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Pharmaceutics, Volume 15, Issue 5 (May 2023) – 249 articles

Cover Story (view full-size image): This manuscript provides an in-depth review of the scientific literature from recent years, focusing on the use of intranasal drug delivery as a promising approach for enhancing the treatment of Alzheimer-type dementia. The authors present a concise and accessible summary of key aspects of the disease, as well as the mechanisms involved in nose-to-brain drug transport. The paper covers important topics, such as the anatomical–physiological features of the nasal route and the challenges associated with delivering drugs to the brain through this pathway. Furthermore, the review critically analyzes the most promising trends in nano lipid carriers (NLCs) that have the potential to yield therapeutically valuable outcomes. The emphasis is placed on highlighting the most significant and relevant findings based on current knowledge in the field. View this paper
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51 pages, 3041 KiB  
Review
Current Principles, Challenges, and New Metrics in pH-Responsive Drug Delivery Systems for Systemic Cancer Therapy
by Roman A. Verkhovskii, Alexey N. Ivanov, Ekaterina V. Lengert, Ksenia A. Tulyakova, Natalia Yu. Shilyagina and Alexey V. Ermakov
Pharmaceutics 2023, 15(5), 1566; https://doi.org/10.3390/pharmaceutics15051566 - 22 May 2023
Cited by 5 | Viewed by 2112
Abstract
The paradigm of drug delivery via particulate formulations is one of the leading ideas that enable overcoming limitations of traditional chemotherapeutic agents. The trend toward more complex multifunctional drug carriers is well-traced in the literature. Nowadays, the prospectiveness of stimuli-responsive systems capable of [...] Read more.
The paradigm of drug delivery via particulate formulations is one of the leading ideas that enable overcoming limitations of traditional chemotherapeutic agents. The trend toward more complex multifunctional drug carriers is well-traced in the literature. Nowadays, the prospectiveness of stimuli-responsive systems capable of controlled cargo release in the lesion nidus is widely accepted. Both endogenous and exogenous stimuli are employed for this purpose; however, endogenous pH is the most common trigger. Unfortunately, scientists encounter multiple challenges on the way to the implementation of this idea related to the vehicles’ accumulation in off-target tissues, their immunogenicity, the complexity of drug delivery to intracellular targets, and finally, the difficulties in the fabrication of carriers matching all imposed requirements. Here, we discuss fundamental strategies for pH-responsive drug delivery, as well as limitations related to such carriers’ application, and reveal the main problems, weaknesses, and reasons for poor clinical results. Moreover, we attempted to formulate the profiles of an “ideal” drug carrier in the frame of different strategies drawing on the example of metal-comprising materials and considered recently published studies through the lens of these profiles. We believe that this approach will facilitate the formulation of the main challenges facing researchers and the identification of the most promising trends in technology development. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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15 pages, 2052 KiB  
Article
RETRACTED: An Innovative Tool for Evidence-Based, Personalized Treatment Trials in Mucopolysaccharidosis
by Anna-Maria Wiesinger, Brian Bigger, Roberto Giugliani, Christina Lampe, Maurizio Scarpa, Tobias Moser, Christoph Kampmann, Georg Zimmermann and Florian B. Lagler
Pharmaceutics 2023, 15(5), 1565; https://doi.org/10.3390/pharmaceutics15051565 - 22 May 2023
Cited by 1 | Viewed by 2257 | Retraction
Abstract
Mucopolysaccharidosis (MPS) is a group of rare metabolic diseases associated with reduced life expectancy and a substantial unmet medical need. Immunomodulatory drugs could be a relevant treatment approach for MPS patients, although they are not licensed for this population. Therefore, we aim to [...] Read more.
Mucopolysaccharidosis (MPS) is a group of rare metabolic diseases associated with reduced life expectancy and a substantial unmet medical need. Immunomodulatory drugs could be a relevant treatment approach for MPS patients, although they are not licensed for this population. Therefore, we aim to provide evidence justifying fast access to innovative individual treatment trials (ITTs) with immunomodulators and a high-quality evaluation of drug effects by implementing a risk–benefit model for MPS. The iterative methodology of our developed decision analysis framework (DAF) consists of the following steps: (i) a comprehensive literature analysis on promising treatment targets and immunomodulators for MPS; (ii) a quantitative risk–benefit assessment (RBA) of selected molecules; and (iii) allocation phenotypic profiles and a quantitative assessment. These steps allow for the personalized use of the model and are in accordance with expert and patient representatives. The following four promising immunomodulators were identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra might be the treatment of choice for patients with neurocognitive involvement. Nevertheless, a RBA should always be completed on an individual basis. Our evidence-based DAF model for ITTs directly addresses the substantial unmet medical need in MPS and characterizes a first approach toward precision medicine with immunomodulatory drugs. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Rare Genetic Diseases)
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14 pages, 3076 KiB  
Article
Design and Synthesis of Amphiphilic Graft Polyphosphazene Micelles for Docetaxel Delivery
by Diana Serbezeanu, Tǎchițǎ Vlad-Bubulac, Ana-Maria Macsim and Vera Bǎlan
Pharmaceutics 2023, 15(5), 1564; https://doi.org/10.3390/pharmaceutics15051564 - 22 May 2023
Viewed by 1103
Abstract
The structural versatility of polydichlorophosphazene derived from the inestimable possibilities to functionalize the two halogens, attached to each phosphazene main chain unit, attracted increasing attention in the last decade. This uncountable chemical derivatization is doubled by the amphiphilic roleplay demonstrated by polyphosphazenes containing [...] Read more.
The structural versatility of polydichlorophosphazene derived from the inestimable possibilities to functionalize the two halogens, attached to each phosphazene main chain unit, attracted increasing attention in the last decade. This uncountable chemical derivatization is doubled by the amphiphilic roleplay demonstrated by polyphosphazenes containing twofold side-chained hydrophilic and hydrophobic moieties. Thus, it is able to encapsulate specific bioactive molecules for various targeted nanomedicine applications. A new amphiphilic graft, polyphosphazenes (PPP/PEG–NH/Hys/MAB), was synthesized via the thermal ring-opening polymerization of hexachlorocyclotriphosphazene, followed by a subsequent two-step substitution reaction of chlorine atoms with hydrophilic methoxypolyethylene glycol amine/histamine dihydrochloride adduct (PEG–NH2)/(Hys) and hydrophobic methyl-p-aminobenzoate (MAB), respectively. Fourier transform infrared spectroscopy (FTIR) and 1H and 31P-nuclear magnetic resonance spectroscopy (NMR) have been used to validate the expected architectural assembly of the copolymer. Docetaxel loaded micelles based on synthesized PPP/PEG–NH/Hys/MAB were designed by dialysis method. The micelles size was evaluated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The drug release profiles from the PPP/PEG–NH/Hys/MAB micelles were established. In vitro cytotoxicity tests of PPP/PEG–NH/Hys/MAB micelles loaded with Docetaxel revealed that designed polymeric micelles exhibited an increased cytotoxic effect on MCF-7 cells. Full article
(This article belongs to the Special Issue Biomaterials in Skin Wound Healing and Tissue Regenerations Volume II)
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25 pages, 2979 KiB  
Article
Differential Expression of ABC Transporter Genes in Brain Vessels vs. Peripheral Tissues and Vessels from Human, Mouse and Rat
by Wandong Zhang, Qing Yan Liu, Arsalan S. Haqqani, Ziying Liu, Caroline Sodja, Sonia Leclerc, Ewa Baumann, Christie E. Delaney, Eric Brunette and Danica B. Stanimirovic
Pharmaceutics 2023, 15(5), 1563; https://doi.org/10.3390/pharmaceutics15051563 - 22 May 2023
Cited by 5 | Viewed by 1461
Abstract
Background: ATP-binding cassette (ABC) transporters comprise a superfamily of genes encoding membrane proteins with nucleotide-binding domains (NBD). These transporters, including drug efflux across the blood–brain barrier (BBB), carry a variety of substrates through plasma membranes against substrate gradients, fueled by hydrolyzing ATP. The [...] Read more.
Background: ATP-binding cassette (ABC) transporters comprise a superfamily of genes encoding membrane proteins with nucleotide-binding domains (NBD). These transporters, including drug efflux across the blood–brain barrier (BBB), carry a variety of substrates through plasma membranes against substrate gradients, fueled by hydrolyzing ATP. The expression patterns/enrichment of ABC transporter genes in brain microvessels compared to peripheral vessels and tissues are largely uncharacterized. Methods: In this study, the expression patterns of ABC transporter genes in brain microvessels, peripheral tissues (lung, liver and spleen) and lung vessels were investigated using RNA-seq and WesTM analyses in three species: human, mouse and rat. Results: The study demonstrated that ABC drug efflux transporter genes (including ABCB1, ABCG2, ABCC4 and ABCC5) were highly expressed in isolated brain microvessels in all three species studied; the expression of ABCB1, ABCG2, ABCC1, ABCC4 and ABCC5 was generally higher in rodent brain microvessels compared to those of humans. In contrast, ABCC2 and ABCC3 expression was low in brain microvessels, but high in rodent liver and lung vessels. Overall, most ABC transporters (with the exception of drug efflux transporters) were enriched in peripheral tissues compared to brain microvessels in humans, while in rodent species, additional ABC transporters were found to be enriched in brain microvessels. Conclusions: This study furthers the understanding of species similarities and differences in the expression patterns of ABC transporter genes; this is important for translational studies in drug development. In particular, CNS drug delivery and toxicity may vary among species depending on their unique profiles of ABC transporter expression in brain microvessels and BBB. Full article
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34 pages, 9560 KiB  
Review
Ginkgo Biloba and Long COVID: In Vivo and In Vitro Models for the Evaluation of Nanotherapeutic Efficacy
by Thelma Akanchise and Angelina Angelova
Pharmaceutics 2023, 15(5), 1562; https://doi.org/10.3390/pharmaceutics15051562 - 22 May 2023
Cited by 9 | Viewed by 3183
Abstract
Coronavirus infections are neuroinvasive and can provoke injury to the central nervous system (CNS) and long-term illness consequences. They may be associated with inflammatory processes due to cellular oxidative stress and an imbalanced antioxidant system. The ability of phytochemicals with antioxidant and anti-inflammatory [...] Read more.
Coronavirus infections are neuroinvasive and can provoke injury to the central nervous system (CNS) and long-term illness consequences. They may be associated with inflammatory processes due to cellular oxidative stress and an imbalanced antioxidant system. The ability of phytochemicals with antioxidant and anti-inflammatory activities, such as Ginkgo biloba, to alleviate neurological complications and brain tissue damage has attracted strong ongoing interest in the neurotherapeutic management of long COVID. Ginkgo biloba leaf extract (EGb) contains several bioactive ingredients, e.g., bilobalide, quercetin, ginkgolides A–C, kaempferol, isorhamnetin, and luteolin. They have various pharmacological and medicinal effects, including memory and cognitive improvement. Ginkgo biloba, through its anti-apoptotic, antioxidant, and anti-inflammatory activities, impacts cognitive function and other illness conditions like those in long COVID. While preclinical research on the antioxidant therapies for neuroprotection has shown promising results, clinical translation remains slow due to several challenges (e.g., low drug bioavailability, limited half-life, instability, restricted delivery to target tissues, and poor antioxidant capacity). This review emphasizes the advantages of nanotherapies using nanoparticle drug delivery approaches to overcome these challenges. Various experimental techniques shed light on the molecular mechanisms underlying the oxidative stress response in the nervous system and help comprehend the pathophysiology of the neurological sequelae of SARS-CoV-2 infection. To develop novel therapeutic agents and drug delivery systems, several methods for mimicking oxidative stress conditions have been used (e.g., lipid peroxidation products, mitochondrial respiratory chain inhibitors, and models of ischemic brain damage). We hypothesize the beneficial effects of EGb in the neurotherapeutic management of long-term COVID-19 symptoms, evaluated using either in vitro cellular or in vivo animal models of oxidative stress. Full article
(This article belongs to the Special Issue Innovative Drug Release and Vaccine Delivery Systems)
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17 pages, 4256 KiB  
Article
Herb Robert’s Gift against Human Diseases: Anticancer and Antimicrobial Activity of Geranium robertianum L.
by Łukasz Świątek, Inga Wasilewska, Anastazja Boguszewska, Agnieszka Grzegorczyk, Jakub Rezmer, Barbara Rajtar, Małgorzata Polz-Dacewicz and Elwira Sieniawska
Pharmaceutics 2023, 15(5), 1561; https://doi.org/10.3390/pharmaceutics15051561 - 22 May 2023
Cited by 1 | Viewed by 1531
Abstract
Geranium robertianum L. is a widely distributed plant used as a traditional herbal medicine, but the knowledge of its biological properties still needs to be improved. Thus, the purpose of this presented research was to assess the phytochemical profile of extracts from aerial [...] Read more.
Geranium robertianum L. is a widely distributed plant used as a traditional herbal medicine, but the knowledge of its biological properties still needs to be improved. Thus, the purpose of this presented research was to assess the phytochemical profile of extracts from aerial parts of G. robertianum, commercially available in Poland and to study their anticancer potential and antimicrobial properties, including the antiviral, antibacterial, and antifungal effects. Additionally, the bioactivity of fractions obtained from the hexane and ethyl acetate extract was analyzed. The phytochemical analysis revealed the presence of organic and phenolic acids, hydrolysable tannins (gallo- and ellagitannins), and flavonoids. Significant anticancer activity was found for G. robertianum hexane extract (GrH) and ethyl acetate extract (GrEA) with an SI (selectivity index) between 2.02 and 4.39. GrH and GrEA inhibited the development of HHV-1-induced cytopathic effect (CPE) in virus-infected cells and decreased the viral load by 0.52 log and 1.42 log, respectively. Among the analyzed fractions, only those obtained from GrEA showed the ability to decrease the CPE and reduce the viral load. The extracts and fractions from G. robertianum showed a versatile effect on the panel of bacteria and fungi. The highest activity was observed for fraction GrEA4 against Gram-positive bacteria, including Micrococcus luteus ATCC 10240 (MIC 8 μg/mL), Staphylococcus epidermidis ATCC 12228 (MIC 16 μg/mL), Staphylococcus aureus ATCC 43300 (MIC 125 μg/mL), Enterococcus faecalis ATCC 29212 (MIC 125 μg/mL), and Bacillus subtilis ATCC 6633 (MIC 125 μg/mL). The observed antibacterial effect may justify the traditional use of G. robertianum to treat hard-to-heal wounds. Full article
(This article belongs to the Special Issue Biomedical Applications of Natural Plant Extract)
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31 pages, 3391 KiB  
Review
Transforming Wound Management: Nanomaterials and Their Clinical Impact
by Ashwini T, Ashlesh Prabhu, Vishal Baliga, Shreesha Bhat, Siddarth T. Thenkondar, Yogendra Nayak and Usha Y. Nayak
Pharmaceutics 2023, 15(5), 1560; https://doi.org/10.3390/pharmaceutics15051560 - 22 May 2023
Cited by 6 | Viewed by 2531
Abstract
Wound healing is a complex process that can be further complicated in chronic wounds, leading to prolonged healing times, high healthcare costs, and potential patient morbidity. Nanotechnology has shown great promise in developing advanced wound dressings that promote wound healing and prevent infection. [...] Read more.
Wound healing is a complex process that can be further complicated in chronic wounds, leading to prolonged healing times, high healthcare costs, and potential patient morbidity. Nanotechnology has shown great promise in developing advanced wound dressings that promote wound healing and prevent infection. The review article presents a comprehensive search strategy that was applied to four databases, namely Scopus, Web of Science, PubMed, and Google Scholar, using specific keywords and inclusion/exclusion criteria to select a representative sample of 164 research articles published between 2001 and 2023. This review article provides an updated overview of the different types of nanomaterials used in wound dressings, including nanofibers, nanocomposites, silver-based nanoparticles, lipid nanoparticles, and polymeric nanoparticles. Several recent studies have shown the potential benefits of using nanomaterials in wound care, including the use of hydrogel/nano silver-based dressings in treating diabetic foot wounds, the use of copper oxide-infused dressings in difficult-to-treat wounds, and the use of chitosan nanofiber mats in burn dressings. Overall, developing nanomaterials in wound care has complemented nanotechnology in drug delivery systems, providing biocompatible and biodegradable nanomaterials that enhance wound healing and provide sustained drug release. Wound dressings are an effective and convenient method of wound care that can prevent wound contamination, support the injured area, control hemorrhaging, and reduce pain and inflammation. This review article provides valuable insights into the potential role of individual nanoformulations used in wound dressings in promoting wound healing and preventing infections, and serves as an excellent resource for clinicians, researchers, and patients seeking improved healing outcomes. Full article
(This article belongs to the Special Issue Nanotechnology-Based Drug Delivery Systems)
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16 pages, 762 KiB  
Review
Oral Mucosa Models to Evaluate Drug Permeability
by Elena Mazzinelli, Ilaria Favuzzi, Alessandro Arcovito, Raffaella Castagnola, Giorgia Fratocchi, Alvaro Mordente and Giuseppina Nocca
Pharmaceutics 2023, 15(5), 1559; https://doi.org/10.3390/pharmaceutics15051559 - 22 May 2023
Cited by 4 | Viewed by 3133
Abstract
Due to its numerous advantages, such as excellent drug accessibility, rapid absorption, and bypass of first-pass metabolism, the route of drug administration that involves crossing the oral mucosa is highly favored. As a result, there is significant interest in investigating the permeability of [...] Read more.
Due to its numerous advantages, such as excellent drug accessibility, rapid absorption, and bypass of first-pass metabolism, the route of drug administration that involves crossing the oral mucosa is highly favored. As a result, there is significant interest in investigating the permeability of drugs through this region. The purpose of this review is to describe the various ex vivo and in vitro models used to study the permeability of conveyed and non-conveyed drugs through the oral mucosa, with a focus on the most effective models. Currently, there is a growing need for standardized models of this mucosa that can be used for developing new drug delivery systems. Oral Mucosa Equivalents (OMEs) may provide a promising future perspective as they are capable of overcoming limitations present in many existing models. Full article
(This article belongs to the Special Issue Advances in Oral and Buccal Drug Delivery)
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12 pages, 1934 KiB  
Review
Pharmacotherapeutic Potential of Aloe secundiflora against Colorectal Cancer Growth and Proliferation
by John M. Macharia, Veronica Ngure, Barnabás Emődy, Bence Király, Zsolt Káposztás, Nóra Rozmann, Attila Erdélyi and Bence Raposa
Pharmaceutics 2023, 15(5), 1558; https://doi.org/10.3390/pharmaceutics15051558 - 22 May 2023
Cited by 4 | Viewed by 1430
Abstract
Aloe species are widespread and diverse in African ecosystems, and this commonly correlates to their habitual use as reservoirs of herbal medicine. The side effects associated with chemotherapy and the development of antimicrobial resistance to empirically used antimicrobial drugs are substantial, paving the [...] Read more.
Aloe species are widespread and diverse in African ecosystems, and this commonly correlates to their habitual use as reservoirs of herbal medicine. The side effects associated with chemotherapy and the development of antimicrobial resistance to empirically used antimicrobial drugs are substantial, paving the way for novel phytotherapeutic approaches. This comprehensive study aimed to evaluate and present Aloe secundiflora (A. secundiflora) as a compelling alternative with potential benefits in colorectal cancer (CRC) treatment. Important databases were systematically searched for relevant literature, and out of a large collection of 6421 titles and abstracts, only 68 full-text articles met the inclusion criteria. A. secundiflora possesses an abundant presence of bioactive phytoconstituents in the leaves and roots, including anthraquinones, naphthoquinones, phenols, alkaloids, saponins, tannins, and flavonoids, among others. These metabolites have proven diverse efficacy in inhibiting cancer growth. The presence of innumerable biomolecules in A. secundiflora signifies the beneficial effects of incorporating the plant as a potential anti-CRC agent. Nonetheless, we recommend further research to determine the optimal concentrations necessary to elicit beneficial effects in the management of CRC. Furthermore, they should be investigated as potential raw ingredients for making conventional medications. Full article
(This article belongs to the Special Issue Pharmaceutical Applications of Plant Extracts)
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19 pages, 2764 KiB  
Review
Challenges in the Development and Application of Organ-on-Chips for Intranasal Drug Delivery Studies
by Muhammad Usman Khan, Xinyu Cai, Zhiwei Shen, Taye Mekonnen, Agisilaos Kourmatzis, Shaokoon Cheng and Hanieh Gholizadeh
Pharmaceutics 2023, 15(5), 1557; https://doi.org/10.3390/pharmaceutics15051557 - 22 May 2023
Cited by 1 | Viewed by 1966
Abstract
With the growing demand for the development of intranasal (IN) products, such as nasal vaccines, which has been especially highlighted during the COVID-19 pandemic, the lack of novel technologies to accurately test the safety and effectiveness of IN products in vitro so that [...] Read more.
With the growing demand for the development of intranasal (IN) products, such as nasal vaccines, which has been especially highlighted during the COVID-19 pandemic, the lack of novel technologies to accurately test the safety and effectiveness of IN products in vitro so that they can be delivered promptly to the market is critically acknowledged. There have been attempts to manufacture anatomically relevant 3D replicas of the human nasal cavity for in vitro IN drug tests, and a couple of organ-on-chip (OoC) models, which mimic some key features of the nasal mucosa, have been proposed. However, these models are still in their infancy, and have not completely recapitulated the critical characteristics of the human nasal mucosa, including its biological interactions with other organs, to provide a reliable platform for preclinical IN drug tests. While the promising potential of OoCs for drug testing and development is being extensively investigated in recent research, the applicability of this technology for IN drug tests has barely been explored. This review aims to highlight the importance of using OoC models for in vitro IN drug tests and their potential applications in IN drug development by covering the background information on the wide usage of IN drugs and their common side effects where some classical examples of each area are pointed out. Specifically, this review focuses on the major challenges of developing advanced OoC technology and discusses the need to mimic the physiological and anatomical features of the nasal cavity and nasal mucosa, the performance of relevant drug safety assays, as well as the fabrication and operational aspects, with the ultimate goal to highlight the much-needed consensus, to converge the effort of the research community in this area of work. Full article
(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)
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18 pages, 3942 KiB  
Article
Pre-Clinical Assessment of Roflumilast Therapy in a Thoracic Model of Spinal Cord Injury
by Carla S. Sousa, Rui Lima, Jorge R. Cibrão, Eduardo D. Gomes, Luís S. Fernandes, Tiffany S. Pinho, Deolinda Silva, Jonas Campos, António J. Salgado and Nuno A. Silva
Pharmaceutics 2023, 15(5), 1556; https://doi.org/10.3390/pharmaceutics15051556 - 21 May 2023
Cited by 3 | Viewed by 1294
Abstract
The failure of axons to regenerate after a spinal cord injury (SCI) remains one of the greatest challenges in neuroscience. The initial mechanical trauma is followed by a secondary injury cascade, creating a hostile microenvironment, which not only is not permissive to regeneration [...] Read more.
The failure of axons to regenerate after a spinal cord injury (SCI) remains one of the greatest challenges in neuroscience. The initial mechanical trauma is followed by a secondary injury cascade, creating a hostile microenvironment, which not only is not permissive to regeneration but also leads to further damage. One of the most promising approaches for promoting axonal regeneration is to maintain the levels of cyclic adenosine monophosphate (cAMP), specifically by a phosphodiesterase-4 (PDE4) inhibitor expressed in neural tissues. Therefore, in our study, we evaluated the therapeutic effect of an FDA-approved PDE4 inhibitor, Roflumilast (Rof), in a thoracic contusion rat model. Results indicate that the treatment was effective in promoting functional recovery. Rof-treated animals showed improvements in both gross and fine motor function. Eight weeks post-injury, the animals significantly recovered by achieving occasional weight-supported plantar steps. Histological assessment revealed a significant decrease in cavity size, less reactive microglia, as well as higher axonal regeneration in treated animals. Molecular analysis revealed that IL-10 and IL-13 levels, as well as VEGF, were increased in the serum of Rof-treated animals. Overall, Roflumilast promotes functional recovery and supports neuroregeneration in a severe thoracic contusion injury model and may be important in SCI treatment. Full article
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17 pages, 8919 KiB  
Article
Biocompatible Calcium Ion-Doped Magnesium Ferrite Nanoparticles as a New Family of Photothermal Therapeutic Materials for Cancer Treatment
by Panchanathan Manivasagan, Sekar Ashokkumar, Ala Manohar, Ara Joe, Hyo-Won Han, Sun-Hwa Seo, Thavasyappan Thambi, Hai-Sang Duong, Nagendra Kumar Kaushik, Ki Hyeon Kim, Eun Ha Choi and Eue-Soon Jang
Pharmaceutics 2023, 15(5), 1555; https://doi.org/10.3390/pharmaceutics15051555 - 21 May 2023
Cited by 11 | Viewed by 1788
Abstract
Novel biocompatible and efficient photothermal (PT) therapeutic materials for cancer treatment have recently garnered significant attention, owing to their effective ablation of cancer cells, minimal invasiveness, quick recovery, and minimal damage to healthy cells. In this study, we designed and developed calcium ion-doped [...] Read more.
Novel biocompatible and efficient photothermal (PT) therapeutic materials for cancer treatment have recently garnered significant attention, owing to their effective ablation of cancer cells, minimal invasiveness, quick recovery, and minimal damage to healthy cells. In this study, we designed and developed calcium ion-doped magnesium ferrite nanoparticles (Ca2+-doped MgFe2O4 NPs) as novel and effective PT therapeutic materials for cancer treatment, owing to their good biocompatibility, biosafety, high near-infrared (NIR) absorption, easy localization, short treatment period, remote controllability, high efficiency, and high specificity. The studied Ca2+-doped MgFe2O4 NPs exhibited a uniform spherical morphology with particle sizes of 14.24 ± 1.32 nm and a strong PT conversion efficiency (30.12%), making them promising for cancer photothermal therapy (PTT). In vitro experiments showed that Ca2+-doped MgFe2O4 NPs had no significant cytotoxic effects on non-laser-irradiated MDA-MB-231 cells, confirming that Ca2+-doped MgFe2O4 NPs exhibited high biocompatibility. More interestingly, Ca2+-doped MgFe2O4 NPs exhibited superior cytotoxicity to laser-irradiated MDA-MB-231 cells, inducing significant cell death. Our study proposes novel, safe, high-efficiency, and biocompatible PT therapeutics for treating cancers, opening new vistas for the future development of cancer PTT. Full article
(This article belongs to the Special Issue Metal Nanoparticles for Cancer Therapy)
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22 pages, 3071 KiB  
Article
Development of Lyophilised Eudragit® Retard Nanoparticles for the Sustained Release of Clozapine via Intranasal Administration
by Rosamaria Lombardo, Marika Ruponen, Jarkko Rautio, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Laura Calosi, Daniele Bani, Riikka Lampinen, Katja M. Kanninen, Anne M. Koivisto, Elina Penttilä, Heikki Löppönen and Rosario Pignatello
Pharmaceutics 2023, 15(5), 1554; https://doi.org/10.3390/pharmaceutics15051554 - 21 May 2023
Cited by 4 | Viewed by 1519
Abstract
Clozapine (CZP) is the only effective drug in schizophrenia resistant to typical antipsychotics. However, existing dosage forms (oral or orodispersible tablets, suspensions or intramuscular injection) show challenging limitations. After oral administration, CZP has low bioavailability due to a large first-pass effect, while the [...] Read more.
Clozapine (CZP) is the only effective drug in schizophrenia resistant to typical antipsychotics. However, existing dosage forms (oral or orodispersible tablets, suspensions or intramuscular injection) show challenging limitations. After oral administration, CZP has low bioavailability due to a large first-pass effect, while the i.m. route is often painful, with low patient compliance and requiring specialised personnel. Moreover, CZP has a very low aqueous solubility. This study proposes the intranasal route as an alternative route of administration for CZP, through its encapsulation in polymeric nanoparticles (NPs) based on Eudragit® RS100 and RL100 copolymers. Slow-release polymeric NPs with dimensions around 400–500 nm were formulated to reside and release CZP in the nasal cavity, where it can be absorbed through the nasal mucosa and reach the systemic circulation. CZP-EUD-NPs showed a controlled release of CZP for up to 8 h. Furthermore, to reduce mucociliary clearance and increase the residence time of NPs in the nasal cavity to improve drug bioavailability, mucoadhesive NPs were formulated. This study shows that the NPs already exhibited strong electrostatic interactions with mucin at time zero due to the presence of the positive charge of the used copolymers. Furthermore, to improve the solubility, diffusion and adsorption of CZPs and the storage stability of the formulation, it was lyophilised using 5% (w/v) HP-β-CD as a cryoprotectant. It ensured the preservation of the NPs’ size, PDI and charge upon reconstitution. Moreover, physicochemical characterisation studies of solid-state NPs were performed. Finally, toxicity studies were performed in vitro on MDCKII cells and primary human olfactory mucosa cells and in vivo on the nasal mucosa of CD-1 mice. The latter showed non-toxicity of B-EUD-NPs and mild CZP-EUD-NP-induced tissue abnormalities. Full article
(This article belongs to the Special Issue Polymer-Based Micro- and Nanocarriers for Drug Delivery and Targeting)
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14 pages, 1510 KiB  
Article
Using Natural Deep Eutectic Systems as Alternative Media for Ocular Applications
by Célia Sarmento, Hugo Monteiro, Alexandre Paiva, Ana Rita C. Duarte and Ana Rita Jesus
Pharmaceutics 2023, 15(5), 1553; https://doi.org/10.3390/pharmaceutics15051553 - 21 May 2023
Cited by 4 | Viewed by 1416
Abstract
The major goal of this work was to study the potential of natural deep eutectic systems (NADES) as new media for ocular formulations. In formulating eye drops, it is important to increase the retention time of the drug on the surface of eye; [...] Read more.
The major goal of this work was to study the potential of natural deep eutectic systems (NADES) as new media for ocular formulations. In formulating eye drops, it is important to increase the retention time of the drug on the surface of eye; hence, due to their high viscosity, NADES may be interesting candidates for formulation. Different systems composed of combinations of sugars, polyols, amino acids, and choline derivatives were prepared and then characterized in terms of rheological and physicochemical properties. Our results showed that 5–10% (w/v) aqueous solutions of NADES have a good profile in terms of viscosity (0.8 to 1.2 mPa.s), osmolarity (412 to 1883 mOsmol), and pH (7.4) for their incorporation of ocular drops. Additionally, contact angle and refractive index were determined. Acetazolamide (ACZ), a highly insoluble drug used to treat glaucoma, was used as proof-of-concept. Herein, we show that NADES can increase the solubility of ACZ in aqueous solutions by at least up to 3 times, making it useful for the formulation of ACZ into ocular drops and thereby enabling more efficient treatment. The cytotoxicity assays demonstrated that NADES are biocompatible up to 5% (w/v) in aqueous media, promoting cell viability (above 80%) when compared to the control after 24 h incubation in ARPE-19 cells. Furthermore, when ACZ is dissolved in aqueous solutions of NADES, the cytotoxicity is not affected in this range of concentrations. Although further studies are necessary to design an optimal formulation incorporating NADES, this study shows that these eutectics can be powerful tools in the formulation of ocular drugs. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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14 pages, 1026 KiB  
Review
Application of Modelling and Simulation Approaches to Predict Pharmacokinetics of Therapeutic Monoclonal Antibodies in Pediatric Population
by Andrew Lim, Pradeep Sharma, Oleg Stepanov and Venkatesh Pilla Reddy
Pharmaceutics 2023, 15(5), 1552; https://doi.org/10.3390/pharmaceutics15051552 - 20 May 2023
Cited by 1 | Viewed by 2436
Abstract
Ethical regulations and limited paediatric participants are key challenges that contribute to a median delay of 6 years in paediatric mAb approval. To overcome these barriers, modelling and simulation methodologies have been adopted to design optimized paediatric clinical studies and reduce patient burden. [...] Read more.
Ethical regulations and limited paediatric participants are key challenges that contribute to a median delay of 6 years in paediatric mAb approval. To overcome these barriers, modelling and simulation methodologies have been adopted to design optimized paediatric clinical studies and reduce patient burden. The classical modelling approach in paediatric pharmacokinetic studies for regulatory submissions is to apply body weight-based or body surface area-based allometric scaling to adult PK parameters derived from a popPK model to inform the paediatric dosing regimen. However, this approach is limited in its ability to account for the rapidly changing physiology in paediatrics, especially in younger infants. To overcome this limitation, PBPK modelling, which accounts for the ontogeny of key physiological processes in paediatrics, is emerging as an alternative modelling strategy. While only a few mAb PBPK models have been published, PBPK modelling shows great promise demonstrating a similar prediction accuracy to popPK modelling in an Infliximab paediatric case study. To facilitate future PBPK studies, this review consolidated comprehensive data on the ontogeny of key physiological processes in paediatric mAb disposition. To conclude, this review discussed different use-cases for pop-PK and PBPK modelling and how they can complement each other to increase confidence in pharmacokinetic predictions. Full article
(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)
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15 pages, 2167 KiB  
Article
Preparation of Nanoparticle-Loaded Extracellular Vesicles Using Direct Flow Filtration
by Shomit Mansur, Shahriar Habib, Mikayla Hawkins, Spenser R. Brown, Steven T. Weinman and Yuping Bao
Pharmaceutics 2023, 15(5), 1551; https://doi.org/10.3390/pharmaceutics15051551 - 20 May 2023
Viewed by 2046
Abstract
Extracellular vesicles (EVs) have shown great potential as cell-free therapeutics and biomimetic nanocarriers for drug delivery. However, the potential of EVs is limited by scalable, reproducible production and in vivo tracking after delivery. Here, we report the preparation of quercetin-iron complex nanoparticle-loaded EVs [...] Read more.
Extracellular vesicles (EVs) have shown great potential as cell-free therapeutics and biomimetic nanocarriers for drug delivery. However, the potential of EVs is limited by scalable, reproducible production and in vivo tracking after delivery. Here, we report the preparation of quercetin-iron complex nanoparticle-loaded EVs derived from a breast cancer cell line, MDA-MB-231br, using direct flow filtration. The morphology and size of the nanoparticle-loaded EVs were characterized using transmission electron microscopy and dynamic light scattering. The SDS-PAGE gel electrophoresis of those EVs showed several protein bands in the range of 20–100 kDa. The analysis of EV protein markers by a semi-quantitative antibody array confirmed the presence of several typical EV markers, such as ALIX, TSG101, CD63, and CD81. Our EV yield quantification suggested a significant yield increase in direct flow filtration compared with ultracentrifugation. Subsequently, we compared the cellular uptake behaviors of nanoparticle-loaded EVs with free nanoparticles using MDA-MB-231br cell line. Iron staining studies indicated that free nanoparticles were taken up by cells via endocytosis and localized at a certain area within the cells while uniform iron staining across cells was observed for cells treated with nanoparticle-loaded EVs. Our studies demonstrate the feasibility of using direct flow filtration for the production of nanoparticle-loaded EVs from cancer cells. The cellular uptake studies suggested the possibility of deeper penetration of the nanocarriers because the cancer cells readily took up the quercetin-iron complex nanoparticles, and then released nanoparticle-loaded EVs, which can be further delivered to regional cells. Full article
(This article belongs to the Special Issue Recent Advances in Exosomes as Drug Carriers)
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19 pages, 4569 KiB  
Review
Catestatin: Antimicrobial Functions and Potential Therapeutics
by Suborno Jati, Sumana Mahata, Soumita Das, Saurabh Chatterjee and Sushil K. Mahata
Pharmaceutics 2023, 15(5), 1550; https://doi.org/10.3390/pharmaceutics15051550 - 20 May 2023
Cited by 4 | Viewed by 1286
Abstract
The rapid increase in drug-resistant and multidrug-resistant infections poses a serious challenge to antimicrobial therapies, and has created a global health crisis. Since antimicrobial peptides (AMPs) have escaped bacterial resistance throughout evolution, AMPs are a category of potential alternatives for antibiotic-resistant “superbugs”. The [...] Read more.
The rapid increase in drug-resistant and multidrug-resistant infections poses a serious challenge to antimicrobial therapies, and has created a global health crisis. Since antimicrobial peptides (AMPs) have escaped bacterial resistance throughout evolution, AMPs are a category of potential alternatives for antibiotic-resistant “superbugs”. The Chromogranin A (CgA)-derived peptide Catestatin (CST: hCgA352–372; bCgA344–364) was initially identified in 1997 as an acute nicotinic-cholinergic antagonist. Subsequently, CST was established as a pleiotropic hormone. In 2005, it was reported that N-terminal 15 amino acids of bovine CST (bCST1–15 aka cateslytin) exert antibacterial, antifungal, and antiyeast effects without showing any hemolytic effects. In 2017, D-bCST1–15 (where L-amino acids were changed to D-amino acids) was shown to exert very effective antimicrobial effects against various bacterial strains. Beyond antimicrobial effects, D-bCST1–15 potentiated (additive/synergistic) antibacterial effects of cefotaxime, amoxicillin, and methicillin. Furthermore, D-bCST1–15 neither triggered bacterial resistance nor elicited cytokine release. The present review will highlight the antimicrobial effects of CST, bCST1–15 (aka cateslytin), D-bCST1–15, and human variants of CST (Gly364Ser-CST and Pro370Leu-CST); evolutionary conservation of CST in mammals; and their potential as a therapy for antibiotic-resistant “superbugs”. Full article
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17 pages, 3177 KiB  
Article
The Phase Diagram of the API Benzocaine and Its Highly Persistent, Metastable Crystalline Polymorphs
by Ivo B. Rietveld, Hiroshi Akiba, Osamu Yamamuro, Maria Barrio, René Céolin and Josep-Lluís Tamarit
Pharmaceutics 2023, 15(5), 1549; https://doi.org/10.3390/pharmaceutics15051549 - 20 May 2023
Cited by 1 | Viewed by 1181
Abstract
The availability of sufficient amounts of form I of benzocaine has led to the investigation of its phase relationships with the other two existing forms, II and III, using adiabatic calorimetry, powder X-ray diffraction, and high-pressure differential thermal analysis. The latter two forms [...] Read more.
The availability of sufficient amounts of form I of benzocaine has led to the investigation of its phase relationships with the other two existing forms, II and III, using adiabatic calorimetry, powder X-ray diffraction, and high-pressure differential thermal analysis. The latter two forms were known to have an enantiotropic phase relationship in which form III is stable at low-temperatures and high-pressures, while form II is stable at room temperature with respect to form III. Using adiabatic calorimetry data, it can be concluded, that form I is the stable low-temperature, high-pressure form, which also happens to be the most stable form at room temperature; however, due to its persistence at room temperature, form II is still the most convenient polymorph to use in formulations. Form III presents a case of overall monotropy and does not possess any stability domain in the pressure–temperature phase diagram. Heat capacity data for benzocaine have been obtained by adiabatic calorimetry from 11 K to 369 K above its melting point, which can be used to compare to results from in silico crystal structure prediction. Full article
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18 pages, 2133 KiB  
Article
Autophagy Regulation Using Multimodal Chlorin e6-Loaded Polysilsesquioxane Nanoparticles to Improve Photodynamic Therapy
by Hemapriyadarshini Vadarevu, Adeola Julian Sorinolu, Mariya Munir and Juan L. Vivero-Escoto
Pharmaceutics 2023, 15(5), 1548; https://doi.org/10.3390/pharmaceutics15051548 - 20 May 2023
Cited by 1 | Viewed by 1313
Abstract
Photodynamic therapy (PDT) is a promising anticancer noninvasive technique that relies on the generation of reactive oxygen species (ROS). Unfortunately, PDT still has many limitations, including the resistance developed by cancer cells to the cytotoxic effect of ROS. Autophagy, which is a stress [...] Read more.
Photodynamic therapy (PDT) is a promising anticancer noninvasive technique that relies on the generation of reactive oxygen species (ROS). Unfortunately, PDT still has many limitations, including the resistance developed by cancer cells to the cytotoxic effect of ROS. Autophagy, which is a stress response mechanism, has been reported as a cellular pathway that reduces cell death following PDT. Recent studies have demonstrated that PDT in combination with other therapies can eliminate anticancer resistance. However, combination therapy is usually challenged by the differences in the pharmacokinetics of the drugs. Nanomaterials are excellent delivery systems for the efficient codelivery of two or more therapeutic agents. In this work, we report on the use of polysilsesquioxane (PSilQ) nanoparticles for the codelivery of chlorin-e6 (Ce6) and an autophagy inhibitor for early- or late-stage autophagy. Our results, obtained from a reactive oxygen species (ROS) generation assay and apoptosis and autophagy flux analyses, demonstrate that the reduced autophagy flux mediated by the combination approach afforded an increase in the phototherapeutic efficacy of Ce6-PSilQ nanoparticles. We envision that the promising results in the use of multimodal Ce6-PSilQ material as a codelivery system against cancer pave the way for its future application with other clinically relevant combinations. Full article
(This article belongs to the Special Issue Study of Nanoparticles for Photodynamic Therapy and Imaging)
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19 pages, 5641 KiB  
Article
A Gold Nanocage Probe Targeting Survivin for the Diagnosis of Pancreatic Cancer
by Lina Song, Shuai Ren, Yali Yue, Ying Tian and Zhongqiu Wang
Pharmaceutics 2023, 15(5), 1547; https://doi.org/10.3390/pharmaceutics15051547 - 19 May 2023
Cited by 1 | Viewed by 1398
Abstract
In this paper, Au nanocages (AuNCs) loaded with the MRI contrast agent gadolinium (Gd) and capped with the tumor-targeting gene survivin (Sur–AuNC•Gd–Cy7 nanoprobes) were designed and applied as a targeted imaging agent for pancreatic cancer. With its capacity to transport fluorescent dyes and [...] Read more.
In this paper, Au nanocages (AuNCs) loaded with the MRI contrast agent gadolinium (Gd) and capped with the tumor-targeting gene survivin (Sur–AuNC•Gd–Cy7 nanoprobes) were designed and applied as a targeted imaging agent for pancreatic cancer. With its capacity to transport fluorescent dyes and MR imaging agents, the gold cage is an outstanding platform. Furthermore, it has the potential to transport different drugs in the future, making it a unique carrier platform. The utilization of Sur–AuNC•Gd–Cy7 nanoprobes has proven to be an effective means of targeting and localizing survivin-positive BxPC-3 cells within their cytoplasm. By targeting survivin, an antiapoptotic gene, the Sur–AuNC•Gd–Cy7 nanoprobe was able to induce pro-apoptotic effects in BxPC-3 pancreatic cancer cells. The biocompatibility of AuNCs•Gd, AuNCs•Gd–Cy7 nanoparticles, and Sur–AuNC•Gd–Cy7 nanoprobes is evaluated through the hemolysis rate assay. The stability of AuNCs•Gd, AuNCs•Gd–Cy7 nanoparticles, and Sur–AuNC•Gd–Cy7 nanoprobes was evaluated by determining their hydrodynamic dimensions following storage in different pH solutions for a corresponding duration. Excellent biocompatibility and stability of the Sur–AuNC•Gd–Cy7 nanoprobes will facilitate their further utilization in vivo and in vitro. The surface-bound survivin plays a role in facilitating the Sur–AuNC•Gd–Cy7 nanoprobes’ ability to locate the BxPC-3 tumor. The probe was modified to incorporate Gd and Cy7, thereby enabling the simultaneous utilization of magnetic resonance imaging (MRI) and fluorescence imaging (FI) techniques. In vivo, the Sur–AuNC•Gd–Cy7 nanoprobes were found to effectively target and localize survivin-positive BxPC-3 tumors through the use of MRI and FI. After being injected via the caudal vein, the Sur–AuNC•Gd–Cy7 nanoprobes were found to accumulate effectively in an in situ pancreatic cancer model within 24 h. Furthermore, these nanoprobes were observed to be eliminated from the body through the kidneys within 72 h after a single injection. This characteristic is crucial for a diagnostic agent. Based on the aforementioned outcomes, the Sur–AuNC•Gd–Cy7 nanoprobes have significant potential advantages for the theranostic treatment of pancreatic cancer. This nanoprobe possesses distinctive characteristics, such as advanced imaging abilities and specific drug delivery, which offer the possibility of enhancing the precision of diagnosis and efficacy of treatment for this destructive illness. Full article
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15 pages, 6506 KiB  
Article
Redox-Responsive Lipidic Prodrug Nano-Delivery System Improves Antitumor Effect of Curcumin Derivative C210
by Xin Guo, Min Wu, Yanping Deng, Yan Liu, Yanpeng Liu and Jianhua Xu
Pharmaceutics 2023, 15(5), 1546; https://doi.org/10.3390/pharmaceutics15051546 - 19 May 2023
Cited by 2 | Viewed by 1436
Abstract
The poor bioavailability of curcumin and its derivatives limits their antitumor efficacy and clinical translation. Although curcumin derivative C210 has more potent antitumor activity than curcumin, it has a similar deficiency to curcumin. In order to improve its bioavailability and accordingly enhance its [...] Read more.
The poor bioavailability of curcumin and its derivatives limits their antitumor efficacy and clinical translation. Although curcumin derivative C210 has more potent antitumor activity than curcumin, it has a similar deficiency to curcumin. In order to improve its bioavailability and accordingly enhance its antitumor activity in vivo, we developed a redox-responsive lipidic prodrug nano-delivery system of C210. Briefly, we synthesized three conjugates of C210 and oleyl alcohol (OA) via different linkages containing single sulfur/disulfide/carbon bonds and prepared their nanoparticles using a nanoprecipitation method. The prodrugs required only a very small amount of DSPE-PEG2000 as a stabilizer to self-assemble in aqueous solution to form nanoparticles (NPs) with a high drug loading capacity (~50%). Among them, the prodrug (single sulfur bond) nanoparticles (C210-S-OA NPs) were the most sensitive to the intracellular redox level of cancer cells; therefore, they could rapidly release C210 in cancer cells and thus had the strongest cytotoxicity to cancer cells. Furthermore, C210-S-OA NPs exerted a dramatic improvement in its pharmacokinetic behavior; that is, the area under the curve (AUC), mean retention time and accumulation in tumor tissue were 10, 7 and 3 folds that of free C210, respectively. Thus, C210-S-OA NPs exhibited the strongest antitumor activity in vivo than C210 or other prodrug NPs in mouse models of breast cancer and liver cancer. The results demonstrated that the novel prodrug self-assembled redox-responsive nano-delivery platform was able to improve the bioavailability and antitumor activity of curcumin derivative C210, which provides a basis for further clinical applications of curcumin and its derivatives. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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49 pages, 8253 KiB  
Review
Carbon Nanomaterials (CNMs) in Cancer Therapy: A Database of CNM-Based Nanocarrier Systems
by Hugh Mohan, Andrew Fagan and Silvia Giordani
Pharmaceutics 2023, 15(5), 1545; https://doi.org/10.3390/pharmaceutics15051545 - 19 May 2023
Cited by 2 | Viewed by 1885
Abstract
Carbon nanomaterials (CNMs) are an incredibly versatile class of materials that can be used as scaffolds to construct anticancer nanocarrier systems. The ease of chemical functionalisation, biocompatibility, and intrinsic therapeutic capabilities of many of these nanoparticles can be leveraged to design effective anticancer [...] Read more.
Carbon nanomaterials (CNMs) are an incredibly versatile class of materials that can be used as scaffolds to construct anticancer nanocarrier systems. The ease of chemical functionalisation, biocompatibility, and intrinsic therapeutic capabilities of many of these nanoparticles can be leveraged to design effective anticancer systems. This article is the first comprehensive review of CNM-based nanocarrier systems that incorporate approved chemotherapy drugs, and many different types of CNMs and chemotherapy agents are discussed. Almost 200 examples of these nanocarrier systems have been analysed and compiled into a database. The entries are organised by anticancer drug type, and the composition, drug loading/release metrics, and experimental results from these systems have been compiled. Our analysis reveals graphene, and particularly graphene oxide (GO), as the most frequently employed CNM, with carbon nanotubes and carbon dots following in popularity. Moreover, the database encompasses various chemotherapeutic agents, with antimicrotubule agents being the most common payload due to their compatibility with CNM surfaces. The benefits of the identified systems are discussed, and the factors affecting their efficacy are detailed. Full article
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14 pages, 5871 KiB  
Article
Development of Biopredictive Dissolution Method for Extended-Release Desvenlafaxine Tablets
by Gustavo Vaiano Carapeto, Marcelo Dutra Duque, Michele Georges Issa and Humberto Gomes Ferraz
Pharmaceutics 2023, 15(5), 1544; https://doi.org/10.3390/pharmaceutics15051544 - 19 May 2023
Cited by 4 | Viewed by 1666
Abstract
This study aimed to develop a biopredictive dissolution method for desvenlafaxine ER tablets using design of experiments (DoE) and physiologically based biopharmaceutics modeling (PBBM) to address the challenge of developing generic drug products by reducing the risk of product failure in pivotal bioequivalence [...] Read more.
This study aimed to develop a biopredictive dissolution method for desvenlafaxine ER tablets using design of experiments (DoE) and physiologically based biopharmaceutics modeling (PBBM) to address the challenge of developing generic drug products by reducing the risk of product failure in pivotal bioequivalence studies. For this purpose, a PBBM was developed in GastroPlus® and combined with a Taguchi L9 design, to evaluate the impact of different drug products (Reference, Generic #1 and Generic #2) and dissolution test conditions on desvenlafaxine release. The influence of the superficial area/volume ratio (SA/V) of the tablets was observed, mainly for Generic #1, which presented higher SA/V than the others, and a high amount of drug dissolved under similar test conditions. The dissolution test conditions of 900 mL of 0.9% NaCl and paddle at 50 rpm with sinker showed to be biopredictive, as it was possible to demonstrate virtual bioequivalence for all products, despite their release-pattern differences, including Generic #3 as an external validation. This approach led to a rational development of a biopredictive dissolution method for desvenlafaxine ER tablets, providing knowledge that may help the process of drug product and dissolution method development. Full article
(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)
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5 pages, 206 KiB  
Editorial
Current and Future Cancer Chemoprevention Strategies
by Juan F. Santibanez, Victor H. Villar and Cesar Echeverria
Pharmaceutics 2023, 15(5), 1543; https://doi.org/10.3390/pharmaceutics15051543 - 19 May 2023
Viewed by 946
Abstract
Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020 and ranking as the second-leading cause of death in economically developed countries [...] Full article
(This article belongs to the Section Drug Targeting and Design)
17 pages, 1877 KiB  
Article
Photoprotection and Antiaging Activity of Extracts from Honeybush (Cyclopia sp.)—In Vitro Wound Healing and Inhibition of the Skin Extracellular Matrix Enzymes: Tyrosinase, Collagenase, Elastase and Hyaluronidase
by Anna Hering, Justyna Stefanowicz-Hajduk, Magdalena Gucwa, Bartosz Wielgomas and Jadwiga Renata Ochocka
Pharmaceutics 2023, 15(5), 1542; https://doi.org/10.3390/pharmaceutics15051542 - 19 May 2023
Cited by 7 | Viewed by 1535
Abstract
Cyclopia sp. (honeybush) is an African shrub known as a rich source of polyphenols. The biological effects of fermented honeybush extracts were investigated. The influence of honeybush extracts on extracellular matrix (ECM) enzymes responsible for the skin malfunction and aging process—collagenase, elastase, tyrosinase [...] Read more.
Cyclopia sp. (honeybush) is an African shrub known as a rich source of polyphenols. The biological effects of fermented honeybush extracts were investigated. The influence of honeybush extracts on extracellular matrix (ECM) enzymes responsible for the skin malfunction and aging process—collagenase, elastase, tyrosinase and hyaluronidase—was analysed. The research also included assessment of the in vitro photoprotection efficiency of honeybush extracts and their contribution to the wound healing process. Antioxidant properties of the prepared extracts were evaluated, and quantification of the main compounds in the extracts was achieved. The research showed that the analysed extracts had a significant ability to inhibit collagenase, tyrosinase and hyaluronidase and a weak influence on elastase activity. Tyrosinase was inhibited effectively by honeybush acetone (IC50 26.18 ± 1.45 µg/mL), ethanol (IC50 45.99 ± 0.76 µg/mL) and water (IC50 67.42 ± 1.75 µg/mL) extracts. Significant hyaluronidase inhibition was observed for ethanol, acetone and water extracts (IC50 were 10.99 ± 1.56, 13.21 ± 0.39 and 14.62 ± 0.21µg/mL, respectively). Collagenase activity was inhibited effectively by honeybush acetone extract (IC50 42.5 ± 1.05 μg/mL). The wound healing properties of the honeybush extracts, estimated in vitro in human keratinocytes (HaCaTs), were indicated for water and ethanol extracts. In vitro sun protection factor (SPF in vitro) showed medium photoprotection potential for all the honeybush extracts. The quantity of polyphenolic compounds was estimated with the use of high-performance liquid chromatography equipped with diode-array detection (HPLC-DAD), indicating the highest mangiferin contents in ethanol, acetone and n-butanol extracts, while in the water extract hesperidin was the dominant compound. The antioxidant properties of the honeybush extracts were estimated with FRAP (2,4,6-Tris(2-pyridyl)-s-triazine) and DPPH (2,2-diphenyl-1-picrylhydrazyl) tests, indicating their strong antioxidant activity, similar to ascorbic acid for the acetone extract in both tests. The wound healing abilities, estimation of SPF in vitro and the direct influence on selected enzymes (elastase, tyrosinase, collagenase and hyaluronidase) of the tested honeybush extracts were analysed for the first time, indicating a high potential of these well-known herbal tea for antiaging, anti-inflammation, regeneration and protection of the skin. Full article
(This article belongs to the Special Issue Biomedical Applications of Natural Plant Extract)
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14 pages, 4153 KiB  
Article
Luteolin and Vernodalol as Bioactive Compounds of Leaf and Root Vernonia amygdalina Extracts: Effects on α-Glucosidase, Glycation, ROS, Cell Viability, and In Silico ADMET Parameters
by Francine Medjiofack Djeujo, Valentina Stablum, Elisa Pangrazzi, Eugenio Ragazzi and Guglielmina Froldi
Pharmaceutics 2023, 15(5), 1541; https://doi.org/10.3390/pharmaceutics15051541 - 19 May 2023
Cited by 5 | Viewed by 1633
Abstract
The aqueous decoctions of Vernonia amygdalina (VA) leaves and roots are widely used in traditional African medicine as an antidiabetic remedy. The amount of luteolin and vernodalol in leaf and root extracts was detected, and their role was studied regarding α-glucosidase activity, bovine [...] Read more.
The aqueous decoctions of Vernonia amygdalina (VA) leaves and roots are widely used in traditional African medicine as an antidiabetic remedy. The amount of luteolin and vernodalol in leaf and root extracts was detected, and their role was studied regarding α-glucosidase activity, bovine serum albumin glycation (BSA), reactive oxygen species (ROS) formation, and cell viability, together with in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Vernodalol did not affect α-glucosidase activity, whereas luteolin did. Furthermore, luteolin inhibited the formation of advanced glycation end products (AGEs) in a concentration-dependent manner, whereas vernodalol did not reduce it. Additionally, luteolin exhibited high antiradical activity, while vernodalol demonstrated a lower scavenger effect, although similar to that of ascorbic acid. Both luteolin and vernodalol inhibited HT-29 cell viability, showing a half-maximum inhibitory concentration (IC50) of 22.2 µM (−Log IC50 = 4.65 ± 0.05) and 5.7 µM (−Log IC50 = 5.24 ± 0.16), respectively. Finally, an in silico ADMET study showed that both compounds are suitable candidates as drugs, with appropriate pharmacokinetics. This research underlines for the first time the greater presence of vernodalol in VA roots compared to leaves, while luteolin is prevalent in the latter, suggesting that the former could be used as a natural source of vernodalol. Consequently, root extracts could be proposed for vernodalol-dependent antiproliferative activity, while leaf extracts could be suggested for luteolin-dependent effects, such as antioxidant and antidiabetic effects. Full article
(This article belongs to the Special Issue Biomedical Applications of Natural Plant Extract)
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17 pages, 3655 KiB  
Article
Immunometabolism Modulation by Extracts from Pistachio Stalks Formulated in Phospholipid Vesicles
by Simone Pani, Ilaria Pappalardo, Anna Santarsiero, Antonio Vassallo, Rosa Paola Radice, Giuseppe Martelli, Francesco Siano, Simona Todisco, Paolo Convertini, Carla Caddeo and Vittoria Infantino
Pharmaceutics 2023, 15(5), 1540; https://doi.org/10.3390/pharmaceutics15051540 - 19 May 2023
Cited by 1 | Viewed by 1335
Abstract
Several studies have demonstrated the effectiveness of plant extracts against various diseases, especially skin disorders; namely, they exhibit overall protective effects. The Pistachio (Pistacia vera L.) is known for having bioactive compounds that can effectively contribute to a person’s healthy status. However, [...] Read more.
Several studies have demonstrated the effectiveness of plant extracts against various diseases, especially skin disorders; namely, they exhibit overall protective effects. The Pistachio (Pistacia vera L.) is known for having bioactive compounds that can effectively contribute to a person’s healthy status. However, these benefits may be limited by the toxicity and low bioavailability often inherent in bioactive compounds. To overcome these problems, delivery systems, such as phospholipid vesicles, can be employed. In this study, an essential oil and a hydrolate were produced from P. vera stalks, which are usually discarded as waste. The extracts were characterized by liquid and gas chromatography coupled with mass spectrometry and formulated in phospholipid vesicles intended for skin application. Liposomes and transfersomes showed small size (<100 nm), negative charge (approximately −15 mV), and a longer storage stability for the latter. The entrapment efficiency was determined via the quantification of the major compounds identified in the extracts and was >80%. The immune-modulating activity of the extracts was assayed in macrophage cell cultures. Most interestingly, the formulation in transfersomes abolished the cytotoxicity of the essential oil while increasing its ability to inhibit inflammatory mediators via the immunometabolic citrate pathway. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)
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25 pages, 4794 KiB  
Article
Thermodynamic Modeling of the Amorphous Solid Dispersion-Water Interfacial Layer and Its Impact on the Release Mechanism
by Stefanie Dohrn, Samuel O. Kyeremateng, Esther Bochmann, Ekaterina Sobich, Andrea Wahl, Bernd Liepold, Gabriele Sadowski and Matthias Degenhardt
Pharmaceutics 2023, 15(5), 1539; https://doi.org/10.3390/pharmaceutics15051539 - 19 May 2023
Cited by 3 | Viewed by 2672
Abstract
During the dissolution of amorphous solid dispersion (ASD) formulations, the gel layer that forms at the ASD/water interface strongly dictates the release of the active pharmaceutical ingredient (API) and, hence, the dissolution performance. Several studies have demonstrated that the switch of the gel [...] Read more.
During the dissolution of amorphous solid dispersion (ASD) formulations, the gel layer that forms at the ASD/water interface strongly dictates the release of the active pharmaceutical ingredient (API) and, hence, the dissolution performance. Several studies have demonstrated that the switch of the gel layer from eroding to non-eroding behavior is API-specific and drug-load (DL)-dependent. This study systematically classifies the ASD release mechanisms and relates them to the phenomenon of the loss of release (LoR). The latter is thermodynamically explained and predicted via a modeled ternary phase diagram of API, polymer, and water, and is then used to describe the ASD/water interfacial layers (below and above the glass transition). To this end, the ternary phase behavior of the APIs, naproxen, and venetoclax with the polymer poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) and water was modeled using the perturbed-chain statistical associating fluid theory (PC-SAFT). The glass transition was modeled using the Gordon–Taylor equation. The DL-dependent LoR was found to be caused by API crystallization or liquid-liquid phase separation (LLPS) at the ASD/water interface. If crystallization occurs, it was found that API and polymer release was impeded above a threshold DL at which the APIs crystallized directly at the ASD interface. If LLPS occurs, an API-rich phase and a polymer-rich phase are formed. Above a threshold DL, the less mobile and hydrophobic API-rich phase accumulates at the interface which prevents API release. LLPS is further influenced by the composition and glass transition temperature of the evolving phases and was investigated at 37 °C and 50 °C regarding impact of temperature of. The modeling results and LoR predictions were experimentally validated by means of dissolution experiments, microscopy, Raman spectroscopy, and size exclusion chromatography. The experimental results were found to be in very good agreement with the predicted release mechanisms deduced from the phase diagrams. Thus, this thermodynamic modeling approach represents a powerful mechanistic tool that can be applied to classify and quantitatively predict the DL-dependent LoR release mechanism of PVPVA64-based ASDs in water. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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33 pages, 866 KiB  
Review
Uses and Challenges of Antiviral Polyclonal and Monoclonal Antibody Therapies
by Evi B. Struble, Jonathan M. O. Rawson, Tzanko Stantchev, Dorothy Scott and Marjorie A. Shapiro
Pharmaceutics 2023, 15(5), 1538; https://doi.org/10.3390/pharmaceutics15051538 - 19 May 2023
Cited by 2 | Viewed by 2167
Abstract
Viral diseases represent a major public health concerns and ever-present risks for developing into future pandemics. Antiviral antibody therapeutics, either alone or in combination with other therapies, emerged as valuable preventative and treatment options, including during global emergencies. Here we will discuss polyclonal [...] Read more.
Viral diseases represent a major public health concerns and ever-present risks for developing into future pandemics. Antiviral antibody therapeutics, either alone or in combination with other therapies, emerged as valuable preventative and treatment options, including during global emergencies. Here we will discuss polyclonal and monoclonal antiviral antibody therapies, focusing on the unique biochemical and physiological properties that make them well-suited as therapeutic agents. We will describe the methods of antibody characterization and potency assessment throughout development, highlighting similarities and differences between polyclonal and monoclonal products as appropriate. In addition, we will consider the benefits and challenges of antiviral antibodies when used in combination with other antibodies or other types of antiviral therapeutics. Lastly, we will discuss novel approaches to the characterization and development of antiviral antibodies and identify areas that would benefit from additional research. Full article
(This article belongs to the Special Issue Drugs for Antiviral Combination Therapy)
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13 pages, 3928 KiB  
Article
Cinchonain Ia Shows Promising Antitumor Effects in Combination with L-Asparaginase-Loaded Nanoliposomes
by Thi Nga Nguyen, Thi Phuong Do, Thi Cuc Nguyen, Ha Phuong Trieu, Thi Giang An Nguyen and Thi Thao Do
Pharmaceutics 2023, 15(5), 1537; https://doi.org/10.3390/pharmaceutics15051537 - 19 May 2023
Cited by 1 | Viewed by 1171
Abstract
Cancer is among the leading causes of death worldwide, with no effective and safe treatment to date. This study is the first to co-conjugate the natural compound cinchonain Ia, which has promising anti-inflammatory activity, and L-asparaginase (ASNase), which has anticancer potential, to manufacture [...] Read more.
Cancer is among the leading causes of death worldwide, with no effective and safe treatment to date. This study is the first to co-conjugate the natural compound cinchonain Ia, which has promising anti-inflammatory activity, and L-asparaginase (ASNase), which has anticancer potential, to manufacture nanoliposomal particles (CALs). The CAL nanoliposomal complex had a mean size of approximately 118.7 nm, a zeta potential of −47.00 mV, and a polydispersity index (PDI) of 0.120. ASNase and cinchonain Ia were encapsulated into liposomes with approximately 93.75% and 98.53% efficiency, respectively. The CAL complex presented strong synergistic anticancer potency, with a combination index (CI) < 0.32 in two-dimensional culture and 0.44 in a three-dimensional model, as tested on NTERA-2 cancer stem cells. Importantly, the CAL nanoparticles demonstrated outstanding antiproliferative efficiency on cell growth in NTERA-2 cell spheroids, with greater than 30- and 2.5-fold increases in cytotoxic activity compared to either cinchonain Ia or ASNase liposomes, respectively. CALs also presented extremely enhanced antitumor effects, reaching approximately 62.49% tumor growth inhibition. Tumorized mice under CALs treatment showed a survival rate of 100%, compared to 31.2% in the untreated control group (p < 0.01), after 28 days of the experiment. Thus, CALs may represent an effective material for anticancer drug development. Full article
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