeneration, as they can protect fragile GFs and control their release. Moreover, functional nanomaterials can directly activate endogenous GFs, modulating the regeneration process. This review provides a summary of the latest advances in using nanomaterials to deliver exogenous GFs and activate endogenous GFs to promote bone regeneration. We also discuss the potential for synergistic applications of nanomaterials and GFs in bone regeneration, along with the challenges and future directions that need to be addressed. Full article
(This article belongs to the Special Issue Porous Nanomaterials for Tissue Engineering and Drug Delivery)
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12 pages, 1343 KiB  
Article
Design and Characterization of a Novel Venetoclax-Zanubrutinib Nano-Combination for Enhancing Leukemic Cell Uptake and Long-Acting Plasma Exposure
by James Griffin, Yan Wu, Qingxin Mu, Xinyan Li and Rodney J. Y. Ho
Pharmaceutics 2023, 15(3), 1016; https://doi.org/10.3390/pharmaceutics15031016 - 22 Mar 2023
Viewed by 1828
Abstract
Leukemia remains incurable partly due to difficulties in reaching and maintaining therapeutic drug concentrations in the target tissues and cells. Next-generation drugs targeted to multiple cell checkpoints, including the orally active venetoclax (Bcl-2 target) and zanubrutinib (BTK target), are effective and have improved [...] Read more.
Leukemia remains incurable partly due to difficulties in reaching and maintaining therapeutic drug concentrations in the target tissues and cells. Next-generation drugs targeted to multiple cell checkpoints, including the orally active venetoclax (Bcl-2 target) and zanubrutinib (BTK target), are effective and have improved safety and tolerability compared to conventional, nontargeted chemotherapies. However, dosing with a single agent frequently leads to drug resistance; asynchronous coverage due to the peak-and-trough time-course of two or more oral drugs has prevented drug combinations from simultaneously knocking out the respective drugs’ targets for sustained leukemia suppression. Higher doses of the drugs may potentially overcome asynchronous drug exposure in leukemic cells by saturating target occupancy, but higher doses often cause dose-limiting toxicities. To synchronize multiple drug target knockout, we have developed and characterized a drug combination nanoparticle (DcNP), which enables the transformation of two short-acting, orally active leukemic drugs, venetoclax and zanubrutinib, into long-acting nanoformulations (VZ-DCNPs). VZ-DCNPs exhibit synchronized and enhanced cell uptake and plasma exposure of both venetoclax and zanubrutinib. Both drugs are stabilized by lipid excipients to produce the VZ-DcNP nanoparticulate (d ~ 40 nm) product in suspension. The VZ-DcNP formulation has enhanced uptake of the two drugs (VZ) in immortalized leukemic cells (HL-60), threefold over that of its free drug counterpart. Additionally, drug-target selectivity of VZ was noted with MOLT-4 and K562 cells that overexpress each target. When given subcutaneously to mice, the half-lives of venetoclax and zanubrutinib were extended by approximately 43- and 5-fold, respectively, compared to an equivalent free VZ. Collectively, these data suggest that VZ in VZ-DcNP warrant consideration for preclinical and clinical development as a synchronized and long-acting drug-combination for the treatment of leukemia. Full article
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17 pages, 2740 KiB  
Article
Sinonasal Stent Coated with Sustained-Release Varnish of Mometasone Furoate Inhibits Pro-Inflammatory Cytokine Release from Macrophages: An In Vitro Study
by Alessandra Cataldo Russomando, Doron Steinberg, Irith Gati, Ronit Vogt Sionov, Ron Eliashar, Michael Friedman and Menachem Gross
Pharmaceutics 2023, 15(3), 1015; https://doi.org/10.3390/pharmaceutics15031015 - 22 Mar 2023
Cited by 1 | Viewed by 1362
Abstract
The aim of the study was to develop a sustained-release varnish (SRV) containing mometasone furoate (MMF) for sinonasal stents (SNS) to reduce mucosa inflammation in the sinonasal cavity. The SNS’ segments coated with SRV-MMF or an SRV-placebo were incubated daily in a fresh [...] Read more.
The aim of the study was to develop a sustained-release varnish (SRV) containing mometasone furoate (MMF) for sinonasal stents (SNS) to reduce mucosa inflammation in the sinonasal cavity. The SNS’ segments coated with SRV-MMF or an SRV-placebo were incubated daily in a fresh DMEM at 37 °C for 20 days. The immunosuppressive activity of the collected DMEM supernatants was tested on the ability of mouse RAW 264.7 macrophages to secrete the cytokines’ tumor necrosis factor α (TNFα) and interleukin (IL)-10 and IL-6 in response to lipopolysaccharide (LPS). The cytokine levels were determined by respective Enzyme-Linked Immunosorbent Assays (ELISAs). We found that the daily amount of MMF released from the coated SNS was sufficient to significantly inhibit LPS-induced IL-6 and IL-10 secretion from the macrophages up to days 14 and 17, respectively. SRV-MMF had, however, only a mild inhibitory effect on LPS-induced TNFα secretion as compared to the SRV-placebo-coated SNS. In conclusion, the coating of SNS with SRV-MMF provides a sustained delivery of MMF for at least 2 weeks, maintaining a level sufficient for inhibiting pro-inflammatory cytokine release. This technological platform is, therefore, expected to provide anti-inflammatory benefits during the postoperative healing period and may play a significant role in the future treatment of chronic rhinosinusitis. Full article
(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)
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4 pages, 194 KiB  
Editorial
In Silico Pharmacology for Evidence-Based and Precision Medicine
by Marios Spanakis
Pharmaceutics 2023, 15(3), 1014; https://doi.org/10.3390/pharmaceutics15031014 - 22 Mar 2023
Viewed by 1716
Abstract
Personalized/precision medicine (PM) originates from the application of molecular pharmacology in clinical practice, representing a new era in healthcare that aims to identify and predict optimum treatment outcomes for a patient or a cohort with similar genotype/phenotype characteristics [...] Full article
(This article belongs to the Special Issue In Silico Pharmacology for Evidence-Based and Precision Medicine)
11 pages, 2918 KiB  
Communication
Mesoporous Organosilica Nanoparticles with Tetrasulphide Bond to Enhance Plasmid DNA Delivery
by Yue Zhang, He Xian, Ekaterina Strounina, Kimberley S. Gunther, Matthew J. Sweet, Chen Chen, Chengzhong Yu and Yue Wang
Pharmaceutics 2023, 15(3), 1013; https://doi.org/10.3390/pharmaceutics15031013 - 22 Mar 2023
Cited by 2 | Viewed by 1891
Abstract
Cellular delivery of plasmid DNA (pDNA) specifically into dendritic cells (DCs) has provoked wide attention in various applications. However, delivery tools that achieve effective pDNA transfection in DCs are rare. Herein, we report that tetrasulphide bridged mesoporous organosilica nanoparticles (MONs) have enhanced pDNA [...] Read more.
Cellular delivery of plasmid DNA (pDNA) specifically into dendritic cells (DCs) has provoked wide attention in various applications. However, delivery tools that achieve effective pDNA transfection in DCs are rare. Herein, we report that tetrasulphide bridged mesoporous organosilica nanoparticles (MONs) have enhanced pDNA transfection performance in DC cell lines compared to conventional mesoporous silica nanoparticles (MSNs). The mechanism of enhanced pDNA delivery efficacy is attributed to the glutathione (GSH) depletion capability of MONs. Reduction of initially high GSH levels in DCs further increases the mammalian target of rapamycin complex 1 (mTORc1) pathway activation, enhancing translation and protein expression. The mechanism was further validated by showing that the increased transfection efficiency was apparent in high GSH cell lines but not in low GSH ones. Our findings may provide a new design principle of nano delivery systems where the pDNA delivery to DCs is important. Full article
(This article belongs to the Special Issue Smart Drug Delivery Strategies Based on Porous Materials)
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19 pages, 3999 KiB  
Article
Intragastric Carbon Dioxide Release Prolongs the Gastric Residence Time of Postprandially Administered Caffeine
by Stefan Senekowitsch, Constantin Foja, Toni Wildgrube, Philipp Schick, Christoph Rosenbaum, Julius Krause, Friederike Brokmann, Marie-Luise Kromrey, Stefan Engeli, Werner Weitschies and Michael Grimm
Pharmaceutics 2023, 15(3), 1012; https://doi.org/10.3390/pharmaceutics15031012 - 22 Mar 2023
Cited by 4 | Viewed by 1849
Abstract
Sparkling water is said to increase gastric motility by the release of carbon dioxide, thereby potentially affecting the pharmacokinetics of orally administered drugs. The hypothesis of the present work was that the induction of gastric motility by intragastric release of carbon dioxide from [...] Read more.
Sparkling water is said to increase gastric motility by the release of carbon dioxide, thereby potentially affecting the pharmacokinetics of orally administered drugs. The hypothesis of the present work was that the induction of gastric motility by intragastric release of carbon dioxide from effervescent granules could promote the mixing of drugs into the chyme under postprandial conditions, resulting in a prolonged drug absorption. For this purpose, an effervescent and a non-effervescent granule formulation of caffeine as a marker for gastric emptying were developed. In a three-way crossover study with twelve healthy volunteers, the salivary caffeine pharmacokinetics, after administration of the effervescent granules with still water and the administration of the non-effervescent granules with still and sparkling water, were investigated after intake of a standard meal. While the administration of the effervescent granules with 240 mL of still water led to a significantly prolonged gastric residence of the substance compared to the administration of the non-effervescent granules with 240 mL still water, the application of the non-effervescent granules with 240 mL sparkling water did not prolong gastric residence via mixing into caloric chyme. Overall, the mixing of caffeine into the chyme following the administration of the effervescent granules did not seem to be a motility mediated process. Full article
(This article belongs to the Special Issue Recent Advances in Oral Biopharmaceutics)
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14 pages, 3174 KiB  
Article
pH-Dependent Behavior of Novel 5-FU Delivery System in Environmental Conditions Comparable to the Gastro-Intestinal Tract
by Geza Lazar, Fran Nekvapil, Branko Glamuzina, Tudor Tamaș, Lucian Barbu-Tudoran, Maria Suciu and Simona Cinta Pinzaru
Pharmaceutics 2023, 15(3), 1011; https://doi.org/10.3390/pharmaceutics15031011 - 21 Mar 2023
Cited by 3 | Viewed by 1634
Abstract
A biogenic carrier for 5-fluorouracil (5-FU) loading and subsequent tableting as a new drug formulation for slow release has been proposed using the biomineral from blue crab carapace. Due to its highly ordered 3D porous nanoarchitecture, the biogenic carbonate carrier could achieve increased [...] Read more.
A biogenic carrier for 5-fluorouracil (5-FU) loading and subsequent tableting as a new drug formulation for slow release has been proposed using the biomineral from blue crab carapace. Due to its highly ordered 3D porous nanoarchitecture, the biogenic carbonate carrier could achieve increased effectiveness in colorectal cancer cure provided that the formulation would successfully pass through the gastric acid conditions. Following the recently proven viability of the concept by demonstrating the slow release of the drug from the carrier using the highly sensitive SERS technique, here we investigated the 5-FU release from the composite tablet drug in pH conditions replicating the gastric environment. The released drug from the tablet was studied in solutions with three relevant pH values, pH 2, pH 3, and pH 4. The 5-FU SERS spectral signature for each pH value was used to build calibration curves for quantitative SERS analysis. The results suggested a similarly slow-releasing pattern in acid pH environments to that in neutral conditions. Although biogenic calcite dissolution was expected in acid conditions, the X-ray diffraction and Raman spectroscopy showed preservation of calcite mineral along with the monohydrocalcite during acid solution exposure for two hours. The total released amount in a time course of seven hours, however, was lower in acidic pH solutions, with a maximum fraction of ~40% of the total amount of loaded drug, for pH 2, as opposed to ~80% for neutral values. Nonetheless, these results clearly prove that the novel composite drug retains its slow-releasing character in environmental conditions compatible with the gastrointestinal pH and that it is a viable and biocompatible alternative for oral delivery of anticancer drug to reach the lower gastro-intestinal tract. Full article
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14 pages, 4588 KiB  
Article
Use of a Cellulase from Trichoderma reesei as an Adjuvant for Enterococcus faecalis Biofilm Disruption in Combination with Antibiotics as an Alternative Treatment in Secondary Endodontic Infection
by Selene Velázquez-Moreno, Ana Maria González-Amaro, Antonio Aragón-Piña, Lluvia Itzel López-López, Roberto Sánchez-Sánchez, Mario Alberto Pérez-Díaz, Ricardo Oliva Rodríguez, Ana C. Lorenzo-Leal, Omar González-Ortega, Fidel Martinez-Gutierrez and Horacio Bach
Pharmaceutics 2023, 15(3), 1010; https://doi.org/10.3390/pharmaceutics15031010 - 21 Mar 2023
Cited by 3 | Viewed by 2287
Abstract
Apical periodontitis is an inflammation leading to the injury and destruction of periradicular tissues. It is a sequence of events that starts from root canal infection, endodontic treatment, caries, or other dental interventions. Enterococcus faecalis is a ubiquitous oral pathogen that is challenging [...] Read more.
Apical periodontitis is an inflammation leading to the injury and destruction of periradicular tissues. It is a sequence of events that starts from root canal infection, endodontic treatment, caries, or other dental interventions. Enterococcus faecalis is a ubiquitous oral pathogen that is challenging to eradicate because of biofilm formation during tooth infection. This study evaluated a hydrolase (CEL) from the fungus Trichoderma reesei combined with amoxicillin/clavulanic acid as a treatment against a clinical E. faecalis strain. Electron microscopy was used to visualize the structure modification of the extracellular polymeric substances. Biofilms were developed on human dental apices using standardized bioreactors to evaluate the antibiofilm activity of the treatment. Calcein and ethidium homodimer assays were used to evaluate the cytotoxic activity in human fibroblasts. In contrast, the human-derived monocytic cell line (THP-1) was used to evaluate the immunological response of CEL. In addition, the secretion of the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine IL-10 were measured by ELISA. The results demonstrated that CEL did not induce the secretion of IL-6 and TNF-α when compared with lipopolysaccharide used as a positive control. Furthermore, the treatment combining CEL with amoxicillin/clavulanic acid showed excellent antibiofilm activity, with a 91.4% reduction in CFU on apical biofilms and a 97.6% reduction in the microcolonies. The results of this study could be used to develop a treatment to help eradicate persistent E. faecalis in apical periodontitis. Full article
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17 pages, 2181 KiB  
Article
DLin-MC3-Containing mRNA Lipid Nanoparticles Induce an Antibody Th2-Biased Immune Response Polarization in a Delivery Route-Dependent Manner in Mice
by Altan Yavuz, Céline Coiffier, Cynthia Garapon, Serra Gurcan, Claire Monge, Jean-Yves Exposito, Danielle Campiol Arruda and Bernard Verrier
Pharmaceutics 2023, 15(3), 1009; https://doi.org/10.3390/pharmaceutics15031009 - 21 Mar 2023
Cited by 3 | Viewed by 3344
Abstract
mRNA-based vaccines have made a leap forward since the SARS-CoV-2 pandemic and are currently used to develop anti-infectious therapies. If the selection of a delivery system and an optimized mRNA sequence are two key factors to reach in vivo efficacy, the optimal administration [...] Read more.
mRNA-based vaccines have made a leap forward since the SARS-CoV-2 pandemic and are currently used to develop anti-infectious therapies. If the selection of a delivery system and an optimized mRNA sequence are two key factors to reach in vivo efficacy, the optimal administration route for those vaccines remains unclear. We investigated the influence of lipid components and immunization route regarding the intensity and quality of humoral immune responses in mice. The immunogenicity of HIV-p55Gag encoded mRNA encapsulated into D-Lin-MC3-DMA or GenVoy-ionizable lipid-based LNPs was compared after intramuscular or subcutaneous routes. Three sequential mRNA vaccines were administrated followed by a heterologous boost composed of p24-HIV protein antigen. Despite equivalent IgG kinetic profiles of general humoral responses, IgG1/IgG2a ratio analysis showed a Th2/Th1 balance toward a Th1-biased cellular immune response when both LNPs were administrated via the intramuscular route. Surprisingly, a Th2-biased antibody immunity was observed when DLin-containing vaccine was injected subcutaneously. A protein-based vaccine boost appeared to reverse this balance to a cellular-biased response correlated to an increase in antibody avidity. Our finding suggests that the intrinsic adjuvant effect of ionizable lipids appears to be dependent on the delivery route used, which could be relevant to reach potent and long-lasting immunity after mRNA-based immunization. Full article
(This article belongs to the Special Issue State-of-Art in mRNA Therapeutics and Gene Delivery)
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37 pages, 4260 KiB  
Review
Drug Delivery Strategies for Avobenzone: A Case Study of Photostabilization
by Amol D. Gholap, Sadikali F. Sayyad, Navnath T. Hatvate, Vilas V. Dhumal, Sagar R. Pardeshi, Vivek P. Chavda and Lalitkumar K. Vora
Pharmaceutics 2023, 15(3), 1008; https://doi.org/10.3390/pharmaceutics15031008 - 21 Mar 2023
Cited by 14 | Viewed by 5413
Abstract
Several developments and research methods are ongoing in drug technology and chemistry research to elicit effectiveness regarding the therapeutic activity of drugs along with photoprotection for their molecular integrity. The detrimental effect of UV light induces damaged cells and DNA, which leads to [...] Read more.
Several developments and research methods are ongoing in drug technology and chemistry research to elicit effectiveness regarding the therapeutic activity of drugs along with photoprotection for their molecular integrity. The detrimental effect of UV light induces damaged cells and DNA, which leads to skin cancer and other phototoxic effects. The application of sunscreen shields to the skin is important, along with recommended UV filters. Avobenzone is widely used as a UVA filter for skin photoprotection in sunscreen formulations. However, keto-enol tautomerism propagates photodegradation into it, which further channelizes the phototoxic and photoirradiation effects, further limiting its use. Several approaches have been used to counter these issues, including encapsulation, antioxidants, photostabilizers, and quenchers. To seek the gold standard approach for photoprotection in photosensitive drugs, combinations of strategies have been implemented to identify effective and safe sunscreen agents. The stringent regulatory guidelines for sunscreen formulations, along with the availability of limited FDA-approved UV filters, have led many researchers to develop perfect photostabilization strategies for available photostable UV filters, such as avobenzone. From this perspective, the objective of the current review is to summarize the recent literature on drug delivery strategies implemented for the photostabilization of avobenzone that could be useful to frame industrially oriented potential strategies on a large scale to circumvent all possible photounstable issues of avobenzone. Full article
(This article belongs to the Special Issue Formulation of Photosensitive Drugs)
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17 pages, 3288 KiB  
Article
Derivatives of Amaryllidaceae Alkaloid Ambelline as Selective Inhibitors of Hepatic Stage of Plasmodium berghei Infection In Vitro
by Kateřina Hradiská Breiterová, Aneta Ritomská, Diana Fontinha, Jana Křoustková, Daniela Suchánková, Anna Hošťálková, Marcela Šafratová, Eliška Kohelová, Rozálie Peřinová, Rudolf Vrabec, Denise Francisco, Miguel Prudêncio and Lucie Cahlíková
Pharmaceutics 2023, 15(3), 1007; https://doi.org/10.3390/pharmaceutics15031007 - 21 Mar 2023
Cited by 2 | Viewed by 1346
Abstract
The incidence rate of malaria and the ensuing mortality prompts the development of novel antimalarial drugs. In this work, the activity of twenty-eight Amaryllidaceae alkaloids (1–28) belonging to seven different structural types was assessed, as well as twenty semisynthetic derivatives of [...] Read more.
The incidence rate of malaria and the ensuing mortality prompts the development of novel antimalarial drugs. In this work, the activity of twenty-eight Amaryllidaceae alkaloids (1–28) belonging to seven different structural types was assessed, as well as twenty semisynthetic derivatives of the β-crinane alkaloid ambelline (28a–28t) and eleven derivatives of the α-crinane alkaloid haemanthamine (29a–29k) against the hepatic stage of Plasmodium infection. Six of these derivatives (28h, 28m, 28n and 28r–28t) were newly synthesized and structurally identified. The most active compounds, 11-O-(3,5-dimethoxybenzoyl)ambelline (28m) and 11-O-(3,4,5-trimethoxybenzoyl)ambelline (28n), displayed IC50 values in the nanomolar range of 48 and 47 nM, respectively. Strikingly, the derivatives of haemanthamine (29) with analogous substituents did not display any significant activity, even though their structures are quite similar. Interestingly, all active derivatives were strictly selective against the hepatic stage of infection, as they did not demonstrate any activity against the blood stage of Plasmodium infection. As the hepatic stage is a bottleneck of the plasmodial infection, liver-selective compounds can be considered crucial for further development of the malaria prophylactics. Full article
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25 pages, 1013 KiB  
Review
The Exosome-Mediated PI3K/Akt/mTOR Signaling Pathway in Neurological Diseases
by Amin Iranpanah, Leila Kooshki, Seyed Zachariah Moradi, Luciano Saso, Sajad Fakhri and Haroon Khan
Pharmaceutics 2023, 15(3), 1006; https://doi.org/10.3390/pharmaceutics15031006 - 21 Mar 2023
Cited by 9 | Viewed by 3363
Abstract
As major public health concerns associated with a rapidly growing aging population, neurodegenerative diseases (NDDs) and neurological diseases are important causes of disability and mortality. Neurological diseases affect millions of people worldwide. Recent studies have indicated that apoptosis, inflammation, and oxidative stress are [...] Read more.
As major public health concerns associated with a rapidly growing aging population, neurodegenerative diseases (NDDs) and neurological diseases are important causes of disability and mortality. Neurological diseases affect millions of people worldwide. Recent studies have indicated that apoptosis, inflammation, and oxidative stress are the main players of NDDs and have critical roles in neurodegenerative processes. During the aforementioned inflammatory/apoptotic/oxidative stress procedures, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a crucial role. Considering the functional and structural aspects of the blood–brain barrier, drug delivery to the central nervous system is relatively challenging. Exosomes are nanoscale membrane-bound carriers that can be secreted by cells and carry several cargoes, including proteins, nucleic acids, lipids, and metabolites. Exosomes significantly take part in the intercellular communications due to their specific features including low immunogenicity, flexibility, and great tissue/cell penetration capabilities. Due to their ability to cross the blood–brain barrier, these nano-sized structures have been introduced as proper vehicles for central nervous system drug delivery by multiple studies. In the present systematic review, we highlight the potential therapeutic effects of exosomes in the context of NDDs and neurological diseases by targeting the PI3K/Akt/mTOR signaling pathway. Full article
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16 pages, 4862 KiB  
Article
Conjugation of Short Oligopeptides to a Second-Generation Polyamidoamine Dendrimer Shows Antibacterial Activity
by Namyoung Kang, Le Thi Thuy, Viet Dongquoc and Joon Sig Choi
Pharmaceutics 2023, 15(3), 1005; https://doi.org/10.3390/pharmaceutics15031005 - 21 Mar 2023
Viewed by 1558
Abstract
The growing evolution of bacterial resistance to antibiotics represents a global issue that not only impacts healthcare systems but also political and economic processes. This necessitates the development of novel antibacterial agents. Antimicrobial peptides have shown promise in this regard. Thus, in this [...] Read more.
The growing evolution of bacterial resistance to antibiotics represents a global issue that not only impacts healthcare systems but also political and economic processes. This necessitates the development of novel antibacterial agents. Antimicrobial peptides have shown promise in this regard. Thus, in this study, a new functional polymer was synthesized by joining a short oligopeptide sequence (Phe-Lys-Phe-Leu, FKFL) to the surface of a second-generation polyamidoamine (G2 PAMAM) dendrimer as an antibacterial component. This method of synthesis proved simple and resulted in a high conjugation yield of the product FKFL-G2. To determine its antibacterial potential, FKFL-G2 was subsequently analyzed via mass spectrometry, a cytotoxicity assay, bacterial growth assay, colony-forming unit assay, membrane permeabilization assay, transmission electron microscopy, and biofilm formation assay. FKFL-G2 was found to exhibit low toxicity to noncancerous NIH3T3 cells. Additionally, FKFL-G2 had an antibacterial effect on Escherichia coli and Staphylococcus aureus strains by interacting with and disrupting the bacterial cell membrane. Based on these findings, FKFL-G2 shows promise as a potential antibacterial agent. Full article
(This article belongs to the Special Issue Applications of Dendrimers in Biomedicine)
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19 pages, 3846 KiB  
Article
Gene Electrotransfer Efficiency in 2D and 3D Cancer Cell Models Using Different Electroporation Protocols: A Comparative Study
by Alexia de Caro, Elisabeth Bellard, Jelena Kolosnjaj-Tabi, Muriel Golzio and Marie-Pierre Rols
Pharmaceutics 2023, 15(3), 1004; https://doi.org/10.3390/pharmaceutics15031004 - 21 Mar 2023
Cited by 4 | Viewed by 1799
Abstract
Electroporation, a method relying on a pulsed electric field to induce transient cell membrane permeabilization, can be used as a non-viral method to transfer genes in vitro and in vivo. Such transfer holds great promise for cancer treatment, as it can induce or [...] Read more.
Electroporation, a method relying on a pulsed electric field to induce transient cell membrane permeabilization, can be used as a non-viral method to transfer genes in vitro and in vivo. Such transfer holds great promise for cancer treatment, as it can induce or replace missing or non-functioning genes. Yet, while efficient in vitro, gene-electrotherapy remains challenging in tumors. To assess the differences of gene electrotransfer in respect to applied pulses in multi-dimensional (2D, 3D) cellular organizations, we herein compared pulsed electric field protocols applicable to electrochemotherapy and gene electrotherapy and different “High Voltage–Low Voltage” pulses. Our results show that all protocols can result in efficient permeabilization of 2D- and 3D-grown cells. However, their efficiency for gene delivery varies. The gene-electrotherapy protocol is the most efficient in cell suspensions, with a transfection rate of about 50%. Conversely, despite homogenous permeabilization of the entire 3D structure, none of the tested protocols allowed gene delivery beyond the rims of multicellular spheroids. Taken together, our findings highlight the importance of electric field intensity and the occurrence of cell permeabilization, and underline the significance of pulses’ duration, impacting plasmids’ electrophoretic drag. The latter is sterically hindered in 3D structures and prevents the delivery of genes into spheroids’ core. Full article
(This article belongs to the Special Issue Plasmid DNA for Gene Therapy and DNA Vaccine Applications)
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24 pages, 11077 KiB  
Article
Nanoemulsions Based on Sunflower and Rosehip Oils: The Impact of Natural and Synthetic Stabilizers on Skin Penetration and an Ex Vivo Wound Healing Model
by Cynthia Nara Pereira Oliveira, Marcel Nani Leite, Natália Aparecida de Paula, Yugo Araújo Martins, Sonia Aparecida Figueiredo, Marco Andrey Cipriani Frade and Renata Fonseca Vianna Lopez
Pharmaceutics 2023, 15(3), 999; https://doi.org/10.3390/pharmaceutics15030999 - 20 Mar 2023
Cited by 8 | Viewed by 2349
Abstract
Vegetable oils offer excellent biological properties, but their high lipophilicity limits their bioavailability. This work aimed to develop nanoemulsions based on sunflower and rosehip oils and to evaluate their wound-healing activity. The influence of phospholipids of plant origin on nanoemulsions’ characteristics was investigated. [...] Read more.
Vegetable oils offer excellent biological properties, but their high lipophilicity limits their bioavailability. This work aimed to develop nanoemulsions based on sunflower and rosehip oils and to evaluate their wound-healing activity. The influence of phospholipids of plant origin on nanoemulsions’ characteristics was investigated. A nanoemulsion prepared with a mixture of phospholipids and synthetic emulsifiers (Nano-1) was compared with another prepared only with phospholipids (Nano-2). The healing activity was evaluated in wounds induced in human organotypic skin explant culture (hOSEC) based on histological and immunohistochemical analysis. The hOSEC wound model was validated, showing that high nanoparticle concentration in the wound bed interferes with cell mobility and the ability to respond to the treatment. Nanoemulsions were 130 to 370 nm, with a concentration of 1013 particles/mL, and a low potential to induce inflammatory processes. Nano-2 was three times larger than Nano-1 but less cytotoxic and could target the oils to the epidermis. Nano-1 permeated intact skin to the dermis and showed a more prominent healing effect than Nano-2 in the hOSEC wound model. Changes in the lipid nanoemulsion stabilizers impacted the cutaneous and cellular penetration of the oils, cytotoxicity, and healing kinetics, resulting in versatile delivery systems. Full article
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25 pages, 3378 KiB  
Review
Nanosystems, Drug Molecule Functionalization and Intranasal Delivery: An Update on the Most Promising Strategies for Increasing the Therapeutic Efficacy of Antidepressant and Anxiolytic Drugs
by Jéssica L. Antunes, Joana Amado, Francisco Veiga, Ana Cláudia Paiva-Santos and Patrícia C. Pires
Pharmaceutics 2023, 15(3), 998; https://doi.org/10.3390/pharmaceutics15030998 - 20 Mar 2023
Cited by 6 | Viewed by 2557
Abstract
Depression and anxiety are high incidence and debilitating psychiatric disorders, usually treated by antidepressant or anxiolytic drug administration, respectively. Nevertheless, treatment is usually given through the oral route, but the low permeability of the blood–brain barrier reduces the amount of drug that will [...] Read more.
Depression and anxiety are high incidence and debilitating psychiatric disorders, usually treated by antidepressant or anxiolytic drug administration, respectively. Nevertheless, treatment is usually given through the oral route, but the low permeability of the blood–brain barrier reduces the amount of drug that will be able to reach it, thus consequently reducing the therapeutic efficacy. Which is why it is imperative to find new solutions to make these treatments more effective, safer, and faster. To overcome this obstacle, three main strategies have been used to improve brain drug targeting: the intranasal route of administration, which allows the drug to be directly transported to the brain by neuronal pathways, bypassing the blood–brain barrier and avoiding the hepatic and gastrointestinal metabolism; the use of nanosystems for drug encapsulation, including polymeric and lipidic nanoparticles, nanometric emulsions, and nanogels; and drug molecule functionalization by ligand attachment, such as peptides and polymers. Pharmacokinetic and pharmacodynamic in vivo studies’ results have shown that intranasal administration can be more efficient in brain targeting than other administration routes, and that the use of nanoformulations and drug functionalization can be quite advantageous in increasing brain–drug bioavailability. These strategies could be the key to future improved therapies for depressive and anxiety disorders. Full article
(This article belongs to the Special Issue Strategies to Enhance Drug Permeability across Biological Barriers)
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22 pages, 4918 KiB  
Article
Targeting Glioblastoma-Associated Macrophages for Photodynamic Therapy Using AGuIX®-Design Nanoparticles
by Lucie Lerouge, Mickaël Gries, Alicia Chateau, Joël Daouk, François Lux, Paul Rocchi, Jessica Cedervall, Anna-Karin Olsson, Olivier Tillement, Céline Frochot, Samir Acherar, Noémie Thomas and Muriel Barberi-Heyob
Pharmaceutics 2023, 15(3), 997; https://doi.org/10.3390/pharmaceutics15030997 - 20 Mar 2023
Cited by 4 | Viewed by 2474
Abstract
Glioblastoma (GBM) is the most difficult brain cancer to treat, and photodynamic therapy (PDT) is emerging as a complementary approach to improve tumor eradication. Neuropilin-1 (NRP-1) protein expression plays a critical role in GBM progression and immune response. Moreover, various clinical databases highlight [...] Read more.
Glioblastoma (GBM) is the most difficult brain cancer to treat, and photodynamic therapy (PDT) is emerging as a complementary approach to improve tumor eradication. Neuropilin-1 (NRP-1) protein expression plays a critical role in GBM progression and immune response. Moreover, various clinical databases highlight a relationship between NRP-1 and M2 macrophage infiltration. In order to induce a photodynamic effect, multifunctional AGuIX®-design nanoparticles were used in combination with a magnetic resonance imaging (MRI) contrast agent, as well as a porphyrin as the photosensitizer molecule and KDKPPR peptide ligand for targeting the NRP-1 receptor. The main objective of this study was to characterize the impact of macrophage NRP-1 protein expression on the uptake of functionalized AGuIX®-design nanoparticles in vitro and to describe the influence of GBM cell secretome post-PDT on the polarization of macrophages into M1 or M2 phenotypes. By using THP-1 human monocytes, successful polarization into the macrophage phenotypes was argued via specific morphological traits, discriminant nucleocytoplasmic ratio values, and different adhesion abilities based on real-time cell impedance measurements. In addition, macrophage polarization was confirmed via the transcript-level expression of TNFα, CXCL10, CD-80, CD-163, CD-206, and CCL22 markers. In relation to NRP-1 protein over-expression, we demonstrated a three-fold increase in functionalized nanoparticle uptake for the M2 macrophages compared to the M1 phenotype. The secretome of the post-PDT GBM cells led to nearly a three-fold increase in the over-expression of TNFα transcripts, confirming the polarization to the M1 phenotype. The in vivo relationship between post-PDT efficiency and the inflammatory effects points to the extensive involvement of macrophages in the tumor zone. Full article
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