Cancer treatment has been greatly improved by the combined use of targeted therapies and novel biotechnological methods. Regarding the former, pegylated liposomal doxorubicin (PLD) has a preferential accumulation within cancer tumors, thus having lower toxicity on healthy cells. PLD has been implemented in the targeted treatment of sarcoma, ovarian, breast, and lung cancer. In comparison with conventional doxorubicin, PLD has lower cardiotoxicity and hematotoxicity; however, PLD can induce mucositis and palmo-plantar erythrodysesthesia (PPE, hand-foot syndrome), which limits its use. Therapeutical apheresis is a clinically proven solution against early PLD toxicity without hindering the efficacy of the treatment. The present review summarizes the pharmacokinetics and pharmacodynamics of PLD and the beneficial effects of extracorporeal apheresis on the incidence of PPE during chemoradiotherapy in cancer patients. Full article

Osimertinib (OSI, AZD9291), is a third-generation, irreversible tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. OSI has been approved as a first-line treatment of EGFR-mutant lung cancer and for metastatic EGFR T790M-mutant non-small cell lung cancer. Liposome-based delivery of OSI can provide a new formulation of the drug that can be administered via alternative delivery routes (intravenous, inhalation). In this manuscript, we report for the first time development and characterization of liposomal OSI formulations with diameters of ca. 115 nm. Vesicles were composed of phosphatidylcholines with various saturation and carbon chain lengths, cholesterol and pegylated phosphoethanolamine. Liposomes were loaded with OSI passively, resulting in a drug being dissolved in the phospholipid matrix or actively via remote-loading leading to the formation of OSI precipitate in the liposomal core. Remotely loaded liposomes were characterized by nearly 100% entrapment efficacy and represent a depot of OSI. Passively-loaded vesicles released OSI following the Peppas-Sahlin model, in a mechanism combining drug diffusion and liposome relaxation. OSI-loaded liposomes composed of l-α-phosphatidylcholine (egg-PC) demonstrated a higher toxicity in non-small lung cancer cells with EGFR T790M resistance mutation (H-1975) when compared with free OSI. Developed OSI formulations did not show antiproliferative activity in vitro in healthy lung epithelial cells (MRC-5) without the EGFR mutation. Full article

This study was designed to develop and validate a 10 probe drug cocktail named “Dual Cocktail”, composed of caffeine (Cyp1a2 in rat and CYP1A2 in human, 1 mg/kg), diclofenac (Cyp2c11 in rat and CYP2C9 in human, 2 mg/kg), omeprazole (Cyp2c11 in rat and CYP2C19 in human, 2 mg/kg), dextromethorphan (Cyp2d2 in rat and CYP2D6 in human, 10 mg/kg), nifedipine (Cyp3a1 in rat and CYP3A4 in human, 0.5 mg/kg), metformin (Oct1/2 in rat and OCT1/2 in human, 0.5 mg/kg), furosemide (Oat1/3 in rat and OAT1/3 in human, 0.1 mg/kg), valsartan (Oatp2 in rat and OATP1B1/1B3 in human, 0.2 mg/kg), digoxin (P-gp in rat and human, 2 mg/kg), and methotrexate (Mrp2 in rat and MRP2 in human, 0.5 mg/kg), for the evaluation of pharmacokinetic drug–drug and herb-drug interactions through the modulation of a representative panel of CYP enzymes or transporters in rats. To ensure no interaction among the ten probe substrates, we developed a 2-step evaluation protocol. In the first step, the pharmacokinetic properties of five individual CYP probe substrates and five individual transporter substrates were compared with the pharmacokinetics of five CYP cocktail or five transporters cocktails in two groups of randomly assigned rats. Next, a pharmacokinetic comparison was conducted between the CYP or transporter cocktail group and the dual cocktail group, respectively. None of the ten comparison groups was found to be statistically significant, indicating the CYP and transporter substrate sets or dual cocktail set could be concomitantly administered in rats. The “Dual Cocktail” was further validated by assessing the metabolism of nifedipine and omeprazole, which was significantly reduced by a single oral dose of ketoconazole (10 mg/kg); however, no changes were observed in the pharmacokinetic parameters of other probe substrates. Additionally, multiple oral doses of rifampin (20 mg/kg) reduced the plasma concentrations of nifedipine and digoxin, although not any of the other substrates. In conclusion, the dual cocktail can be used to characterize potential pharmacokinetic drug–drug interactions by simultaneously monitoring the activity of multiple CYP isoforms and transporters. Full article

Passive immunotherapy, i.e., treatment with therapeutic antibodies, has been increasingly used over the last decade in several diseases such as cancers or inflammation. However, these proteins have some limitations that single-domain antibodies could potentially solve. One of the main issues of conventional antibodies is their limited brain penetration because of the blood–brain barrier (BBB). In this review, we aim at exploring the different options single-domain antibodies (sDAbs) such as variable domain of heavy-chain antibodies (VHHs) and variable new antigen receptors (VNARs) have already taken to reach the brain allowing them to be used as therapeutic, diagnosis or transporter tools. Full article

Nebulization could be a valuable solution to administer drugs to neonates receiving noninvasive respiratory support. Small and irregular tidal volumes and air leaks at the patient interface, which are specific characteristics of this patient population and are primarily responsible for the low doses delivered to the lung (D_DL) found in this application, have not been thoroughly addressed in in vitro and in vivo studies for quantifying D_DL. Therefore, we propose a compartment-based mathematical model able to describe convective aerosol transport mechanisms to complement the existing deposition models. Our model encompasses a mechanical ventilator, a nebulizer, and the patient; the model considers the gas flowing between compartments, including air leaks at the patient–ventilator interface. Aerosol particles are suspended in the gas flow and homogeneously distributed. The impact of breathing pattern variability, volume of the nebulizer, and leaks level on D_DL is assessed in representative conditions. The main finding of this study is that convective mechanisms associated to air leaks and breathing patterns with tidal volumes smaller than the nebulizer dramatically reduce the D_DL (up to 70%). This study provides a possible explanation to the inconsistent results of drug aerosolization in clinical studies and may provide guidance to improve nebulizer design and clinical procedures. Full article

Background: Enalapril is often used in the treatment of cardiovascular diseases. Clinical data suggest that the urinary excretion of enalaprilat, the active metabolite of enalapril, is mediated by renal transporters. We aimed to identify enalaprilat specificity for renal proximal tubular transporters. Methods: Baculovirus-transduced HEK293 cells overexpressing proximal tubular transporters were used to study enalaprilat cellular uptake. Uptake into cells overexpressing the basolateral transporters OCT2, OAT1, OAT2, or OAT3 and apical transporters OAT4, PEPT1, PEPT2, OCTN1, OCTN2, MATE1, MATE2k, and URAT1 was compared with mock-transduced control cells. Transport by renal efflux transporters MRP2, MPR4, P-gp, and BCRP was tested using a vesicular assay. Enalaprilat concentrations were measured using LC-MS/MS. Results: Uptake of enalaprilat into cells expressing OAT3 as well as OAT4 was significantly higher compared to control cells. The enalaprilat affinity for OAT3 was 640 (95% CI: 520–770) µM. For OAT4, no reliable affinity constant could be determined using concentrations up to 3 mM. No transport was observed for other transporters. Conclusion: The affinity of enalaprilat for OAT3 and OAT4 was notably low compared to other substrates. Taking this affinity and clinically relevant plasma concentrations of enalaprilat and other OAT3 substrates into account, we believe that drug–drug interactions on a transporter level do not have a therapeutic consequence and will not require dose adjustments of enalaprilat itself or other OAT3 substrates. Full article

Traumatic brain injury (TBI) presents a serious challenge for modern medicine due to the poor regenerative capabilities of the brain, complex pathophysiology, and lack of effective treatment for TBI to date. Tissue-engineered scaffolds have shown some experimental success in vivo; unfortunately, none have yielded consummate results of clinical efficacy. N-acetylcysteine has shown neuroprotective potential. To this end, we developed a N-acetylcysteine (NAC)-loaded poly(lactic-co-glycolic acid) (PLGA) electrospun system for potential neural tissue application for TBI. Scanning electron microscopy showed nanofiber diameters ranging 72–542 nm and 124–592 nm for NAC-free and NAC-loaded PLGA nanofibers, respectively. NAC loading was obtained at 28%, and drug entrapment efficacy was obtained at 84%. A biphasic NAC release pattern that featured an initial burst release (13.9%) stage and a later sustained release stage was noted, thus enabling the prolonged replenishing of NAC and drastically improving cell viability and proliferation. This was evidenced by a significantly higher cell viability and proliferation on NAC-loaded nanofibers for rat pheochromocytoma (PC12) and human glioblastoma multiform (A172) cell lines in comparison to PLGA-only nanofibers. The increased cell viability and cell proliferation on NAC-loaded nanofiber substantiates for the repositioning of NAC as a pharmacological agent in neural tissue regeneration applications. Full article

This review aims to provide an overview of studies that address the use, in therapeutic applications, of solid dispersions (SDs) with biological activities in vitro and/or in vivo mainly made up of polymeric matrices, as well as to evaluate the bioactive activity of their constituents. This bibliographic survey shows that the development of solid dispersions provides benefits in the physicochemical properties of bioactive compounds, which lead to an increase in their biological potential. However, despite the reports found on solid dispersions, there is still a need for biological assay-based studies, mainly in vivo, to assist in the investigation and to devise new applications. Therefore, studies based on such an approach are of great importance to enhance and extend the use of solid dispersions in the most diverse therapeutic applications. Full article

Obesity is a major health concern worldwide, and it is leading to worsening disease morbidity and mortality. Herbal supplements and diet-based therapies have attracted interest in the treatment of obesity. It is known that Garcinia cambogia (GA) and mulberry leaf, which contain polyphenols, have anti-obesity activity. Herein, we developed a combined tablet consisting of GA extract and bioconverted mulberry leaf extract (BMUL) using a statistical design approach. The ratio and amount of sustained polymers were set as factors. In the cell study, the combination of GA and BMUL showed synergistic anti-obesity activity. In a statistical model, the optimized amounts of hydroxypropyl methylcellulose 2208 (HPMC 2208) and polyethylene oxide 303 (POLYOX 303) were 41.02% and 58.98%, respectively. Additionally, the selected ratio of microcrystalline cellulose (MCC) was 0.33. When the release, hardness, and friability of the GABMUL tablet were evaluated, the error percentages of the response were lower than 10%. This indicates that the GABMUL tablet was successfully prepared. Full article

Owing to their unique biological functions, hyaluronic acid (HA) and its derivatives have been explored extensively for biomedical applications such as tissue engineering, drug delivery, and molecular imaging. In particular, self-assembled HA nanoparticles (HA-NPs) have been used widely as target-specific and long-acting nanocarriers for the delivery of a wide range of therapeutic or diagnostic agents. Recently, it has been demonstrated that empty HA-NPs without bearing any therapeutic agent can be used therapeutically for the treatment of inflammatory diseases via modulating inflammatory responses. In this review, we aim to provide an overview of the significant achievements in this field and highlight the potential of HA-NPs for the treatment of inflammatory diseases. Full article

Osteochondral defects involve both the articular cartilage and the underlying subchondral bone. If left untreated, they may lead to osteoarthritis. Advanced biomaterial-guided delivery of gene vectors has recently emerged as an attractive therapeutic concept for osteochondral repair. The goal of this review is to provide an overview of the variety of biomaterials employed as nonviral or viral gene carriers for osteochondral repair approaches both in vitro and in vivo, including hydrogels, solid scaffolds, and hybrid materials. The data show that a site-specific delivery of therapeutic gene vectors in the context of acellular or cellular strategies allows for a spatial and temporal control of osteochondral neotissue composition in vitro. In vivo, implantation of acellular hydrogels loaded with nonviral or viral vectors has been reported to significantly improve osteochondral repair in translational defect models. These advances support the concept of scaffold-mediated gene delivery for osteochondral repair. Full article

Triple negative breast cancer (TNBC) is one of the most aggressive types of breast cancer. Owing to the absenteeism of hormonal receptors expressed at the cancerous breast cells, hormonal therapies and other medications targeting human epidermal growth factor receptor 2 (HER2) are ineffective in TNBC patients, making traditional chemotherapeutic agents the only current appropriate regimen. Patients’ predisposition to relapse and metastasis, chemotherapeutics’ cytotoxicity and resistance and poor prognosis of TNBC necessitates researchers to investigate different novel-targeted therapeutics. The role of small interfering RNA (siRNA) in silencing the genes/proteins that are aberrantly overexpressed in carcinoma cells showed great potential as part of TNBC therapeutic regimen. However, targeting specificity, siRNA stability, and delivery efficiency cause challenges in the progression of this application clinically. Nanotechnology was highlighted as a promising approach for encapsulating and transporting siRNA with high efficiency-low toxicity profile. Advances in preclinical and clinical studies utilizing engineered siRNA-loaded nanotherapeutics for treatment of TNBC were discussed. Specific and selective targeting of diverse signaling molecules/pathways at the level of tumor proliferation and cell cycle, tumor invasion and metastasis, angiogenesis and tumor microenvironment, and chemotherapeutics’ resistance demonstrated greater activity via integration of siRNA-complexed nanoparticles. Full article

Neurodegenerative diseases (ND) are one of the main problems of public health systems in the 21st century. The rise of nanotechnology-based drug delivery systems (DDS) has become in an emerging approach to target and treat these disorders related to the central nervous system (CNS). Among others, the use of nanostructured lipid carriers (NLCs) has increased in the last few years. Up to today, most of the developed NLCs have been made of a mixture of solid and liquid lipids without any active role in preventing or treating diseases. In this study, we successfully developed NLCs made of a functional lipid, such as the hydroxylated derivate of docohexaenoic acid (DHAH), named DHAH-NLCs. The newly developed nanocarriers were around 100 nm in size, with a polydispersity index (PDI) value of <0.3, and they exhibited positive zeta potential due to the successful chitosan (CS) and TAT coating. DHAH-NLCs were shown to be safe in both dopaminergic and microglia primary cell cultures. Moreover, they exhibited neuroprotective effects in dopaminergic neuron cell cultures after exposition to 6-hydroxydopamine hydrochloride (6-OHDA) neurotoxin and decreased the proinflammatory cytokine levels in microglia primary cell cultures after lipopolysaccharide (LPS) stimuli. The levels of the three tested cytokines, IL-6, IL-1β and TNF-α were decreased almost to control levels after the treatment with DHAH-NLCs. Taken together, these data suggest the suitability of DHAH-NLCs to attaining enhanced and synergistic effects for the treatment of NDs. Full article

This study assesses the efficacy of different nanoemulsion formulations as new and innovative adjuvants for improving the in vivo immunization against the Tityus serrulatus scorpion venom. Nanoemulsions were designed testing key-variables such as surfactants, co-solvents, and the influence of the temperature, which would be able to induce the phase transition from a liquid crystal to a stable nanoemulsion, assessed for four months. Additionally, cationic-covered nanoemulsion with hyper-branched poly(ethyleneimine) was prepared and its performance was compared to the non-cationic ones. The physicochemical properties of the selected nanoemulsions and the interactions among their involved formulation compounds were carefully monitored. The cytotoxicity studies in murine macrophages (RAW 264.7) and red blood cells were used to compare different formulations. Moreover, the performance of the nanoemulsion systems as biocompatible adjuvants was evaluated using mice immunization protocol. The FTIR shifts and the zeta potential changes (from −18.3 ± 1.0 to + 8.4 ± 1.4) corroborated with the expected supramolecular anchoring of venom proteins on the surface of the nanoemulsion droplets. Cell culture assays demonstrated the non-toxicity of the formulations at concentrations less than 1.0 mg/mL, which were able to inhibit the hemolytic effect of the scorpion venom. The cationic-covered nanoemulsion has shown superior adjuvant activity, revealing the highest IgG titer in the immunized animals compared to both the non-cationic counterpart and the traditional aluminum adjuvant. In this approach, we demonstrate the incredible potential application of nanoemulsions as adjuvants, using a nanotechnology platform for antigen delivery system on immune cells. Additionally, the functionalization with hyper-branched poly(ethyleneimine) enhances this recognition and improves its action in immunization. Full article

Nitric oxide (NO), a highly reactive and lipophilic molecule, is one of the molecules present in the wound environment and implicated as an important regulator in all phases of wound healing. Here, we developed an NO-releasing thermoresponsive hydrogel (GSNO-PL/AL) composed of S-nitrosoglutathione (GSNO), pluronic F127 (PL), and alginate (AL) for the treatment of infected wounds. The GSNO was incorporated into the thermoresponsive PL/AL hydrogel, and differential scanning calorimetry techniques were used for the hydrogel characterization. The hydrogel was assessed by in vitro NO release, antibacterial activity, cytotoxicity, and wound-healing activity. The GSNO-PL/AL hydrogel demonstrated thermal responsiveness and biocompatibility, and it showed sustained NO release for 7 days. It also exhibited potent bactericidal activity against Gram-positive methicillin-resistant Staphylococcus aureus and Gram-negative multidrug-resistant Pseudomonas aeruginosa (MRPA). Moreover, the GSNO-PL/AL treatment of MRPA-infected wounds accelerated healing with a reduced bacterial burden in the wounds. The GSNO-PL/AL hydrogel would be a promising option for the treatment of infected wounds. Full article