Next Issue
Volume 13, December
Previous Issue
Volume 13, October

Pharmaceutics, Volume 13, Issue 11 (November 2021) – 244 articles

Cover Story (view full-size image): The anatomy and physiology of the eye strongly limit the bioavailability of locally administered drugs. An effective strategy for the topical treatment of several ocular disorders is the entrapment of therapeutics into nanocarriers; this enables drugs to reside on the ocular surface and/or to penetrate different ocular compartments.
Hyaluronan-cholesterol nanogels (NHs) have been revealed to be effective ocular permeation enhancers. Owing to their bioadhesive properties, NHs firmly interact with the superficial corneal epithelium, without penetrating the stroma, thus modifying the transcorneal penetration of loaded therapeutics, as well as hydrophilic and hydrophobic therapeutics.
Therefore, NHs formulations can improve the ocular bioavailability of the instilled drugs, thus driving the application of HA-based NHs in the treatment of eye diseases. View this paper
  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Readerexternal link to open them.
Order results
Result details
Section
Select all
Export citation of selected articles as:
Article
Delivery of pDNA to the Lung by Lipopolyplexes Using N-Lauroylsarcosine and Effect on the Pulmonary Fibrosis
Pharmaceutics 2021, 13(11), 1983; https://doi.org/10.3390/pharmaceutics13111983 - 22 Nov 2021
Viewed by 304
Abstract
In a previous study, we constructed a lung-targeting lipopolyplex containing polyethyleneimine (PEI), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), and N-lauroylsarcosine (LS). The lipopolyplex exhibited an extremely high gene expression in the lung after intravenous administration. Here, we optimized the lipopolyplex and used it [...] Read more.
In a previous study, we constructed a lung-targeting lipopolyplex containing polyethyleneimine (PEI), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), and N-lauroylsarcosine (LS). The lipopolyplex exhibited an extremely high gene expression in the lung after intravenous administration. Here, we optimized the lipopolyplex and used it to deliver a TGF-β1 shRNA to treat refractory pulmonary fibrosis. We constructed several lipopolyplexes with pDNA, various cationic polymers, cationic lipids, and LS to select the most effective formulation. Then, the pDNA encoding shRNA against mouse TGF-β1 was encapsulated in the lipopolyplex and injected into mice with bleomycin-induced pulmonary fibrosis. After optimizing the lipopolyplex, dendrigraft poly-L-lysine (DGL) and DOTMA were selected as the appropriate cationic polymer and lipid, respectively. The lipopolyplex was constructed with a pDNA, DGL, DOTMA, and LS charge ratio of 1:2:2:4 showed the highest gene expression. After intravenous administration of the lipopolyplex, the highest gene expression was observed in the lung. In the in vitro experiment, the lipopolyplex delivered pDNA into the cells via endocytosis. As a result, the lipopolyplex containing pDNA encoding TGF-β1 shRNA significantly decreased hydroxyproline in the pulmonary fibrosis model mice. We have successfully inhibited pulmonary fibrosis using a novel lung-targeting lipopolyplex. Full article
Show Figures

Figure 1

Article
Manganese-Doped N-Hydroxyphthalimide-Derived Carbon Dots—Theranostics Applications in Experimental Breast Cancer Models
Pharmaceutics 2021, 13(11), 1982; https://doi.org/10.3390/pharmaceutics13111982 - 22 Nov 2021
Viewed by 317
Abstract
Background: Theranostics, a novel concept in medicine, is based on the use of an agent for simultaneous diagnosis and treatment. Nanomaterials provide promising novel approaches to theranostics. Carbon Dots have been shown to exhibit anti-tumoral properties in various cancer models. The aim of [...] Read more.
Background: Theranostics, a novel concept in medicine, is based on the use of an agent for simultaneous diagnosis and treatment. Nanomaterials provide promising novel approaches to theranostics. Carbon Dots have been shown to exhibit anti-tumoral properties in various cancer models. The aim of the present study is to develop gadolinium, Fe3+, and Mn2+-doped N-hydroxyphthalimide-derived Carbon Dots. The resulted doped Carbon Dots should preserve the anti-tumoral properties while gaining magnetic resonance imaging properties. Methods: Normal and cancer cell lines have been treated with doped Carbon Dots, and the cell viability has been measured. The doped Carbon Dots that exhibited the most prominent anti-tumoral effect accompanied by the lowest toxicity have been further in vivo tested. Magnetic resonance imaging evaluates both in vitro and in vivo the possibility of using doped Carbon Dots as a contrast agent. Results: According to the results obtained from both the in vitro and in vivo experimental models used in our study, Mn2+-doped Carbon Dots (Mn-CDs-NHF) exhibit anti-tumoral properties, do not significantly impair the cell viability of normal cells, and reduce lung metastasis and the volume of mammary primary tumors while allowing magnetic resonance imaging. Conclusions: Our findings prove that Mn-CDs-NHF can be used as theranostics agents in pre-clinical models. Full article
Show Figures

Graphical abstract

Review
Design of 3D Scaffolds for Hard Tissue Engineering: From Apatites to Silicon Mesoporous Materials
Pharmaceutics 2021, 13(11), 1981; https://doi.org/10.3390/pharmaceutics13111981 - 22 Nov 2021
Viewed by 311
Abstract
Advanced bioceramics for bone regeneration constitutes one of the pivotal interests in the multidisciplinary and far-sighted scientific trajectory of Prof. Vallet Regí. The different pathologies that affect osseous tissue substitution are considered to be one of the most important challenges from the health, [...] Read more.
Advanced bioceramics for bone regeneration constitutes one of the pivotal interests in the multidisciplinary and far-sighted scientific trajectory of Prof. Vallet Regí. The different pathologies that affect osseous tissue substitution are considered to be one of the most important challenges from the health, social and economic point of view. 3D scaffolds based on bioceramics that mimic the composition, environment, microstructure and pore architecture of hard tissues is a consolidated response to such concerns. This review describes not only the different types of materials utilized: from apatite-type to silicon mesoporous materials, but also the fabrication techniques employed to design and adequate microstructure, a hierarchical porosity (from nano to macro scale), a cell-friendly surface; the inclusion of different type of biomolecules, drugs or cells within these scaffolds and the influence on their successful performance is thoughtfully reviewed. Full article
Show Figures

Graphical abstract

Review
Modulating the Blood–Brain Barrier: A Comprehensive Review
Pharmaceutics 2021, 13(11), 1980; https://doi.org/10.3390/pharmaceutics13111980 - 22 Nov 2021
Viewed by 475
Abstract
The highly secure blood–brain barrier (BBB) restricts drug access to the brain, limiting the molecular toolkit for treating central nervous system (CNS) diseases to small, lipophilic drugs. Development of a safe and effective BBB modulator would revolutionise the treatment of CNS diseases and [...] Read more.
The highly secure blood–brain barrier (BBB) restricts drug access to the brain, limiting the molecular toolkit for treating central nervous system (CNS) diseases to small, lipophilic drugs. Development of a safe and effective BBB modulator would revolutionise the treatment of CNS diseases and future drug development in the area. Naturally, the field has garnered a great deal of attention, leading to a vast and diverse range of BBB modulators. In this review, we summarise and compare the various classes of BBB modulators developed over the last five decades—their recent advancements, advantages and disadvantages, while providing some insight into their future as BBB modulators. Full article
Show Figures

Figure 1

Article
A Combination Approach in Inhibiting Type 2 Diabetes-Related Enzymes Using Ecklonia radiata Fucoidan and Acarbose
Pharmaceutics 2021, 13(11), 1979; https://doi.org/10.3390/pharmaceutics13111979 - 22 Nov 2021
Viewed by 287
Abstract
Although there are chemotherapeutic efforts in place for Type 2 diabetes mellitus (T2DM), there is a need for novel strategies (including natural products) to manage T2DM. Fucoidan, a sulphated polysaccharide was extracted from Ecklonia radiata. The integrity of the fucoidan was confirmed [...] Read more.
Although there are chemotherapeutic efforts in place for Type 2 diabetes mellitus (T2DM), there is a need for novel strategies (including natural products) to manage T2DM. Fucoidan, a sulphated polysaccharide was extracted from Ecklonia radiata. The integrity of the fucoidan was confirmed by structural analysis techniques such as FT-IR, NMR and TGA. In addition, the fucoidan was chemically characterised and tested for cell toxicity. The fucoidan was investigated with regards to its potential to inhibit α-amylase and α-glucosidase. The fucoidan was not cytotoxic and inhibited α-glucosidase (IC50 19 µg/mL) more strongly than the standard commercial drug acarbose (IC50 332 µg/mL). However, the fucoidan lacked potency against α-amylase. On the other hand, acarbose was a more potent inhibitor of α-amylase (IC50 of 109 µg/mL) than α-glucosidase. Due to side effects associated with the use of acarbose, a combination approach using acarbose and fucoidan was investigated. The combination showed synergistic inhibition (>70%) of α-glucosidase compared to when the drugs were used alone. The medicinal implication of this synergism is that a regimen with a reduced acarbose dose may be used, thus minimising side effects to the patient, while achieving the desired therapeutic effect for managing T2DM. Full article
(This article belongs to the Special Issue The Role of Natural Products on Diabetes Mellitus Treatment)
Show Figures

Graphical abstract

Review
Promising Strategies of Colloidal Drug Delivery-Based Approaches in Psoriasis Management
Pharmaceutics 2021, 13(11), 1978; https://doi.org/10.3390/pharmaceutics13111978 - 22 Nov 2021
Viewed by 368
Abstract
Psoriasis is a chronic inflammatory autoimmune disorder that moderately affects social and interpersonal relationships. Conventional treatments for psoriasis have certain problems, such as poor drug penetration through the skin, hyper-pigmentation, and a burning sensation on normal and diseased skin. Colloidal drug delivery systems [...] Read more.
Psoriasis is a chronic inflammatory autoimmune disorder that moderately affects social and interpersonal relationships. Conventional treatments for psoriasis have certain problems, such as poor drug penetration through the skin, hyper-pigmentation, and a burning sensation on normal and diseased skin. Colloidal drug delivery systems overcome the pitfalls of conventional approaches for psoriasis therapeutics and have improved patient safety parameters, compliance, and superior effectiveness. They also entail reduced toxicity. This comprehensive review’s topics include the pathogenesis of psoriasis, causes and types of psoriasis, conventional treatment alternatives for psoriasis, the need for colloidal drug delivery systems, and recent studies in colloidal drug delivery systems for the treatment of psoriasis. This review briefly describes colloidal drug delivery approaches, such as emulsion systems—i.e., multiple emulsion, microemulsion, and nano-emulsion; vesicular systems—i.e., liposomes, ethosomes, noisomes, and transferosomes; and particulate systems—i.e., solid lipid nanoparticles, solid lipid microparticles, nano-structured lipid carriers, dendrimers, nanocrystals, polymeric nanoparticles, and gold nanoparticles. The review was compiled through an extensive search of the literature through the PubMed, Google Scholar, and ScienceDirect databases. A survey of literature revealed seven formulations based upon emulsion systems, six vesicular drug delivery systems, and fourteen particulate systems reported for antipsoriatic drugs. Based on the literature studies of colloidal approaches for psoriasis management carried out in recent years, it has been concluded that colloidal pharmaceutical formulations could be investigated broadly and have a broad scope for effective management of many skin disorders in the coming decades. Full article
Show Figures

Figure 1

Article
Effect of UV Irradiation (A and C) on Casuarina equisetifolia-Mediated Biosynthesis and Characterization of Antimicrobial and Anticancer Activity of Biocompatible Zinc Oxide Nanoparticles
Pharmaceutics 2021, 13(11), 1977; https://doi.org/10.3390/pharmaceutics13111977 - 22 Nov 2021
Viewed by 307
Abstract
The green synthesis of nanoparticles has emerged as a simple, safe, sustainable, reliable and eco-friendly protocol. Among different types of NPs, green-synthesized zinc oxide NPs (ZnONPs) show various promising biological uses due to their interesting magnetic, electrical, optical and chemical characteristics. Keeping in [...] Read more.
The green synthesis of nanoparticles has emerged as a simple, safe, sustainable, reliable and eco-friendly protocol. Among different types of NPs, green-synthesized zinc oxide NPs (ZnONPs) show various promising biological uses due to their interesting magnetic, electrical, optical and chemical characteristics. Keeping in view the dependence of the therapeutic efficacy of NPs on their physico-chemical characteristics, the green synthesis of ZnONPs using Casuarina equisetifolia leaf extract under UV-A and UV-C light was carried out in this study. UV-irradiation helped to control the size and morphology of ZnONPs by exciting the electrons in the photoactive compounds of plant extracts to enhance the bio-reduction of ZnO into ZnONPs. C. equisetifolia leaf extract was found enriched with phenolic (2.47 ± 0.12 mg GAE/g DW) and flavonoid content (0.88 ± 0.28 mg QE/g DW) contributing to its 74.33% free-radical scavenging activity. FTIR spectra showed the involvement of polyphenols in the bio-reduction, stabilization and capping of ZnONPs. Moreover, SEM-EDX and XRD analyses showed great potential of UV-C light in yielding smaller (34–39 nm) oval-shaped ZnONPs, whereas UV-A irradiation resulted in the formation of fairly spherical 67–71 nm ZnONPs and control ZnONPs were of mixed shape and even larger size (84–89 nm). Green-synthesized ZnONPs, notably CE-UV-C-ZnONPs, showed promising anti-bacterial activities against Bacillus subtilis, Pseudomonas fluorescens and Pseudomonas aeruginosa. Moreover, ZnONPs also enhanced ROS production which led to a significant loss of mitochondrial membrane potential and activated caspase-3 gene expression and caspase-3/7 activity in human hepatocellular carcinoma (HepG2) cells. CE-UV-C-ZnONP treatment reduced HepG2 cell viability to as low as 36.97% owing to their unique shape and smaller size. Lastly, ZnONPs were found to be highly biocompatible towards brine shrimp and human red blood cells suggesting their bio-safe nature. This research study sheds light on the plausible role of UV radiation in the green synthesis of ZnONPs with reasonable control over their size and morphology, thus improving their biological efficacy. Full article
(This article belongs to the Special Issue Applied Nanotechnology in Chronic Human Disease Management)
Show Figures

Figure 1

Article
Efficacy of Ursolic Acid-Enriched Water-Soluble and Not Cytotoxic Nanoparticles against Enterococci
Pharmaceutics 2021, 13(11), 1976; https://doi.org/10.3390/pharmaceutics13111976 - 21 Nov 2021
Viewed by 387
Abstract
Ursolic acid (UA), a pentacyclic triterpenoid acid found in many medicinal plants and aromas, is known for its antibacterial effects against multi-drug-resistant (MDR) Gram-positive bacteria, which seriously threaten human health. Unfortunately, UA water-insolubility, low bioavailability, and systemic toxicity limit the possibilities of its [...] Read more.
Ursolic acid (UA), a pentacyclic triterpenoid acid found in many medicinal plants and aromas, is known for its antibacterial effects against multi-drug-resistant (MDR) Gram-positive bacteria, which seriously threaten human health. Unfortunately, UA water-insolubility, low bioavailability, and systemic toxicity limit the possibilities of its application in vivo. Consequently, the beneficial activities of UA observed in vitro lose their potential clinical relevance unless water-soluble, not cytotoxic UA formulations are developed. With a nano-technologic approach, we have recently prepared water-soluble UA-loaded dendrimer nanoparticles (UA-G4K NPs) non-cytotoxic on HeLa cells, with promising physicochemical properties for their clinical applications. In this work, with the aim of developing a new antibacterial agent based on UA, UA-G4K has been tested on different strains of the Enterococcus genus, including marine isolates, toward which UA-G4K has shown minimum inhibitory concentrations (MICs) very low (0.5–4.3 µM), regardless of their resistance to antibiotics. Time-kill experiments, in addition to confirming the previously reported bactericidal activity of UA against E. faecium, also established it for UA-G4K. Furthermore, cytotoxicity experiments on human keratinocytes revealed that nanomanipulation of UA significantly reduced the cytotoxicity of UA, providing UA-G4K NPs with very high LD50 (96.4 µM) and selectivity indices, which were in the range 22.4–192.8, depending on the enterococcal strain tested. Due to its physicochemical and biological properties, UA-G4K could be seriously evaluated as a novel oral-administrable therapeutic option for tackling difficult-to-treat enterococcal infections. Full article
(This article belongs to the Special Issue New Trends in Therapy: From Natural Products to Nanomedicine)
Show Figures

Graphical abstract

Review
Antidepressants and Circadian Rhythm: Exploring Their Bidirectional Interaction for the Treatment of Depression
Pharmaceutics 2021, 13(11), 1975; https://doi.org/10.3390/pharmaceutics13111975 - 21 Nov 2021
Viewed by 341
Abstract
Scientific evidence that circadian rhythms affect pharmacokinetics and pharmacodynamics has highlighted the importance of drug dosing-time. Circadian oscillations alter drug absorption, distribution, metabolism, and excretion (ADME) as well as intracellular signaling systems, target molecules (e.g., receptors, transporters, and enzymes), and gene transcription. Although [...] Read more.
Scientific evidence that circadian rhythms affect pharmacokinetics and pharmacodynamics has highlighted the importance of drug dosing-time. Circadian oscillations alter drug absorption, distribution, metabolism, and excretion (ADME) as well as intracellular signaling systems, target molecules (e.g., receptors, transporters, and enzymes), and gene transcription. Although several antidepressant drugs are clinically available, less than 50% of depressed patients respond to first-line pharmacological treatments. Chronotherapeutic approaches to enhance the effectiveness of antidepressants are not completely known. Even so, experimental results found until this day suggest a positive influence of drug dosing-time on the efficacy of depression therapy. On the other hand, antidepressants have also demonstrated to modulate circadian rhythmicity and sleep–wake cycles. This review aims to evidence the potential of chronotherapy to improve the efficacy and/or safety of antidepressants. It includes pre-clinical and clinical studies that demonstrate the relevance of determining the most appropriate time of administration for antidepressant drugs. In parallel, their positive influence on the resynchronization of disrupted circadian rhythms is also herein discussed. It is expected that this review will promote the investigation of chronotherapy for the treatment of depression, contribute to a better understanding of the relationship between antidepressants and circadian rhythms, and consequently promote the development of new therapeutics. Full article
(This article belongs to the Special Issue Chronotherapy and Chronomodulated Drug Delivery)
Show Figures

Figure 1

Article
The Influence of Domain Permutations of an Albumin-Binding Domain-Fused HER2-Targeting Affibody-Based Drug Conjugate on Tumor Cell Proliferation and Therapy Efficacy
Pharmaceutics 2021, 13(11), 1974; https://doi.org/10.3390/pharmaceutics13111974 - 21 Nov 2021
Viewed by 326
Abstract
Human epidermal growth factor receptor 2 (HER2) is a clinically validated target for breast cancer therapy. Previously, a drug-fused HER2-targeting affinity protein construct successfully extended the survival of mice bearing HER2-expressing xenografts. The aim of this study was to evaluate the influence of [...] Read more.
Human epidermal growth factor receptor 2 (HER2) is a clinically validated target for breast cancer therapy. Previously, a drug-fused HER2-targeting affinity protein construct successfully extended the survival of mice bearing HER2-expressing xenografts. The aim of this study was to evaluate the influence of the number and positioning of the protein domains in the drug conjugate. Seven HER2-targeting affibody-based constructs, including one or two affibody molecules (Z) with or without an albumin-binding domain (ABD), namely Z, Z-ABD, ABD-Z, Z-Z, Z-Z-ABD, Z-ABD-Z, and ABD-Z-Z, were evaluated on their effects on cell growth, in vivo targeting, and biodistribution. The biodistribution study demonstrated that the monomeric constructs had longer blood retention and lower hepatic uptake than the dimeric ones. A dimeric construct, specifically ABD-Z-Z, could stimulate the proliferation of HER2 expressing SKOV-3 cells in vitro and the growth of tumors in vivo, whereas the monomeric construct Z-ABD could not. These two constructs demonstrated a therapeutic effect when coupled to mcDM1; however, the effect was more pronounced for the non-stimulating Z-ABD. The median survival of the mice treated with Z-ABD-mcDM1 was 63 days compared to the 37 days for those treated with ABD-Z-Z-mcDM1 or for the control animals. Domain permutation of an ABD-fused HER2-targeting affibody-based drug conjugate significantly influences tumor cell proliferation and therapy efficacy. The monomeric conjugate Z-ABD is the most promising format for targeted delivery of the cytotoxic drug DM1. Full article
(This article belongs to the Special Issue Pharmaceutical and Bioengineering Advances in Medicine)
Show Figures

Figure 1

Article
Genetic Polymorphisms Affecting Ranibizumab Response in High Myopia Patients
Pharmaceutics 2021, 13(11), 1973; https://doi.org/10.3390/pharmaceutics13111973 - 20 Nov 2021
Viewed by 536
Abstract
High myopia is an ophthalmic pathology that affects half of the young adults in the United States and Europe and it is predicted that a third of the world’s population could be nearsighted at the end of this decade. It is characterized by [...] Read more.
High myopia is an ophthalmic pathology that affects half of the young adults in the United States and Europe and it is predicted that a third of the world’s population could be nearsighted at the end of this decade. It is characterized by at least 6 diopters or axial length > 26 mm and, choroidal neovascularization (CNV) in 5 to 11% of cases. Ranibizumab is a recombinant humanized monoclonal antibody fragment. It is an anti-vascular endothelial growth factor (anti-VEGF) drug used in the treatment of CNV. Many genetic polymorphisms have been associated with interindividual differences in the response to ranibizumab, but these associations were not yet assessed among patients with high myopia and CNV. We performed a retrospective study assessing the association of genetic polymorphisms with response to ranibizumab in patients with CNV secondary to high myopia (mCNV). We included genetic polymorphisms previously associated with the response to drugs used in CNV patients (bevacizumab, ranibizumab, aflibercept, and photodynamic therapy (PDT)). We also included genetic variants in the VEGFA gene. Based on our results, ARMS2 (rs10490924) and CFH (rs1061170) are associated with response to ranibizumab in high myopia patients; and, included VEGFA genetic polymorphisms are not associated with ranibizumab response in our population but might be related to a higher risk of CNV. Full article
(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)
Show Figures

Figure 1

Review
Smart Nanotherapeutics and Lung Cancer
Pharmaceutics 2021, 13(11), 1972; https://doi.org/10.3390/pharmaceutics13111972 - 20 Nov 2021
Viewed by 661
Abstract
Lung cancer is a significant health problem worldwide. Unfortunately, current therapeutic strategies lack a sufficient level of specificity and can harm adjacent healthy cells. Consequently, to address the clinical need, novel approaches to improve treatment efficiency with minimal side effects are required. Nanotechnology [...] Read more.
Lung cancer is a significant health problem worldwide. Unfortunately, current therapeutic strategies lack a sufficient level of specificity and can harm adjacent healthy cells. Consequently, to address the clinical need, novel approaches to improve treatment efficiency with minimal side effects are required. Nanotechnology can substantially contribute to the generation of differentiated products and improve patient outcomes. Evidence from previous research suggests that nanotechnology-based drug delivery systems could provide a promising platform for the targeted delivery of traditional chemotherapeutic drugs and novel small molecule therapeutic agents to treat lung cancer cells more effectively. This has also been found to improve the therapeutic index and reduce the required drug dose. Nanodrug delivery systems also provide precise control over drug release, resulting in reduced toxic side effects, controlled biodistribution, and accelerated effects or responses. This review highlights the most advanced and novel nanotechnology-based strategies, including targeted nanodrug delivery systems, stimuli-responsive nanoparticles, and bio-nanocarriers, which have recently been employed in preclinical and clinical investigations to overcome the current challenges in lung cancer treatments. Full article
(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)
Show Figures

Figure 1

Article
Intestinal Cellular Biomarkers of Mucosal Lesion Progression in Pediatric Celiac Disease
Pharmaceutics 2021, 13(11), 1971; https://doi.org/10.3390/pharmaceutics13111971 - 20 Nov 2021
Viewed by 323
Abstract
Celiac disease (CD) is a chronic intestinal inflammation caused by gluten ingestion in genetically predisposed individuals. Overt-CD and potential-CD are the two main forms of gluten intolerance in pediatric patients with different grades of intestinal mucosa lesion and clinical management. For overt-CD patients [...] Read more.
Celiac disease (CD) is a chronic intestinal inflammation caused by gluten ingestion in genetically predisposed individuals. Overt-CD and potential-CD are the two main forms of gluten intolerance in pediatric patients with different grades of intestinal mucosa lesion and clinical management. For overt-CD patients the gluten-free diet is mandatory, while for potential-CD the dietary therapy is recommended only for those subjects becoming clinically symptomatic overtime. To date, specific early biomarkers of evolution to villous atrophy in potential-CD are lacking. We recently observed an expansion of TCRγδ+ T cells and a concomitant disappearance of IL4-producing T cells in the intestinal mucosa of overt-CD patients compared to potential-CD children, suggesting the involvement of these two cells subsets in the transition from potential-CD to overt-CD. In this study, we demonstrated that the intestinal densities of IL4+ T cells inversely correlated with TCRγδ+ T cell expansion (p < 0.005) and with the serum levels of anti-tissue transglutaminase antibodies (p < 0.01). The changes of these two cell subsets strongly correlated with mucosal lesions, according to the histological Marsh classification, as the transition from M0 to M3 lesions was associated with a significant reduction of IL4+ T cells (M0 vs. M1 p < 0.04, M0 vs. M3 p < 0.007) and an increase of TCRγδ+ T cells (M0 vs. M1 p < 0.05, M0 vs. M3 p < 0.0006). These findings strongly suggest that the detection of TCRγδ+ and IL4+ T cells could serve as cellular biomarkers of mucosal lesion and targets of novel immunomodulatory therapies for CD. Full article
Show Figures

Figure 1

Article
Effect of the Interrelation between CYP3A5 Genotype, Concentration/Dose Ratio and Intrapatient Variability of Tacrolimus on Kidney Graft Function: Monte Carlo Simulation Approach
Pharmaceutics 2021, 13(11), 1970; https://doi.org/10.3390/pharmaceutics13111970 - 20 Nov 2021
Viewed by 293
Abstract
Background: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. Aim: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C0/D) over 6–12 months on reduced [...] Read more.
Background: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. Aim: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C0/D) over 6–12 months on reduced estimated glomerular filtration rate (eGFR) values in the late period after kidney transplantation (Tx), applying Monte Carlo (MC) simulation. Methods: The previously published linear regression was the basis for MC simulation, performed to determine how variations in significant predictors affect the distribution of eGFR from 13 to 36 months post-transplantation. The input C0/D values were derived from CYP3A5 genotype subgroups. Results: Patients characterized by high Tac IPV and low mean C0/D over 6–12 months could have been at greater risk of lower eGFR values in a three-year period following Tx compared to the other patient groups. This effect was more pronounced in patients with a lower eGFR at the 6th month and a history of acute rejection. The proven contribution of CYP3A5 expresser genotype to low C0/D values may suggest its indirect effect on long-term graft function. Conclusion: The findings indicate that simultaneous assessment of Tac IPV, C0/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring as a Useful Tool in Therapy Improvement)
Show Figures

Figure 1

Article
Understanding the Effect of Energy Density and Formulation Factors on the Printability and Characteristics of SLS Irbesartan Tablets—Application of the Decision Tree Model
Pharmaceutics 2021, 13(11), 1969; https://doi.org/10.3390/pharmaceutics13111969 - 20 Nov 2021
Viewed by 393
Abstract
Selective laser sintering (SLS) is a rapid prototyping technique for the production of three-dimensional objects through selectively sintering powder-based layer materials. The aim of the study was to investigate the effect of energy density (ED) and formulation factors on the printability and characteristics [...] Read more.
Selective laser sintering (SLS) is a rapid prototyping technique for the production of three-dimensional objects through selectively sintering powder-based layer materials. The aim of the study was to investigate the effect of energy density (ED) and formulation factors on the printability and characteristics of SLS irbesartan tablets. The correlation between formulation factors, ED, and printability was obtained using a decision tree model with an accuracy of 80%. FT-IR results revealed that there was no interaction between irbesartan and the applied excipients. DSC results indicated that irbesartan was present in an amorphous form in printed tablets. ED had a significant influence on tablets’ physical, mechanical, and morphological characteristics. Adding lactose monohydrate enabled faster drug release while reducing the possibility for printing with different laser speeds. However, formulations with crospovidone were printable with a wider range of laser speeds. The adjustment of formulation and process parameters enabled the production of SLS tablets with hydroxypropyl methylcellulose with complete release in less than 30 min. The results suggest that a decision tree could be a useful tool for predicting the printability of pharmaceutical formulations. Tailoring the characteristics of SLS irbesartan tablets by ED is possible; however, it needs to be governed by the composition of the whole formulation. Full article
(This article belongs to the Special Issue Printed Pharmaceuticals in Future Healthcare)
Show Figures

Graphical abstract

Article
Topical Delivery of Niacinamide to Skin Using Hybrid Nanogels Enhances Photoprotection Effect
Pharmaceutics 2021, 13(11), 1968; https://doi.org/10.3390/pharmaceutics13111968 - 20 Nov 2021
Viewed by 390
Abstract
Niacinamide (NIA) has been widely used in halting the features of ageing by acting as an antioxidant and preventing dehydration. NIA’s physicochemical properties suggest difficulties in surpassing the barrier imposed by the stratum corneum layer to reach the target in the skin. To [...] Read more.
Niacinamide (NIA) has been widely used in halting the features of ageing by acting as an antioxidant and preventing dehydration. NIA’s physicochemical properties suggest difficulties in surpassing the barrier imposed by the stratum corneum layer to reach the target in the skin. To improve cutaneous delivery of NIA, a hybrid nanogel was designed using carrageenan and polyvinylpyrrolidone polymers combined with jojoba oil as a permeation enhancer. Three different types of transethosomes were prepared by the thin-film hydration method, made distinct by the presence of either an edge activator or a permeation enhancer, to allow for a controlled delivery of NIA. Formulations were characterized by measurements of size, polydispersity index, zeta potential, encapsulation efficiency, and loading capacity, and by evaluating their chemical interactions and morphology. Skin permeation assays were performed using Franz diffusion cells. The hybrid hydrogels exhibited robust, porous, and highly aligned macrostructures, and when present, jojoba oil changed their morphology. Skin permeation studies with transethosomes-loaded hydrogels showed that nanogels per se exhibit a more controlled and enhanced permeation, in particular when jojoba oil was present in the transethosomes. These promising nanogels protected the human keratinocytes from UV radiation, and thus can be added to sunscreens or after-sun lotions to improve skin protection. Full article
(This article belongs to the Special Issue Novel Nano and Microencapsulation Technologies in Pharmaceutics)
Show Figures

Figure 1

Article
Expression of Chimeric HPV-HIV Protein L1P18 in Pichia pastoris; Purification and Characterization of the Virus-like Particles
Pharmaceutics 2021, 13(11), 1967; https://doi.org/10.3390/pharmaceutics13111967 - 20 Nov 2021
Viewed by 384
Abstract
Currently, three human papillomavirus (HPV) vaccines are already licensed and all of them are based on virus-like particles (VLPs) of HPV L1 capsid protein but not worldwide accessible. While about 38.0 million people were living with HIV in 2019, only 68% of HIV-infected [...] Read more.
Currently, three human papillomavirus (HPV) vaccines are already licensed and all of them are based on virus-like particles (VLPs) of HPV L1 capsid protein but not worldwide accessible. While about 38.0 million people were living with HIV in 2019, only 68% of HIV-infected individuals were accessing antiretroviral therapy as of the end of June 2020 and there is no HIV vaccine yet. Therefore, safe, effective, and affordable vaccines against those two viruses are immediately needed. Both HPV and HIV are sexually transmitted infections and one of the main access routes is the mucosal genital tract. Thus, the development of a combined vaccine that would protect against HPV and HIV infections is a logical effort in the fight against these two major global pathogens. In this study, a recombinant Pichia pastoris producing chimeric HPV-HIV L1P18 protein intracellularly was constructed. After cell disruption, the supernatant was collected, and the VLPs were purified by a combination of ammonium sulfate precipitation, size exclusion chromatography, ultracentrifugation, and ultrafiltration. At the end of purification process, the chimeric VLPs were recovered with 96% purity and 9.23% overall yield, and the morphology of VLPs were confirmed by transmission electron microscopy. This work contributes towards the development of an alternative platform for production of a bivalent vaccine against HPV and HIV in P. pastoris. Full article
Show Figures

Graphical abstract

Article
Enhanced Cellular Uptake of H-Chain Human Ferritin Containing Gold Nanoparticles
Pharmaceutics 2021, 13(11), 1966; https://doi.org/10.3390/pharmaceutics13111966 - 19 Nov 2021
Viewed by 353
Abstract
Gold nanoparticles (AuNP) capped with biocompatible layers have functional optical, chemical, and biological properties as theranostic agents in biomedicine. The ferritin protein containing in situ synthesized AuNPs has been successfully used as an effective and completely biocompatible nanocarrier for AuNPs in human cell [...] Read more.
Gold nanoparticles (AuNP) capped with biocompatible layers have functional optical, chemical, and biological properties as theranostic agents in biomedicine. The ferritin protein containing in situ synthesized AuNPs has been successfully used as an effective and completely biocompatible nanocarrier for AuNPs in human cell lines and animal experiments in vivo. Ferritin can be uptaken by different cell types through receptor-mediated endocytosis. Despite these advantages, few efforts have been made to evaluate the toxicity and cellular internalization of AuNP-containing ferritin nanocages. In this work, we study the potential of human heavy-chain (H) and light-chain (L) ferritin homopolymers as nanoreactors to synthesize AuNPs and their cytotoxicity and cellular uptake in different cell lines. The results show very low toxicity of ferritin-encapsulated AuNPs on different human cell lines and demonstrate that efficient cellular ferritin uptake depends on the specific H or L protein chains forming the ferritin protein cage and the presence or absence of metallic cargo. Cargo-devoid apoferritin is poorly internalized in all cell lines, and the highest ferritin uptake was achieved with AuNP-loaded H-ferritin homopolymers in transferrin-receptor-rich cell lines, showing more than seven times more uptake than apoferritin. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
Show Figures

Figure 1

Review
Encapsulation of Asparaginase as a Promising Strategy to Improve In Vivo Drug Performance
Pharmaceutics 2021, 13(11), 1965; https://doi.org/10.3390/pharmaceutics13111965 - 19 Nov 2021
Viewed by 376
Abstract
Asparaginase (ASNase) is a widely applied chemotherapeutic drug that is used to treat Acute Lymphoblastic Leukemia (ALL); however, immune responses and silent inactivation of the drug often limit its bioavailability. Many strategies have been proposed to overcome these drawbacks, including the development of [...] Read more.
Asparaginase (ASNase) is a widely applied chemotherapeutic drug that is used to treat Acute Lymphoblastic Leukemia (ALL); however, immune responses and silent inactivation of the drug often limit its bioavailability. Many strategies have been proposed to overcome these drawbacks, including the development of improved formulations (biobetters), but only two of them are currently on the market. Nano- and micro-encapsulation are some of the most promising and novel approaches to enhance in vivo performance of ASNase, preventing the direct contact of the enzyme with the environment, protecting it from protease degradation, increasing the enzymes catalytic half-life, and in some cases, reducing immunogenicity. This review summarizes the strategies, particularly for ASNase nano- and micro-encapsulation, and their main findings, constraints, and current gaps in the state-of-the-art knowledge. The pros and cons of the use of different nanocarriers are discussed with the idea to ultimately provide safer and more effective treatments for patients with ALL. Full article
(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)
Show Figures

Figure 1

Article
Aliphatic Quaternary Ammonium Functionalized Nanogels for Gene Delivery
Pharmaceutics 2021, 13(11), 1964; https://doi.org/10.3390/pharmaceutics13111964 - 19 Nov 2021
Viewed by 312
Abstract
Gene therapy is a promising treatment for hereditary diseases, as well as acquired genetic diseases, including cancer. Facing the complicated physiological and pathological environment in vivo, developing efficient non-viral gene vectors is needed for their clinical application. Here, poly(N-isopropylacrylamide) (p(NIPAM)) nanogels [...] Read more.
Gene therapy is a promising treatment for hereditary diseases, as well as acquired genetic diseases, including cancer. Facing the complicated physiological and pathological environment in vivo, developing efficient non-viral gene vectors is needed for their clinical application. Here, poly(N-isopropylacrylamide) (p(NIPAM)) nanogels are presented with either protonatable tertiary amine groups or permanently charged quaternized ammonium groups to achieve DNA complexation ability. In addition, a quaternary ammonium-functionalized nanogel was further provided with an aliphatic moiety using 1-bromododecane to add a membrane-interacting structure to ultimately facilitate intracellular release of the genetic material. The ability of the tertiary amine-, quaternized ammonium-, and aliphatic quaternized ammonium-functionalized p(NIPAM) nanogels (i.e., NGs, NGs-MI, and NGs-BDD, respectively) to mediate gene transfection was evaluated by fluorescence microscopy and flow cytometry. It is observed that NGs-BDD/pDNA complexes exhibit efficient gene loading, gene protection ability, and intracellular uptake similar to that of NGs-MI/pDNA complexes. However, only the NGs-BDD/pDNA complexes show a notable gene transfer efficiency, which can be ascribed to their ability to mediate DNA escape from endosomes. We conclude that NGs-BDD displays a cationic lipid-like behavior that facilitates endosomal escape by perturbing the endosomal/lysosomal membrane. These findings demonstrate that the presence of aliphatic chains within the nanogel is instrumental in accomplishing gene delivery, which provides a rationale for the further development of nanogel-based gene delivery systems. Full article
(This article belongs to the Special Issue Drug Delivery in The Netherlands)
Show Figures

Graphical abstract

Article
Critical Aspects in the Preparation of Extemporaneous Flecainide Acetate Oral Solution for Paediatrics
Pharmaceutics 2021, 13(11), 1963; https://doi.org/10.3390/pharmaceutics13111963 - 19 Nov 2021
Viewed by 299
Abstract
The availability of liquid oral preparations compounded by pharmacists is essential to meet paediatric needs which remain unanswered by the pharmaceutical industry. Unfortunately, compendial monographs are often not available and, in many cases, pre-formulation studies (e.g., compatibility with other excipients and solubility evaluations) [...] Read more.
The availability of liquid oral preparations compounded by pharmacists is essential to meet paediatric needs which remain unanswered by the pharmaceutical industry. Unfortunately, compendial monographs are often not available and, in many cases, pre-formulation studies (e.g., compatibility with other excipients and solubility evaluations) are not performed in-depth, leading, in some rare cases, to the inadvertent administration of a toxic dose. In this study, the preparation of an oral liquid formulation for paediatric use, containing flecainide acetate at different strengths, was considered, taking into account the possible effects of conventionally used excipients. First, the optimal vehicle was selected based on a solubility study, evidencing some unexpected formations of precipitates. As a matter of fact, the buffers commonly used for oral solutions significantly reduced flecainide solubility, and the concomitant presence of citrate buffer and methylparaben even caused the formation of non-resuspendable crystals. Then, chemical, physical, and microbiological stability were assessed. Solutions at strengths of 10 and 20 mg/mL flecainide acetate were stable up to 8 weeks when compounded by using a 40% sucrose solution as a vehicle. Microbiological data showed that the use of methylparaben was not necessary over this time period. Full article
(This article belongs to the Section Clinical Pharmaceutics)
Show Figures

Graphical abstract

Article
Disclosure of a Promising Lead to Tackle Complicated Skin and Skin Structure Infections: Antimicrobial and Antibiofilm Actions of Peptide PP4-3.1
Pharmaceutics 2021, 13(11), 1962; https://doi.org/10.3390/pharmaceutics13111962 - 19 Nov 2021
Viewed by 390
Abstract
Efficient antibiotics are being exhausted, which compromises the treatment of infections, including complicated skin and skin structure infections (cSSTI) often associated with multidrug resistant (MDR) bacteria, methicillin-resistant S. aureus (MRSA) being the most prevalent. Antimicrobial peptides (AMP) are being increasingly regarded as the [...] Read more.
Efficient antibiotics are being exhausted, which compromises the treatment of infections, including complicated skin and skin structure infections (cSSTI) often associated with multidrug resistant (MDR) bacteria, methicillin-resistant S. aureus (MRSA) being the most prevalent. Antimicrobial peptides (AMP) are being increasingly regarded as the new hope for the post-antibiotic era. Thus, future management of cSSTI may include use of peptides that, on the one hand, behave as AMP and, on the other, are able to promote fast and correct skin rebuilding. As such, we combined the well-known cosmeceutical pentapeptide-4 (PP4), devoid of antimicrobial action but possessing collagenesis-boosting properties, with the AMP 3.1, to afford the chimeric peptide PP4-3.1. We further produced its N-methyl imidazole derivative, MeIm-PP4-3.1. Both peptide-based constructs were evaluated in vitro against Gram-negative bacteria, Gram-positive bacteria, and Candida spp. fungi. Additionally, the antibiofilm activity, the toxicity to human keratinocytes, and the activity against S. aureus in simulated wound fluid (SWF) were assessed. The chimeric peptide PP4-3.1 stood out for its potent activity against Gram-positive and Gram-negative bacteria, including against MDR clinical isolates (0.8 ≤ MIC ≤ 5.7 µM), both in planktonic form and in biofilm matrix. The peptide was also active against three clinically relevant species of Candida fungi, with an overall performance superior to that of fluconazole. Altogether, data reveal that PP4-3.1 is as a promising lead for the future development of new topical treatments for severe skin infections. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
Show Figures

Figure 1

Review
The Overview on the Pharmacokinetic and Pharmacodynamic Interactions of Triazoles
Pharmaceutics 2021, 13(11), 1961; https://doi.org/10.3390/pharmaceutics13111961 - 19 Nov 2021
Viewed by 355
Abstract
Second generation triazoles are widely used as first-line drugs for the treatment of invasive fungal infections, including aspergillosis and candidiasis. This class, along with itraconazole, voriconazole, posaconazole, and isavuconazole, is characterized by a broad range of activity, however, individual drugs vary considerably in [...] Read more.
Second generation triazoles are widely used as first-line drugs for the treatment of invasive fungal infections, including aspergillosis and candidiasis. This class, along with itraconazole, voriconazole, posaconazole, and isavuconazole, is characterized by a broad range of activity, however, individual drugs vary considerably in safety, tolerability, pharmacokinetics profiles, and interactions with concomitant medications. The interaction may be encountered on the absorption, distribution, metabolism, and elimination (ADME) step. All triazoles as inhibitors or substrates of CYP isoenzymes can often interact with many drugs, which may result in the change of the activity of the drug and cause serious side effects. Drugs of this class should be used with caution with other agents, and an understanding of their pharmacokinetic profile, safety, and drug-drug interaction profiles is important to provide effective antifungal therapy. The manuscript reviews significant drug interactions of azoles with other medications, as well as with food. The PubMed and Google Scholar bases were searched to collect the literature data. The interactions with anticonvulsants, antibiotics, statins, kinase inhibitors, proton pump inhibitors, non-nucleoside reverse transcriptase inhibitors, opioid analgesics, benzodiazepines, cardiac glycosides, nonsteroidal anti-inflammatory drugs, immunosuppressants, antipsychotics, corticosteroids, biguanides, and anticoagulants are presented. We also paid attention to possible interactions with drugs during experimental therapies for the treatment of COVID-19. Full article
(This article belongs to the Special Issue Drug–Drug Interactions (Volume II))
Article
Variability of Tacrolimus Trough Concentration in Liver Transplant Patients: Which Role of Inflammation?
Pharmaceutics 2021, 13(11), 1960; https://doi.org/10.3390/pharmaceutics13111960 - 19 Nov 2021
Viewed by 325
Abstract
Tacrolimus presents high intra and inter-individual variability in its blood trough concentration (Cmin). Knowledge of the factors that are involved in tacrolimus Cmin variability is thus clinically important to prevent or limit it. Inflammation can affect the pharmacokinetic properties of drugs. We evaluated [...] Read more.
Tacrolimus presents high intra and inter-individual variability in its blood trough concentration (Cmin). Knowledge of the factors that are involved in tacrolimus Cmin variability is thus clinically important to prevent or limit it. Inflammation can affect the pharmacokinetic properties of drugs. We evaluated the contribution of acute inflammation in the pharmacokinetic variability of tacrolimus blood Cmin in a large cohort of liver transplant patients. Demographic, biological, and clinical data from 248 liver transplant patients treated with tacrolimus from January 2010 to December 2016 were retrospectively collected from medical records. In total, 1573 Cmin/dose and concomitant C-reactive protein (CRP) measurements were analysed. In multivariate analysis, the log Cmin/dose of tacrolimus was significantly and positively associated with the hematocrit, ALAT, and CRP concentrations. CRP concentrations were higher (p = 0.003) for patients with tacrolimus overexposure (i.e., tacrolimus Cmin > 15 µg/L) (median CRP (10th–90th percentiles): 27 mg/L (3–149 mg/L), n = 91) than they were for patients with a tacrolimus Cmin ≤ 15 µg/L (13 mg/mL (3–95 mg/L), n = 1482)). CRP in the fourth quartile (49 to 334 mg/L) was associated with a 2.6-fold increased risk of tacrolimus Cmin overexposure. Our study provides evidence that inflammation contributes to tacrolimus Cmin variability and suggests that inflammation should be considered for the correct interpretation of tacrolimus blood concentration. Full article
(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)
Show Figures

Figure 1

Article
Role of Survivin in Bladder Cancer: Issues to Be Overcome When Designing an Efficient Dual Nano-Therapy
Pharmaceutics 2021, 13(11), 1959; https://doi.org/10.3390/pharmaceutics13111959 - 19 Nov 2021
Viewed by 408
Abstract
Bladder cancer is the 10th most diagnosed cancer, with almost 10 M cancer deaths last year worldwide. Currently, chemotherapy is widely used as adjuvant therapy after surgical transurethral resection. Paclitaxel (PTX) is one of the most promising drugs, but cancer cells acquire resistance, [...] Read more.
Bladder cancer is the 10th most diagnosed cancer, with almost 10 M cancer deaths last year worldwide. Currently, chemotherapy is widely used as adjuvant therapy after surgical transurethral resection. Paclitaxel (PTX) is one of the most promising drugs, but cancer cells acquire resistance, causing failure of this treatment and increasing the recurrence of the disease. This poor chemotherapeutic response has been associated with the overexpression of the protein survivin. In this work, we present a novel dual nano-treatment for bladder cancer based on the hypothesis that the inhibition of survivin in cancer cells, using a siRNA gene therapy strategy, could decrease their resistance to PTX. For this purpose, two different polymeric nanoparticles were developed to encapsulate PTX and survivin siRNA independently. PTX nanoparticles showed sizes around 150 nm, with a paclitaxel loading of around 1.5%, that produced sustained tumor cell death. In parallel, siRNA nanoparticles, with similar sizes and loading efficiency of around 100%, achieved the oligonucleotide transfection and knocking down of survivin expression that also resulted in tumor cell death. However, dual treatment did not show the synergistic effect expected. The root cause of this issue was found to be the cell cycle arrest produced by nuclear survivin silencing, which is incompatible with PTX action. Therefore, we concluded that although the vastly reported role of survivin in bladder cancer, its silencing does not sensitize cells to currently applied chemotherapies. Full article
(This article belongs to the Special Issue Functional Nanocarrier Technology to Deliver siRNA for Cancer Therapy)
Show Figures

Figure 1

Article
Optimization of Hemoglobin Encapsulation within PLGA Nanoparticles and Their Investigation as Potential Oxygen Carriers
Pharmaceutics 2021, 13(11), 1958; https://doi.org/10.3390/pharmaceutics13111958 - 18 Nov 2021
Viewed by 426
Abstract
Hemoglobin (Hb)-based oxygen carriers (HBOCs) display the excellent oxygen-carrying properties of red blood cells, while overcoming some of the limitations of donor blood. Various encapsulation platforms have been explored to prepare HBOCs which aim to avoid or minimize the adverse effects caused by [...] Read more.
Hemoglobin (Hb)-based oxygen carriers (HBOCs) display the excellent oxygen-carrying properties of red blood cells, while overcoming some of the limitations of donor blood. Various encapsulation platforms have been explored to prepare HBOCs which aim to avoid or minimize the adverse effects caused by the administration of free Hb. Herein, we entrapped Hb within a poly(lactide-co-glycolide) (PLGA) core, prepared by the double emulsion solvent evaporation method. We study the effect of the concentrations of Hb, PLGA, and emulsifier on the size, polydispersity (PDI), loading capacity (LC), and entrapment efficiency (EE) of the resulting Hb-loaded PLGA nanoparticles (HbNPs). Next, the ability of the HbNPs to reversibly bind and release oxygen was thoroughly evaluated. When needed, trehalose, a well-known protein stabilizer that has never been explored for the fabrication of HBOCs, was incorporated to preserve Hb’s functionality. The optimized formulation had a size of 344 nm, a PDI of 0.172, a LC of 26.9%, and an EE of 40.7%. The HbNPs were imaged by microscopy and were further characterized by FTIR and CD spectroscopy to assess their chemical composition and structure. Finally, the ability of the encapsulated Hb to bind and release oxygen over several rounds was demonstrated, showing the preservation of its functionality. Full article
(This article belongs to the Special Issue Controlled Release of Nanostructured Drug Systems)
Show Figures

Graphical abstract

Article
Beta vulgaris Assisted Fabrication of Novel Ag-Cu Bimetallic Nanoparticles for Growth Inhibition and Virulence in Candida albicans
Pharmaceutics 2021, 13(11), 1957; https://doi.org/10.3390/pharmaceutics13111957 - 18 Nov 2021
Viewed by 510
Abstract
Beta vulgaris extract contains water-soluble red pigment betanin and is used as a food colorant. In this study, the biogenic Ag-Cu bimetallic nanoparticles were synthesized and characterized by different spectroscopic and microscopic techniques, including UV–Visible, FTIR, TEM. SEM-EDX, XRD, and TGA. Further, Ag-Cu [...] Read more.
Beta vulgaris extract contains water-soluble red pigment betanin and is used as a food colorant. In this study, the biogenic Ag-Cu bimetallic nanoparticles were synthesized and characterized by different spectroscopic and microscopic techniques, including UV–Visible, FTIR, TEM. SEM-EDX, XRD, and TGA. Further, Ag-Cu bimetallic nanoparticles capped with Beta vulgaris biomolecules were evaluated for their antifungal activity against Candida albicans via targeting its major virulence factors, including adherence, yeast to hyphae transition, extracellular enzyme secretion, biofilm formation, and the expression of genes related to these pathogenic traits by using standard methods. C. albicans is an opportunistic human fungal pathogen that causes significant morbidity and mortality, mainly in immunocompromised patients. The current antifungal therapy is limited with various shortcomings such as host toxicity and developing multidrug resistance. Therefore, the development of novel antifungal agents is urgently required. Furthermore, NPs were screened for cell viability and cytotoxicity effect. Antifungal susceptibility testing showed potent antifungal activity of the Ag-Cu bimetallic NPs with a significant inhibitory effect on adherence, yeast to hyphae transition, extracellular enzymes secretion, and formation of biofilms in C. albicans at sub-inhibitory and inhibitory concentrations. The RT-qPCR results at an MIC value of the NPs exhibited a varying degree of downregulation in expression levels of virulence genes. Results also revealed the dose-dependent effect of NPs on cellular viability (up to 100%) using MUSE cell analyzer. Moreover, the low cytotoxicity effect of bimetallic NPs has been observed using haemolytic assay. The overall results indicated that the newly synthesized Ag-Cu bimetallic NPs capped with Beta vulgaris are proven to possess a potent anticandidal activity, by affecting the vital pathogenic factors of C. albicans. Full article
Show Figures

Figure 1

Article
Sorafenib Repurposing for Ophthalmic Delivery by Lipid Nanoparticles: A Preliminary Study
Pharmaceutics 2021, 13(11), 1956; https://doi.org/10.3390/pharmaceutics13111956 - 18 Nov 2021
Viewed by 357
Abstract
Uveal melanoma is the second most common melanoma and the most common intraocular malignant tumour of the eye. Among various treatments currently studied, Sorafenib was also proposed as a promising drug, often administered with other compounds in order to avoid resistance mechanisms. Despite [...] Read more.
Uveal melanoma is the second most common melanoma and the most common intraocular malignant tumour of the eye. Among various treatments currently studied, Sorafenib was also proposed as a promising drug, often administered with other compounds in order to avoid resistance mechanisms. Despite its promising cellular activities, the use of Sorafenib by oral administration is limited by its severe side effects and the difficulty to reach the target. The encapsulation into drug delivery systems represents an interesting strategy to overcome these limits. In this study, different lipid nanoparticulate formulations were prepared and compared in order to select the most suitable for the encapsulation of Sorafenib. In particular, two solid lipids (Softisan or Suppocire) at different concentrations were used to produce solid lipid nanoparticles, demonstrating that higher amounts were able to achieve smaller particle sizes, higher homogeneity, and longer physical stability. The selected formulations, which demonstrated to be biocompatible on Statens Seruminstitut Rabbit Cornea cells, were modified to improve their mucoadhesion, evaluating the effect of two monovalent cationic lipids with two lipophilic chains. Sorafenib encapsulation allowed obtaining a sustained and prolonged drug release, thus confirming the potential use of the developed strategy to topically administer Sorafenib in the treatment of uveal melanoma. Full article
(This article belongs to the Special Issue Targeted Nanotherapy in Cancer Disease)
Show Figures

Graphical abstract

Article
Chitosan–Platelet-Rich Plasma Implants Improve Rotator Cuff Repair in a Large Animal Model: Pivotal Study
Pharmaceutics 2021, 13(11), 1955; https://doi.org/10.3390/pharmaceutics13111955 - 18 Nov 2021
Viewed by 310
Abstract
The purpose of this study was to assess the safety and efficacy of chitosan–platelet-rich plasma (PRP) hybrid implants used as an adjunct to surgical rotator cuff repair in a pivotal Good Laboratory Practice (GLP)-compliant study. The infraspinatus tendon was transected in 48 skeletally [...] Read more.
The purpose of this study was to assess the safety and efficacy of chitosan–platelet-rich plasma (PRP) hybrid implants used as an adjunct to surgical rotator cuff repair in a pivotal Good Laboratory Practice (GLP)-compliant study. The infraspinatus tendon was transected in 48 skeletally mature ewes and repaired with a transosseous-equivalent (TOE) technique. In the two treatment groups, a chitosan–PRP solution was injected at the footprint between the tendon and the bone and on top of the repaired site (2 mL or 3 mL doses, n = 12 per group). To further assess chitosan safety, a chitosan–water solution was injected at the same sites (3 mL, n = 12). Outcome measures included Magnetic Resonance Imaging (MRI) assessment and clinical pathology at 3 months and 6 months and histopathology at 6 months. The tendon gap was decreased at 3 months on MRI images and certain histopathological features were improved at 6 months by chitosan–PRP treatment compared to controls. The group treated with chitosan–water was not different from controls. Chitosan–PRP treatment induced no negative effects in the sheep, which suggests high safety. This study provides further evidence on the safety and efficacy of chitosan–PRP for rotator cuff repair augmentation, which could eventually be used in a clinical setting. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
Show Figures

Figure 1

Article
Nanodispersions of Polyelectrolytes Based on Humic Substances: Isolation, Physico-Chemical Characterization and Evaluation of Biological Activity
Pharmaceutics 2021, 13(11), 1954; https://doi.org/10.3390/pharmaceutics13111954 - 18 Nov 2021
Viewed by 344
Abstract
Natural polyelectrolytes, including in the form of complexes with colloidal particles, are increasingly used in pharmacy due to the possibility of regulated attachment of medicinal substances and their targeted delivery to the target organ. However, the formation, stability, and molecular-mass characteristics of polyelectrolyte [...] Read more.
Natural polyelectrolytes, including in the form of complexes with colloidal particles, are increasingly used in pharmacy due to the possibility of regulated attachment of medicinal substances and their targeted delivery to the target organ. However, the formation, stability, and molecular-mass characteristics of polyelectrolyte nanodispersions (ND) vary depending on the nature and composition of the medium of their origin. This is due to the lack of standardized approaches to quality control and regulatory documentation for most natural ND. In this paper, we first introduced the isolation, followed by investigations into their physico-chemical properties and bioactivity. Using the dried droplet method, we were able to detect the “coffee ring effect”. Fractographic studies of the surface structure of EHA and FA dried samples using SEM showed its heterogeneity and the presence of submicron particles encapsulated in the internal molecular cavities of polyelectrolyte. FTIR spectroscopy revealed the ND chemical structure of benzo-α-pyron and benzo-γ-pyron, consisting of nanoparticles and a branched frame part. The main elements detected by X-ray fluorescence in humic substance extract and fulvic acid include Si, P, S, K, Ca, Mn, Fe, Cu, Zn, whereas Fe is in high concentrations. The UV-spectra and fluorescent radiation demonstrated the possibility of studying the effect of the fulvate chromone structure on its optical properties. It is shown that dilution of the initial solutions of polyelectrolytes 1:10 contributes to the detection of smaller nanoparticles and an increase in the absolute value of the negative ζ-potential as a factor of ND stability. A study of the EHS effect on the SARS-CoV-2 virus infectious titer in the Vero E6 cell showed the effective against virus both in the virucidal scheme (the SI is 11.90–22.43) and treatment/prevention scheme (the SI is 34.85–57.33). We assume that polyelectrolyte ND prevent the binding of the coronavirus spike glycoprotein to the receptor. Taking into account the results obtained, we expect that the developed approach can become unified for the standardization of the ND natural polyelectrolytes complex, which has great prospects for use in pharmacy and medicine as a drug with antiviral activity. Full article
(This article belongs to the Special Issue New Properties of Supramolecular Complexes and Drug Nanoparticles)
Show Figures

Figure 1

Previous Issue
Next Issue
Back to TopTop