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Pharmaceutics, Volume 14, Issue 5 (May 2022) – 226 articles

Cover Story (view full-size image): The future continuous growth of the global older population augments the burden of retinal diseases worldwide. Retinal characteristics isolating and protecting the sensitive neuro-retina from the rest of the ocular tissues challenge drug delivery and necessitate research and development toward new horizons. In this review, we wish to describe the unmet medical needs, discuss the novel modes of delivery, and disclose to the reader a spectrum of older-to-novel drug delivery technologies, innovations, and the frontier of pharmacodelivery to the retina. View this paper
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Review
Functionalization of Nanoparticulate Drug Delivery Systems and Its Influence in Cancer Therapy
Pharmaceutics 2022, 14(5), 1113; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051113 - 23 May 2022
Viewed by 694
Abstract
Research into the application of nanocarriers in the delivery of cancer-fighting drugs has been a promising research area for decades. On the other hand, their cytotoxic effects on cells, low uptake efficiency, and therapeutic resistance have limited their therapeutic use. However, the urgency [...] Read more.
Research into the application of nanocarriers in the delivery of cancer-fighting drugs has been a promising research area for decades. On the other hand, their cytotoxic effects on cells, low uptake efficiency, and therapeutic resistance have limited their therapeutic use. However, the urgency of pressing healthcare needs has resulted in the functionalization of nanoparticles’ (NPs) physicochemical properties to improve clinical outcomes of new, old, and repurposed drugs. This article reviews recent research on methods for targeting functionalized nanoparticles to the tumor microenvironment (TME). Additionally, the use of relevant engineering techniques for surface functionalization of nanocarriers (liposomes, dendrimers, and mesoporous silica) and their critical roles in overcoming the current limitations in cancer therapy—targeting ligands used for targeted delivery, stimuli strategies, and multifunctional nanoparticles—were all reviewed. The limitations and future perspectives of functionalized nanoparticles were also finally discussed. Using relevant keywords, published scientific literature from all credible sources was retrieved. A quick search of the literature yielded almost 400 publications. The subject matter of this review was addressed adequately using an inclusion/exclusion criterion. The content of this review provides a reasonable basis for further studies to fully exploit the potential of these nanoparticles in cancer therapy. Full article
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Review
Heterogeneity of In Vitro Expanded Mesenchymal Stromal Cells and Strategies to Improve Their Therapeutic Actions
Pharmaceutics 2022, 14(5), 1112; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051112 - 23 May 2022
Viewed by 636
Abstract
Beneficial properties of mesenchymal stromal cells (MSCs) have prompted their use in preclinical and clinical research. Accumulating evidence has been provided for the therapeutic effects of MSCs in several pathologies, including neurodegenerative diseases, myocardial infarction, skin problems, liver disorders and cancer, among others. [...] Read more.
Beneficial properties of mesenchymal stromal cells (MSCs) have prompted their use in preclinical and clinical research. Accumulating evidence has been provided for the therapeutic effects of MSCs in several pathologies, including neurodegenerative diseases, myocardial infarction, skin problems, liver disorders and cancer, among others. Although MSCs are found in multiple tissues, the number of MSCs is low, making in vitro expansion a required step before MSC application. However, culture-expanded MSCs exhibit notable differences in terms of cell morphology, physiology and function, which decisively contribute to MSC heterogeneity. The changes induced in MSCs during in vitro expansion may account for the variability in the results obtained in different MSC-based therapy studies, including those using MSCs as living drug delivery systems. This review dissects the different changes that occur in culture-expanded MSCs and how these modifications alter their therapeutic properties after transplantation. Furthermore, we discuss the current strategies developed to improve the beneficial effects of MSCs for successful clinical implementation, as well as potential therapeutic alternatives. Full article
(This article belongs to the Special Issue Living Cell-Based Drug Delivery Systems for Biomedical Applications)
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Article
Preparation and Drug Release Profile of Chitosan–Siloxane Hybrid Capsules Coated with Hydroxyapatite
Pharmaceutics 2022, 14(5), 1111; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051111 - 23 May 2022
Viewed by 417
Abstract
Chitosan is a cationic polymer that forms polymerized membranes upon reaction with anionic polymers. Chitosan−carboxymethyl cellulose (CMC) capsules are drug delivery carrier candidates whose mechanical strength and permeability must be controlled to achieve sustained release. In this study, the capsules were prepared from [...] Read more.
Chitosan is a cationic polymer that forms polymerized membranes upon reaction with anionic polymers. Chitosan−carboxymethyl cellulose (CMC) capsules are drug delivery carrier candidates whose mechanical strength and permeability must be controlled to achieve sustained release. In this study, the capsules were prepared from chitosan−γ-glycidoxypropyltrimethoxysilane (GPTMS)−CMC. The mechanical stability of the capsules was improved by crosslinking the chitosan with GPTMS. The capsules were then coated with hydroxyapatite (HAp) by alternately soaking them in calcium chloride solution and disodium hydrogen phosphate solution to prevent rapid initial drug release. Cytochrome C (CC), as a model drug, was introduced into the capsules via two routes, impregnation and injection, and then the CC released from the capsules was examined. HAp was found to be deposited on the internal and external surfaces of the capsules. The amount of CC introduced, and the release rate were reduced by the HAp coating. The injection method was found to result in the greatest CC loading. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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Article
High Performance Gold [email protected] Self-Assembled Drug-Loading System for Cancer Thermo-Chemotherapy in the Second Near-Infrared Optical Window
Pharmaceutics 2022, 14(5), 1110; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051110 - 23 May 2022
Viewed by 522
Abstract
In terms of synergistic cancer therapy, biological nanomaterials with a second near-infrared (NIR-II) window response can greatly increase photothermal effects and photoacoustic imaging performance. Herein, we report a novel stimuli-responsive multifunctional drug-loading system which was constructed by integrating miniature gold nanorods (GNR) as [...] Read more.
In terms of synergistic cancer therapy, biological nanomaterials with a second near-infrared (NIR-II) window response can greatly increase photothermal effects and photoacoustic imaging performance. Herein, we report a novel stimuli-responsive multifunctional drug-loading system which was constructed by integrating miniature gold nanorods (GNR) as the NIR-II photothermal nanorods and cyclic ternary aptamer (CTA) composition as a carrier for chemotherapy drugs. In this system, doxorubicin hydrochloride (DOX, a chemotherapy drug) binds to the G-C base pairs of the CTA, which exhibited a controlled release behavior based on the instability of G-C base pairs in the slightly acidic tumor microenvironment. Upon the 1064 nm (NIR-II biowindow) laser irradiation, the strong photothermal and promoted cargo release properties endow gold [email protected] ([email protected]) nanoparticles displaying excellent synergistic anti-cancer effect. Moreover, the [email protected] of NIR also possesses thermal imaging and photoacoustic (PA) imaging properties due to the strong NIR region absorbance. This work enables to obtaining a stimuli-responsive “all-in-one” nanocarrier, which are promising candidate for bimodal imaging diagnosis and chemo-photothermal synergistic therapy. Full article
(This article belongs to the Special Issue Polymer and Lipid-based Materials for Nanodrug Delivery Systems)
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Review
Bioinspired and Biomimetic Nanomedicines for Targeted Cancer Therapy
Pharmaceutics 2022, 14(5), 1109; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051109 - 23 May 2022
Viewed by 540
Abstract
Undesirable side effects and multidrug resistance are the major obstacles in conventional chemotherapy towards cancers. Nanomedicines provide alternative strategies for tumor-targeted therapy due to their inherent properties, such as nanoscale size and tunable surface features. However, the applications of nanomedicines are hampered in [...] Read more.
Undesirable side effects and multidrug resistance are the major obstacles in conventional chemotherapy towards cancers. Nanomedicines provide alternative strategies for tumor-targeted therapy due to their inherent properties, such as nanoscale size and tunable surface features. However, the applications of nanomedicines are hampered in vivo due to intrinsic disadvantages, such as poor abilities to cross biological barriers and unexpected off-target effects. Fortunately, biomimetic nanomedicines are emerging as promising therapeutics to maximize anti-tumor efficacy with minimal adverse effects due to their good biocompatibility and high accumulation abilities. These bioengineered agents incorporate both the physicochemical properties of diverse functional materials and the advantages of biological materials to achieve desired purposes, such as prolonged circulation time, specific targeting of tumor cells, and immune modulation. Among biological materials, mammalian cells (such as red blood cells, macrophages, monocytes, and neutrophils) and pathogens (such as viruses, bacteria, and fungi) are the functional components most often used to confer synthetic nanoparticles with the complex functionalities necessary for effective nano-biointeractions. In this review, we focus on recent advances in the development of bioinspired and biomimetic nanomedicines (such as mammalian cell-based drug delivery systems and pathogen-based nanoparticles) for targeted cancer therapy. We also discuss the biological influences and limitations of synthetic materials on the therapeutic effects and targeted efficacies of various nanomedicines. Full article
(This article belongs to the Special Issue Frontier Novelties of Nanotechnology in Cancer Targeting)
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Article
Reparative Efficacy of Liposome-Encapsulated Oleanolic Acid against Liver Inflammation Induced by Fine Ambient Particulate Matter and Alcohol in Mice
Pharmaceutics 2022, 14(5), 1108; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051108 - 23 May 2022
Viewed by 565
Abstract
Airborne fine particulate matter (PM2.5) is a severe problem and is associated with health issues including liver diseases. Workers performing manual labor tend to be alcohol consumers during work, where they are also exposed to PM2.5. Long-term PM2.5 [...] Read more.
Airborne fine particulate matter (PM2.5) is a severe problem and is associated with health issues including liver diseases. Workers performing manual labor tend to be alcohol consumers during work, where they are also exposed to PM2.5. Long-term PM2.5 exposure can increase oxidative stress, leading to inflammation. Whether long-term exposure to air pollution and alcohol synergistically increases liver fibrosis risk warrants investigation. Oleanolic acid (OA)—a triterpenoid—has antioxidant and anti-inflammatory activities, but its low water solubility and cytotoxicity impair its potential applications. In this study, we fabricated liposomal OA nanoparticles (Lipo-OAs); then, we evaluated the anti-inflammatory effect on exposed cells and the ameliorative effect of Lipo-OAs on PM2.5 and alcohol-induced liver fibrosis in mice. The half maximal inhibitory concentration of PM2.5 for hepatic stellate cells was 900 μg/mL; at a concentration of ≥600 μg/mL, PM2.5 significantly increased interleukin-6 and tumor necrosis factor-α production. OA encapsulation in Lipo-OAs, 353 ± 140 nm in diameter with 79% encapsulation efficiency, significantly reduced OA cytotoxicity. Lipo-OAs treatment significantly reduced alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase levels; histologically, it alleviated steatosis and improved Ishak’s modified HAI score. In conclusion, Lipo-OAs have potential anti-inflammatory and reparative effects for PM2.5 and alcohol-induced liver injury treatment. Full article
(This article belongs to the Special Issue Nanoformulation of Drug Delivery Systems for Natural Products)
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Article
Simultaneous Improvement of Dissolution Behavior and Oral Bioavailability of Antifungal Miconazole via Cocrystal and Salt Formation
Pharmaceutics 2022, 14(5), 1107; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051107 - 22 May 2022
Viewed by 585
Abstract
Miconazole shows low oral bioavailability in humans due to poor aqueous solubility, although it has demonstrated various pharmacological activities such as antifungal, anti-tubercular and anti-tumor effects. Cocrystal/salt formation is one of the effective methods for solving this problem. In this study, different methods [...] Read more.
Miconazole shows low oral bioavailability in humans due to poor aqueous solubility, although it has demonstrated various pharmacological activities such as antifungal, anti-tubercular and anti-tumor effects. Cocrystal/salt formation is one of the effective methods for solving this problem. In this study, different methods (liquid-assisted grinding, slurrying and lyophilization) were used to investigate their impact on the formation of the miconazole multicomponent crystals with succinic, maleic and dl-tartaric acids. The solid state of the prepared powder was characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. It was found that lyophilization not only promotes partial amorphization of both salts but also allows obtaining a new polymorph of the miconazole salt with dl-tartaric acid. The lyophilized salts compared with the same samples prepared by two other methods showed better dissolution rates but low stability during the studies due to rapid recrystallization. Overall, it was determined that the preparation method of multicomponent crystals affects the solid-state characteristics and miconazole physicochemical properties significantly. The in vivo studies revealed that the miconazole multicomponent crystals indicated the higher peak blood concentration and area under the curve from 0 to 32 h values 2.4-, 2.9- and 4.6-fold higher than the pure drug. Therefore, this study demonstrated that multicomponent crystals are promising formulations for enhancing the oral bioavailability of poorly soluble compounds. Full article
(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)
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Article
Evaluation of 3-Borono-l-Phenylalanine as a Water-Soluble Boron Neutron Capture Therapy Agent
Pharmaceutics 2022, 14(5), 1106; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051106 - 22 May 2022
Viewed by 607
Abstract
Although 4-borono-l-phenylalanine (4-BPA) is currently the only marketed agent available for boron neutron capture therapy (BNCT), its low water solubility raises concerns. In this study, we synthesized 3-borono-l-phenylalanine (3-BPA), a positional isomer of 4-BPA, with improved water solubility. We [...] Read more.
Although 4-borono-l-phenylalanine (4-BPA) is currently the only marketed agent available for boron neutron capture therapy (BNCT), its low water solubility raises concerns. In this study, we synthesized 3-borono-l-phenylalanine (3-BPA), a positional isomer of 4-BPA, with improved water solubility. We further evaluated its physicochemical properties, tumor accumulation, and biodistribution. The water solubility of 3-BPA was 125 g/L, which is more than 100 times higher than that of 4-BPA. Due to the high water solubility, we prepared the administration solution of 3-BPA without a solubilizer sugar, which is inevitably added to 4-BPA preparation and has adverse effects. In in vitro and in vivo experiments, boron accumulation in cancers after administration was statistically equivalent in both sugar-complexed 3-BPA and 4-BPA. Furthermore, the biodistribution of 3-BPA was comparable with that of sugar-complexed 3-BPA. Since 3-BPA has high water solubility and tumor targetability equivalent to 4-BPA, 3-BPA can replace 4-BPA in future BNCT. Full article
(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))
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Article
Impact of Magnesium on Oxytocin Receptor Function
Pharmaceutics 2022, 14(5), 1105; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051105 - 21 May 2022
Viewed by 666
Abstract
Background and Purpose: The intranasal administration of oxytocin (OT) reduces migraine headaches through activation of the oxytocin receptor (OTR). Magnesium ion (Mg2+) concentration is critical to the activation of the OTR, and a low serum Mg2+ concentration is predictive of a [...] Read more.
Background and Purpose: The intranasal administration of oxytocin (OT) reduces migraine headaches through activation of the oxytocin receptor (OTR). Magnesium ion (Mg2+) concentration is critical to the activation of the OTR, and a low serum Mg2+ concentration is predictive of a migraine headache. We, therefore, examined the functional impact of Mg2+ concentration on OT-OTR binding efficacy using two complimentary bioassays. Experimental Approach: Current clamp recordings of rat trigeminal ganglia (TG) neurons measured the impact of Mg2+ on an OT-induced reduction in excitability. In addition, we assessed the impact of Mg2+ on intranasal OT-induced craniofacial analgesia in rats. Key Results: While OT alone dose-dependently hyperpolarized TG neurons, decreasing their excitability, the addition of 1.75 mM Mg2+ significantly enhanced this effect. Similarly, while the intranasal application of OT produced dose-dependent craniofacial analgesia, Mg2+ significantly enhanced these effects. Conclusions and Implications: OT efficacy may be limited by low ambient Mg2+ levels. The addition of Mg2+ to OT formulations may improve its efficacy in reducing headache pain as well as for other OT-dependent processes. Full article
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Article
Green Synthesis of Silver Nanoparticles Using Hypericum perforatum L. Aqueous Extract with the Evaluation of Its Antibacterial Activity against Clinical and Food Pathogens
Pharmaceutics 2022, 14(5), 1104; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051104 - 21 May 2022
Viewed by 596
Abstract
The rapid development of nanotechnology and its applications in medicine has provided the perfect solution against a wide range of different microbes, especially antibiotic-resistant ones. In this study, a one-step approach was used in preparing silver nanoparticles (AgNPs) by mixing silver nitrate with [...] Read more.
The rapid development of nanotechnology and its applications in medicine has provided the perfect solution against a wide range of different microbes, especially antibiotic-resistant ones. In this study, a one-step approach was used in preparing silver nanoparticles (AgNPs) by mixing silver nitrate with hot Hypericum perforatum (St. John’s wort) aqueous extract under high stirring to prevent agglomeration. The formation of silver nanoparticles was monitored by continuous measurement of the surface plasma resonance spectra (UV-VIS). The effect of St. John’s wort aqueous extract on the formation of silver nanoparticles was evaluated and fully characterized by using different physicochemical techniques. The obtained silver nanoparticles were spherical, monodisperse, face-centered cubic (fcc) crystal structures, and the size ranges between 20 to 40 nm. They were covered with a capping layer of organic compounds considered as a nano dimension protective layer that prevents agglomeration and sedimentation. AgNPs revealed antibacterial activity against both tested Gram-positive and Gram-negative bacterial strains causing the formation of 13–32 mm inhibition zones with MIC 6.25–12.5 µg/mL; Escherichia coli strains were resistant to tested AgNPs. The specific growth rate of S. aureus was significantly reduced due to tested AgNPs at concentrations ≥½ MIC. AgNPs did not affect wound migration in fibroblast cell lines compared to control. Our results highlighted the potential use of AgNPs capped with plant extracts in the pharmaceutical and food industries to control bacterial pathogens’ growth; however, further studies are required to confirm their wound healing capability and their health impact must be critically evaluated. Full article
(This article belongs to the Special Issue Pharmaceutical Applications of Plant Extracts)
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Article
Surface Functionalization of Silica Nanoparticles: Strategies to Optimize the Immune-Activating Profile of Carrier Platforms
Pharmaceutics 2022, 14(5), 1103; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051103 - 21 May 2022
Viewed by 590
Abstract
Silica nanoparticles (SiNPs) are generally regarded as safe and may represent an attractive carrier platform for nanomedical applications when loaded with biopharmaceuticals. Surface functionalization by different chemistries may help to optimize protein loading and may further impact uptake into the targeted tissues or [...] Read more.
Silica nanoparticles (SiNPs) are generally regarded as safe and may represent an attractive carrier platform for nanomedical applications when loaded with biopharmaceuticals. Surface functionalization by different chemistries may help to optimize protein loading and may further impact uptake into the targeted tissues or cells, however, it may also alter the immunologic profile of the carrier system. In order to circumvent side effects, novel carrier candidates need to be tested thoroughly, early in their development stage within the pharmaceutical innovation pipeline, for their potential to activate or modify the immune response. Previous studies have identified surface functionalization by different chemistries as providing a plethora of modifications for optimizing efficacy of biopharmaceutical (nano)carrier platforms while maintaining an acceptable safety profile. In this study, we synthesized SiNPs and chemically functionalized them to obtain different surface characteristics to allow their application as a carrier system for allergen-specific immunotherapy. In the present study, crude natural allergen extracts are used in combination with alum instead of well-defined active pharmaceutical ingredients (APIs), such as recombinant allergen, loaded onto (nano)carrier systems with immunologically inert and stable properties in suspension. This study was motivated by the hypothesis that comparing different charge states could allow tailoring of the binding capacity of the particulate carrier system, and hence the optimization of biopharmaceutical uptake while maintaining an acceptable safety profile, which was investigated by determining the maturation of human antigen-presenting cells (APCs). The functionalized nanoparticles were characterized for primary and hydrodynamic size, polydispersity index, zeta potential, endotoxin contamination. As potential candidates for allergen-specific immunotherapy, the differently functionalized SiNPs were non-covalently coupled with a highly purified, endotoxin-free recombinant preparation of the major birch pollen allergen Bet v 1 that functioned for further immunological testing. Binding efficiencies of allergen to SiNPs was controlled to determine uptake of API. For efficacy and safety assessment, we employed human monocyte-derived dendritic cells as model for APCs to detect possible differences in the particles’ APC maturation potential. Functionalization of SiNP did not affect the viability of APCs, however, the amount of API physisorbed onto the nanocarrier system, which induced enhanced uptake, mainly by macropinocytosis. We found slight differences in the maturation state of APCs for the differently functionalized SiNP–API conjugates qualifying surface functionalization as an effective instrument for optimizing the immune response towards SiNPs. This study further suggests that surface-functionalized SiNPs could be a suitable, immunologically inert vehicle for the efficient delivery of biopharmaceutical products, as evidenced here for allergen-specific immunotherapy. Full article
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Article
Ultrasound Triggers Hypericin Activation Leading to Multifaceted Anticancer Activity
Pharmaceutics 2022, 14(5), 1102; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051102 - 21 May 2022
Viewed by 495
Abstract
The use of ultrasound (US) in combination with a responsive chemical agent (sonosensitizer) can selectively trigger the agent’s anticancer activity in a process called sonodynamic therapy (SDT). SDT shares some properties with photodynamic therapy (PDT), which has been clinically approved, but sets itself [...] Read more.
The use of ultrasound (US) in combination with a responsive chemical agent (sonosensitizer) can selectively trigger the agent’s anticancer activity in a process called sonodynamic therapy (SDT). SDT shares some properties with photodynamic therapy (PDT), which has been clinically approved, but sets itself apart because of its use of US rather than light to achieve better tissue penetration. SDT provides anticancer effects mainly via the sonosensitizer-mediated generation of reactive oxygen species (ROS), although the precise nature of the underpinning mechanism is still under debate. This work investigates the SDT anticancer activity of hypericin (Hyp) in vitro in two- (2D) and three-dimensional (3D) HT-29 colon cancer models, and uses PDT as a yardstick due to its well-known Hyp phototoxicity. The cancer cell uptake and cellular localization of Hyp were investigated first to determine the proper noncytotoxic concentration and incubation time of Hyp for SDT. Furthermore, ROS production, cell proliferation, and cell death were evaluated after Hyp was exposed to US. Since cancer relapse and transporter-mediated multidrug resistance (MDR) are important causes of cancer treatment failure, the US-mediated ability of Hyp to elicit immunogenic cell death (ICD) and overcome MDR was also investigated. SDT showed strong ROS-mediated anticancer activity 48 h after treatment in both the HT-29 models. Specific damage-associated molecular patterns that are consistent with ICD, such as calreticulin (CRT) exposure and high-mobility group box 1 protein (HMGB1) release, were observed after SDT with Hyp. Moreover, the expression of the ABC transporter, P-glycoprotein (P-gp), in HT-29/MDR cells was not able to hinder cancer cell responsiveness to SDT with Hyp. This work reveals, for the first time, the US responsiveness of Hyp with significant anticancer activity being displayed, making it a full-fledged sonosensitizer for the SDT of cancer. Full article
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Article
Development of an LNP-Encapsulated mRNA-RBD Vaccine against SARS-CoV-2 and Its Variants
Pharmaceutics 2022, 14(5), 1101; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051101 - 20 May 2022
Viewed by 652
Abstract
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is undoubtedly the most challenging pandemic in the current century and remains a global health emergency. As the number of COVID-19 cases in the world is on the rise and [...] Read more.
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is undoubtedly the most challenging pandemic in the current century and remains a global health emergency. As the number of COVID-19 cases in the world is on the rise and variants continue to emerge, there is an urgent need for vaccines. Among all immunization approaches, mRNA vaccines have demonstrated more promising results in response to this challenge. Herein, we designed an mRNA-based vaccine encoding the receptor-binding domain (RBD) of SARS-CoV-2 encapsulated in lipid nanoparticles (LNPs). Intramuscular (i.m.) administration of the mRNA-RBD vaccine elicited broad-spectrum neutralizing antibodies and cellular responses against not only the wild-type SARS-CoV-2 virus but also Delta and Omicron variants. These results indicated that two doses of mRNA-RBD immunization conferred a strong immune response in mice against the wild-type SARS-CoV-2, while the booster dose provided a sufficient immunity against SARS-CoV-2 and its variants. Taken together, the three-dose regimen strategy of the mRNA-RBD vaccine proposed in the present study appears to be a promising reference for the development of mRNA vaccines targeting SARS-CoV-2 variants. Full article
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Article
Anti-Cancerous Potential of Polysaccharides Derived from Wheat Cell Culture
Pharmaceutics 2022, 14(5), 1100; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051100 - 20 May 2022
Viewed by 563
Abstract
There is a global need to discover effective anti-cancerous compounds from natural sources. Cultivated wheat cells can be a valuable source of non-toxic or low toxic plant-derived polysaccharides. In this study, we evaluated the anti-cancer ability of seven fractions of wheat cell culture [...] Read more.
There is a global need to discover effective anti-cancerous compounds from natural sources. Cultivated wheat cells can be a valuable source of non-toxic or low toxic plant-derived polysaccharides. In this study, we evaluated the anti-cancer ability of seven fractions of wheat cell culture polysaccharides (WCCPSs) in the HCT-116 colon cancer cell line. Almost all (6/7) fractions had an inhibitory effect on the proliferation of colon cancer cells, and two fractions (A-b and A-f) had considerable therapeutic indexes. The WCCPS fractions induced cell cycle arrest in the G1 phase and induced different rates of apoptosis (≤48%). Transmission and scanning electron microscopy revealed that WCCPS fractions caused apoptotic changes in the nucleus and cytoplasm, including damage to mitochondria and external morphological signs of apoptosis. In addition, the WCCPSs induced an increase in the levels of Bax, cytochrome c, and caspases 8 and 3, indicating that cell death progressed through intrinsic and extrinsic pathways of apoptosis. Furthermore, some fractions caused a significant decrease of c-Myc, b-catenin, NFkB2, and HCAM (CD 44) levels, indicating enhanced cell differentiation. Thus, for the first time, our results provide a proof of concept of the anti-cancer capacity of WCCPS fractions in colorectal cancer. Full article
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Article
Crystallization of Form II Paracetamol with the Assistance of Carboxylic Acids toward Batch and Continuous Processes
Pharmaceutics 2022, 14(5), 1099; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051099 - 20 May 2022
Viewed by 478
Abstract
Form II paracetamol has captured the interest of researchers due to its improved compressibility. However, its low stability has made it difficult to be produced on a large scale with good reproducibility. In the present study, the selective polymorphic formation of paracetamol was [...] Read more.
Form II paracetamol has captured the interest of researchers due to its improved compressibility. However, its low stability has made it difficult to be produced on a large scale with good reproducibility. In the present study, the selective polymorphic formation of paracetamol was carried out by cooling crystallization with four types of additives: adipic acid, fumaric acid, oxalic acid, and succinic acid. It was found that: (1) the more additives that were added, the higher the probability of forming Form II paracetamol; (2) Form II paracetamol could be induced by seeding the paracetamol aqueous solution with Form II paracetamol and fumaric acid crystals, and not the other three carboxylic acids; (3) a new solution complex of paracetamol–oxalic acid, evidenced by the solubility diagram, was responsible for the selective nucleation of Form II paracetamol in the oxalic acid aqueous solution; and (4) the range of the degree of supersaturation for nucleating Form II paracetamol was extended with the assistance of oxalic acid or fumaric acid. In large-scale crystallization, Form II paracetamol was produced by the continuous crystallization of 44 mg of paracetamol/mL in 50 wt% of fumaric acid aqueous solution with a flow rate of 150 mL/min. Full article
(This article belongs to the Special Issue Advances in Pharmaceutical Solid Forms)
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Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands
Pharmaceutics 2022, 14(5), 1098; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051098 - 20 May 2022
Viewed by 427
Abstract
Prostate-specific membrane antigen (PSMA) is overexpressed in the majority of prostate cancer cells and is considered to be an important target for the molecular imaging and therapy of prostate cancer. Herein, we present the design, synthesis, and evaluation of 11 PSMA-binding radioligands with [...] Read more.
Prostate-specific membrane antigen (PSMA) is overexpressed in the majority of prostate cancer cells and is considered to be an important target for the molecular imaging and therapy of prostate cancer. Herein, we present the design, synthesis, and evaluation of 11 PSMA-binding radioligands with modified linker structures, focusing on the relationship between molecular structure and targeting properties. The linker design was based on 2-naphthyl-L-alanine-tranexamic acid, the linker structure of PSMA-617. X-ray crystal-structure analysis of PSMA and structure-based design were used to generate the linker modifications, suggesting that substitution of tranexamic acid could lead to interactions with Phe546, Trp541, and Arg43 within the binding cavity. After synthesis through SPPS, analogues were labelled with indium-111 and evaluated in vitro for their specific binding, affinity, and cellular retention. Selected compounds were further evaluated in vivo in PSMA-expressing tumour-bearing mice. Based on the results, 2-naphthyl-L-alanine appears to be crucial for good targeting properties, whereas tranexamic acid could be replaced by other substituents. [111In]In-BQ7859, consisting of a 2-naphthyl-L-alanine-L-tyrosine linker, demonstrated favourable targeting properties. The substitution of tranexamic acid for L-tyrosine in the linker led to an improved tumour-to-blood ratio, highlighting [111In]In-BQ7859 as a promising PSMA-targeting radioligand. Full article
(This article belongs to the Section Drug Targeting and Design)
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Review
Recent Advancements in Microneedle Technology for Multifaceted Biomedical Applications
Pharmaceutics 2022, 14(5), 1097; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051097 - 20 May 2022
Viewed by 934
Abstract
Microneedle (MNs) technology is a recent advancement in biomedical science across the globe. The current limitations of drug delivery, like poor absorption, low bioavailability, inadequate skin permeation, and poor biodistribution, can be overcome by MN-based drug delivery. Nanotechnology made significant changes in fabrication [...] Read more.
Microneedle (MNs) technology is a recent advancement in biomedical science across the globe. The current limitations of drug delivery, like poor absorption, low bioavailability, inadequate skin permeation, and poor biodistribution, can be overcome by MN-based drug delivery. Nanotechnology made significant changes in fabrication techniques for microneedles (MNs) and design shifted from conventional to novel, using various types of natural and synthetic materials and their combinations. Nowadays, MNs technology has gained popularity worldwide in biomedical research and drug delivery technology due to its multifaceted and broad-spectrum applications. This review broadly discusses MN’s types, fabrication methods, composition, characterization, applications, recent advancements, and global intellectual scenarios. Full article
(This article belongs to the Special Issue Recent Advances in Microneedle-Mediated Drug Delivery)
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Article
Topography-Mediated Enhancement of Nonviral Gene Delivery in Stem Cells
Pharmaceutics 2022, 14(5), 1096; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051096 - 20 May 2022
Viewed by 477
Abstract
Gene delivery holds great promise for bioengineering, biomedical applications, biosensors, diagnoses, and gene therapy. In particular, the influence of topography on gene delivery is considered to be an attractive approach due to low toxicity and localized delivery properties. Even though many gene vectors [...] Read more.
Gene delivery holds great promise for bioengineering, biomedical applications, biosensors, diagnoses, and gene therapy. In particular, the influence of topography on gene delivery is considered to be an attractive approach due to low toxicity and localized delivery properties. Even though many gene vectors and transfection systems have been developed to enhance transfection potential and combining it with other forms of stimulations could even further enhance it. Topography is an interesting surface property that has been shown to stimulate differentiation, migration, cell morphology, and cell mechanics. Therefore, it is envisioned that topography might also be able to stimulate transfection. In this study, we tested the hypothesis “topography is able to regulate transfection efficiency”, for which we used nano- and microwave-like topographical substrates with wavelengths ranging from 500 nm to 25 µm and assessed the transfectability of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) and myoblasts. For transfection, Lipofectamine 2000 and a gene encoding plasmid for red-fluorescent protein (m-Cherry) were used and topography-induced cell morphology and transfection efficiency was analyzed. As a result, topography directs cell spreading, elongation, and proliferation as well as the transfection efficiency, which were investigated but were found not to be correlated and dependent on the cell type. A 55% percent improvement of transfection efficiency was identified for hBM-MSCs grown on 2 µm wrinkles (24.3%) as compared to hBM-MSCs cultured on flat controls (15.7%). For myoblast cells, the highest gene-expression efficiency (46.1%) was observed on the 10 µm topography, which enhanced the transfection efficiency by 64% as compared to the flat control (28.1%). From a qualitative assessment, it was observed that the uptake capacity of cationic complexes of TAMRA-labeled oligodeoxynucleotides (ODNs) was not topography-dependent but that the intracellular release was faster, as indicated by the positively stained nuclei on 2 μm for hBM-MSCs and 10 μm for myoblasts. The presented results indicate that topography enhances the gene-delivery capacity and that the responses are dependent on cell type. This study demonstrates the important role of topography on cell stimulation for gene delivery as well as understanding the uptake capacity of lipoplexes and may be useful for developing advanced nonviral gene delivery strategies. Full article
(This article belongs to the Collection Drug Delivery in The Netherlands)
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Review
Controlled-Release Nanosystems with a Dual Function of Targeted Therapy and Radiotherapy in Colorectal Cancer
Pharmaceutics 2022, 14(5), 1095; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051095 - 20 May 2022
Viewed by 596
Abstract
Nanoparticles are excellent platforms for several biomedical applications, including cancer treatment. They can incorporate different molecules to produce combinations of chemotherapeutic agents, radionuclides, and targeting molecules to improve the therapeutic strategies against cancer. These specific nanosystems are designed to have minimal side effects [...] Read more.
Nanoparticles are excellent platforms for several biomedical applications, including cancer treatment. They can incorporate different molecules to produce combinations of chemotherapeutic agents, radionuclides, and targeting molecules to improve the therapeutic strategies against cancer. These specific nanosystems are designed to have minimal side effects on healthy cells and better treatment efficacy against cancer cells when compared to chemotherapeutics, external irradiation, or targeted radiotherapy alone. In colorectal cancer, some metal and polymeric nanoparticle platforms have been used to potentialize external radiation therapy and targeted drug delivery. Polymeric nanoparticles, liposomes, albumin-based nanoparticles, etc., conjugated with PEG and/or HLA, can be excellent platforms to increase blood circulation time and decrease side effects, in addition to the combination of chemo/radiotherapy, which increases therapeutic efficacy. Additionally, radiolabeled nanoparticles have been conjugated to target specific tissues and are mainly used as agents for diagnosis, drug/gene delivery systems, or plasmonic photothermal therapy enhancers. This review aims to analyze how nanosystems are shaping combinatorial therapy and evaluate their status in the treatment of colorectal cancer. Full article
(This article belongs to the Special Issue Novel Strategies for Cancer Targeted Delivery)
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Article
Comparison of Paliperidone Palmitate from Different Crystallization Processes and Effect on Formulations In Vitro and In Vivo
Pharmaceutics 2022, 14(5), 1094; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051094 - 20 May 2022
Viewed by 372
Abstract
The quality of active pharmaceutical ingredients (APIs) is an important factor which can affect the safety and efficacy of pharmaceuticals. This study was designed to investigate the nature of paliperidone palmitate (PP) obtained by different crystallization processes, then compare the characteristics between test [...] Read more.
The quality of active pharmaceutical ingredients (APIs) is an important factor which can affect the safety and efficacy of pharmaceuticals. This study was designed to investigate the nature of paliperidone palmitate (PP) obtained by different crystallization processes, then compare the characteristics between test formulations which prepared PP of different crystallization and reference formulations (Invega Sustenna®) in vitro and in vivo. Two different PPs, namely PP-1 and PP-2, were prepared by different crystallization methods. Contact angle, morphology, and crystallinity of the PPs were characterized. Taking the particle sizes and distribution of Invega Sustenna® as reference, test formulations were prepared by the wet milling method using either a PP-1 or PP-2 sample. Their release behavior, stability in vitro, and pharmacokinetics in vivo were subsequently investigated. The results indicated that PP-2 had a higher surface free energy (SFE). More small particles were attached to the PP-1 surface under the influence of crystallization temperature. Different crystallization processes did not change the crystal of PP, but changed the crystallinity of PP. There was no obvious difference in in vitro releases between test formulations. However, the stability and state of formulation containing PP-2 were better compared to formulations containing PP-1, indicated by differences in crystallinity and SFE. Meanwhile, pharmacokinetic in vivo results demonstrated that the pharmacokinetic profiles and parameters of formulation containing PP-2 and Invega Sustenna® tended to be consistent, but those of formulations containing PP-1 were significantly different from those of formulations containing PP-2 or Invega Sustenna®, and there was burst release phenomenon of formulations containing PP-1 in rats. PP made by different crystallization processes could induce changes in appearance, SFE, and crystallinity, and further affect the stability, state, and pharmacokinetic in vivo formulation. Full article
(This article belongs to the Special Issue Advances in Pharmaceutical Solid Forms)
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Article
Preclinical Assessment of Nebulized Surfactant Delivered through Neonatal High Flow Nasal Cannula Respiratory Support
Pharmaceutics 2022, 14(5), 1093; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051093 - 20 May 2022
Viewed by 383
Abstract
High-flow nasal cannula (HFNC) is a non-invasive respiratory support (NRS) modality to treat premature infants with respiratory distress syndrome (RDS). The delivery of nebulized surfactant during NRS would represent a truly non-invasive method of surfactant administration and could reduce NRS failure rates. However, [...] Read more.
High-flow nasal cannula (HFNC) is a non-invasive respiratory support (NRS) modality to treat premature infants with respiratory distress syndrome (RDS). The delivery of nebulized surfactant during NRS would represent a truly non-invasive method of surfactant administration and could reduce NRS failure rates. However, the delivery efficiency of nebulized surfactant during HFNC has not been evaluated in vitro or in animal models of respiratory distress. We, therefore, performed first a benchmark study to compare the surfactant lung dose delivered by commercially available neonatal nasal cannulas (NCs) and HFNC circuits commonly used in neonatal intensive care units. Then, the pulmonary effect of nebulized surfactant delivered via HFNC was investigated in spontaneously breathing rabbits with induced respiratory distress. The benchmark study revealed the surfactant lung dose to be relatively low for both types of NCs tested (Westmed NCs 0.5 ± 0.45%; Fisher & Paykel NCs 1.8 ± 1.9% of a nominal dose of 200 mg/kg of Poractant alfa). The modest lung doses achieved in the benchmark study are compatible with the lack of the effect of nebulized surfactant in vivo (400 mg/kg), where arterial oxygenation and lung mechanics did not improve and were significantly worse than the intratracheal instillation of surfactant. The results from the present study indicate a relatively low lung surfactant dose and negligible effect on pulmonary function in terms of arterial oxygenation and lung mechanics. This negligible effect can, for the greater part, be explained by the high impaction of aerosol particles in the ventilation circuit and upper airways due to the high air flows used during HFNC. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery, Volume II)
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Article
Experimental Therapy of HER2-Expressing Xenografts Using the Second-Generation HER2-Targeting Affibody Molecule 188Re-ZHER2:41071
Pharmaceutics 2022, 14(5), 1092; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051092 - 20 May 2022
Viewed by 540
Abstract
HER2-targeted radionuclide therapy might be helpful for the treatment of breast, gastric, and ovarian cancers which have developed resistance to antibody and antibody-drug conjugate-based therapies despite preserved high HER2-expression. Affibody molecules are small targeting proteins based on a non-immunoglobulin scaffold. The goal of [...] Read more.
HER2-targeted radionuclide therapy might be helpful for the treatment of breast, gastric, and ovarian cancers which have developed resistance to antibody and antibody-drug conjugate-based therapies despite preserved high HER2-expression. Affibody molecules are small targeting proteins based on a non-immunoglobulin scaffold. The goal of this study was to test in an animal model a hypothesis that the second-generation HER2-targeting Affibody molecule 188Re-ZHER2:41071 might be useful for treatment of HER2-expressing malignant tumors. ZHER2:41071 was efficiently labeled with a beta-emitting radionuclide rhenium-188 (188Re). 188Re-ZHER2:41071 demonstrated preserved specificity and high affinity (KD = 5 ± 3 pM) of binding to HER2-expressing cells. In vivo studies demonstrated rapid washout of 188Re from kidneys. The uptake in HER2-expressing SKOV-3 xenografts was HER2-specific and significantly exceeded the renal uptake 4 h after injection and later. The median survival of mice, which were treated by three injections of 16 MBq 188Re-ZHER2:41071 was 68 days, which was significantly longer (<0.0001 in the log-rank Mantel-Cox test) than survival of mice in the control groups treated with vehicle (29 days) or unlabeled ZHER2:41071 (27.5 days). In conclusion, the experimental radionuclide therapy using 188Re-ZHER2:41071 enabled enhancement of survival of mice with human tumors without toxicity to the kidneys, which is the critical organ. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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Review
Bioactive Loaded Novel Nano-Formulations for Targeted Drug Delivery and Their Therapeutic Potential
Pharmaceutics 2022, 14(5), 1091; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051091 - 19 May 2022
Viewed by 626
Abstract
Plant-based medicines have received a lot of attention in recent years. Such medicines have been employed to treat medical conditions since ancient times, and in those times only the observed symptoms were used to determine dose accuracy, dose efficacy, and therapy. Rather than [...] Read more.
Plant-based medicines have received a lot of attention in recent years. Such medicines have been employed to treat medical conditions since ancient times, and in those times only the observed symptoms were used to determine dose accuracy, dose efficacy, and therapy. Rather than novel formulations, the current research work on plant-based medicines has mostly concentrated on medicinal active phytoconstituents. In the past recent decades, however, researchers have made significant progress in developing “new drug delivery systems” (NDDS) to enhance therapeutic efficacy and reduce unwanted effects of bioactive compounds. Nanocapsules, polymer micelles, liposomes, nanogels, phytosomes, nano-emulsions, transferosomes, microspheres, ethosomes, injectable hydrogels, polymeric nanoparticles, dendrimers, and other innovative therapeutic formulations have all been created using bioactive compounds and plant extracts. The novel formulations can improve solubility, therapeutic efficacy, bioavailability, stability, tissue distribution, protection from physical and chemical damage, and prolonged and targeted administration, to name a few. The current study summarizes existing research and the development of new formulations, with a focus on herbal bioactive components. Full article
(This article belongs to the Special Issue Nanoformulation of Drug Delivery Systems for Natural Products)
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Article
Pharmacokinetic/Pharmacodynamic Evaluation of a New Purine-2,6-Dione Derivative in Rodents with Experimental Autoimmune Diseases
Pharmaceutics 2022, 14(5), 1090; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051090 - 19 May 2022
Viewed by 456
Abstract
Current treatment strategies of autoimmune diseases (ADs) display a limited efficacy and cause numerous adverse effects. Phosphodiesterase (PDE)4 and PDE7 inhibitors have been studied recently as a potential treatment of a variety of ADs. In this study, a PK/PD disease progression modeling approach [...] Read more.
Current treatment strategies of autoimmune diseases (ADs) display a limited efficacy and cause numerous adverse effects. Phosphodiesterase (PDE)4 and PDE7 inhibitors have been studied recently as a potential treatment of a variety of ADs. In this study, a PK/PD disease progression modeling approach was employed to evaluate effects of a new theophylline derivative, compound 34, being a strong PDE4 and PDE7 inhibitor. Activity of the studied compound against PDE1 and PDE3 in vitro was investigated. Animal models of multiple sclerosis (MS), rheumatoid arthritis (RA), and autoimmune hepatitis were utilized to assess the efficacy of this compound, and its pharmacokinetics was investigated in mice and rats. A new PK/PD disease progression model of compound 34 was developed that satisfactorily predicted the clinical score-time courses in mice with experimental encephalomyelitis that is an animal model of MS. Compound 34 displayed a high efficacy in all three animal models of ADs. Simultaneous inhibition of PDE types located in immune cells may constitute an alternative treatment strategy of ADs. The PK/PD encephalomyelitis and arthritis progression models presented in this study may be used in future preclinical research, and, upon modifications, may enable translation of the results of preclinical investigations into the clinical settings. Full article
(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)
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Article
The Influence of Short Motifs on the Anticancer Activity of HB43 Peptide
Pharmaceutics 2022, 14(5), 1089; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051089 - 19 May 2022
Viewed by 433
Abstract
Despite the remarkable similarity in amino acid composition, many anticancer peptides (ACPs) display significant differences in terms of activity. This strongly suggests that particular relative dispositions of amino acids (motifs) play a role in the interaction with their biological target, which is often [...] Read more.
Despite the remarkable similarity in amino acid composition, many anticancer peptides (ACPs) display significant differences in terms of activity. This strongly suggests that particular relative dispositions of amino acids (motifs) play a role in the interaction with their biological target, which is often the cell membrane. To better verify this hypothesis, we intentionally modify HB43, an ACP active against a wide variety of cancers. Sequence alignment of related ACPs by ADAPTABLE web server highlighted the conserved motifs that could be at the origin of the activity. In this study, we show that changing the order of amino acids in such motifs results in a significant loss of activity against colon and breast cancer cell lines. On the contrary, amino acid substitution in key motifs may reinforce or weaken the activity, even when the alteration does not perturb the amphipathicity of the helix formed by HB43 on liposomes mimicking their surface. NMR and MD simulations with different membrane models (micelles, bicelles, and vesicles) indicate that the activity reflects the insertion capability in cancer-mimicking serine-exposing membranes, supported by the insertion of N-terminal phenylalanine in the FAK motif and the anchoring to the carboxylate of phosphatidylserine by means of arginine side chains. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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Article
Leveraging Affinity Interactions to Prolong Drug Delivery of Protein Therapeutics
Pharmaceutics 2022, 14(5), 1088; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051088 - 19 May 2022
Viewed by 445
Abstract
While peptide and protein therapeutics have made tremendous advances in clinical treatments over the past few decades, they have been largely hindered by their ability to be effectively delivered to patients. While bolus parenteral injections have become standard clinical practice, they are insufficient [...] Read more.
While peptide and protein therapeutics have made tremendous advances in clinical treatments over the past few decades, they have been largely hindered by their ability to be effectively delivered to patients. While bolus parenteral injections have become standard clinical practice, they are insufficient to treat diseases that require sustained, local release of therapeutics. Cyclodextrin-based polymers (pCD) have been utilized as a platform to extend the local delivery of small-molecule hydrophobic drugs by leveraging hydrophobic-driven thermodynamic interactions between pCD and payload to extend its release, which has seen success both in vitro and in vivo. Herein, we proposed the novel synthesis of protein–polymer conjugates that are capped with a “high affinity” adamantane. Using bovine serum albumin as a model protein, and anti-interleukin 10 monoclonal antibodies as a functional example, we outline the synthesis of novel protein–polymer conjugates that, when coupled with cyclodextrin delivery platforms, can maintain a sustained release of up to 65 days without largely sacrificing protein structure/function which has significant clinical applications in local antibody-based treatments for immune diseases, cancers, and diabetes. Full article
(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)
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Article
In Vitro CRISPR/Cas9 Transfection and Gene-Editing Mediated by Multivalent Cationic Liposome–DNA Complexes
Pharmaceutics 2022, 14(5), 1087; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051087 - 19 May 2022
Viewed by 544
Abstract
Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated nuclease 9 (Cas9) gene-editing offers exciting new therapeutic possibilities for disease treatment with a genetic etiology such as cancer, cardiovascular, neuronal, and immune disorders. However, its clinical translation is being hampered by the lack [...] Read more.
Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated nuclease 9 (Cas9) gene-editing offers exciting new therapeutic possibilities for disease treatment with a genetic etiology such as cancer, cardiovascular, neuronal, and immune disorders. However, its clinical translation is being hampered by the lack of safe, versatile, and effective nonviral delivery systems. Herein we report on the preparation and application of two cationic liposome–DNA systems (i.e., lipoplexes) for CRISPR/Cas9 gene delivery. For that purpose, two types of cationic lipids are used (DOTAP, monovalent, and MVL5, multivalent with +5e nominal charge), along with three types of helper lipids (DOPC, DOPE, and monoolein (GMO)). We demonstrated that plasmids encoding Cas9 and single-guide RNA (sgRNA), which are typically hard to transfect due to their large size (>9 kb), can be successfully transfected into HEK 293T cells via MVL5-based lipoplexes. In contrast, DOTAP-based lipoplexes resulted in very low transfection rates. MVL5-based lipoplexes presented the ability to escape from lysosomes, which may explain the superior transfection efficiency. Regarding gene editing, MVL5-based lipoplexes achieved promising GFP knockout levels, reaching rates of knockout superior to 35% for charge ratios (+/−) of 10. Despite the knockout efficiency being comparable to that of Lipofectamine 3000® commercial reagent, the non-specific gene knockout is more pronounced in MVL5-based formulations, probably resulting from the considerable cytotoxicity of these formulations. Altogether, these results show that multivalent lipid-based lipoplexes are promising CRISPR/Cas9 plasmid delivery vehicles, which by further optimization and functionalization may become suitable in vivo delivery systems. Full article
(This article belongs to the Special Issue Lipid-Based Nanocarriers for Non-Viral Gene Delivery)
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Article
Towards Development of a Non-Toxigenic Clostridioides difficile Oral Spore Vaccine against Toxigenic C. difficile
Pharmaceutics 2022, 14(5), 1086; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051086 - 19 May 2022
Viewed by 427
Abstract
Clostridioides difficile is an opportunistic gut pathogen which causes severe colitis, leading to significant morbidity and mortality due to its toxins, TcdA and TcdB. Two intra-muscular toxoid vaccines entered Phase III trials and strongly induced toxin-neutralising antibodies systemically but failed to provide local [...] Read more.
Clostridioides difficile is an opportunistic gut pathogen which causes severe colitis, leading to significant morbidity and mortality due to its toxins, TcdA and TcdB. Two intra-muscular toxoid vaccines entered Phase III trials and strongly induced toxin-neutralising antibodies systemically but failed to provide local protection in the colon from primary C. difficile infection (CDI). Alternatively, by immunising orally, the ileum (main immune inductive site) can be directly targeted to confer protection in the large intestine. The gut commensal, non-toxigenic C. difficile (NTCD) was previously tested in animal models as an oral vaccine for natural delivery of an engineered toxin chimera to the small intestine and successfully induced toxin-neutralising antibodies. We investigated whether NTCD could be further exploited to induce antibodies that block the adherence of C. difficile to epithelial cells to target the first stage of pathogenesis. In NTCD strain T7, the colonisation factor, CD0873, and a domain of TcdB were overexpressed. Following oral immunisation of hamsters with spores of recombinant strain, T7-0873 or T7-TcdB, intestinal and systemic responses were investigated. Vaccination with T7-0873 successfully induced intestinal antibodies that significantly reduced adhesion of toxigenic C. difficile to Caco-2 cells, and these responses were mirrored in sera. Additional engineering of NTCD is now warranted to further develop this vaccine. Full article
(This article belongs to the Special Issue Drug Delivery Systems for Oral Immunotherapy)
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Article
Needle-Free Jet Injectors and Nanosuspensions: Exploring the Potential of an Unexpected Pair
Pharmaceutics 2022, 14(5), 1085; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051085 - 19 May 2022
Viewed by 441
Abstract
Needle-free liquid jet injectors are medical devices used to administer pharmaceutical solutions through the skin. Jet injectors generate a high-speed stream of liquid medication that can puncture the skin and deliver the drug to the underlying tissues. In this work, we investigated the [...] Read more.
Needle-free liquid jet injectors are medical devices used to administer pharmaceutical solutions through the skin. Jet injectors generate a high-speed stream of liquid medication that can puncture the skin and deliver the drug to the underlying tissues. In this work, we investigated the feasibility of using liquid jet injectors to administer nanosuspensions, assessing the impact of the jet injection on their pharmaceutical and physicochemical properties. For this purpose, the model drug diclofenac was used to prepare a set of nanosuspensions, stabilized by poloxamer 188, and equilibrated at different pHs. The hydrodynamic diameter and morphology of the nanocrystals were analyzed before and after the jet injection across porcine skin in vitro, together with the solubility and release kinetics of diclofenac in a simulated subcutaneous environment. The efficacy of the jet injection (i.e., the amount of drug delivered across the skin) was evaluated for the nanosuspension and for a solution, which was used as a control. Finally, the nanosuspension was administered to rats by jet injector, and the plasma profile of diclofenac was evaluated and compared to the one obtained by jet injecting a solution with an equal concentration. The nanosuspension features were maintained after the jet injection in vitro, suggesting that no structural changes occur upon high-speed impact with the skin. Accordingly, in vivo studies demonstrated the feasibility of jet injecting a nanosuspension, reaching relevant plasma concentration of the drug. Overall, needle-free jet injectors proved to be a suitable alternative to conventional syringes for the administration of nanosuspensions. Full article
(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)
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Review
BUB3, beyond the Simple Role of Partner
Pharmaceutics 2022, 14(5), 1084; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051084 - 18 May 2022
Viewed by 431
Abstract
The BUB3 protein plays a key role in the activation of the spindle assembly checkpoint (SAC), a ubiquitous surveillance mechanism that ensures the fidelity of chromosome segregation in mitosis and, consequently, prevents chromosome mis-segregation and aneuploidy. Besides its role in SAC signaling, BUB3 [...] Read more.
The BUB3 protein plays a key role in the activation of the spindle assembly checkpoint (SAC), a ubiquitous surveillance mechanism that ensures the fidelity of chromosome segregation in mitosis and, consequently, prevents chromosome mis-segregation and aneuploidy. Besides its role in SAC signaling, BUB3 regulates chromosome attachment to the spindle microtubules. It is also involved in telomere replication and maintenance. Deficiency of the BUB3 gene has been closely linked to premature aging. Upregulation of the BUB3 gene has been found in a variety of human cancers and is associated with poor prognoses. Here, we review the structure and functions of BUB3 in mitosis, its expression in cancer and association with survival prognoses, and its potential as an anticancer target. Full article
(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))
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