Pharmaceutics

14 pages, 3122 KiB

Open AccessArticle

DNA-Binding and Cytotoxicity of Copper(I) Complexes Containing Functionalized Dipyridylphenazine Ligands

by Sammar Alsaedi, Bandar A. Babgi, Magda H. Abdellattif, Muhammad N. Arshad, Abdul-Hamid M. Emwas, Mariusz Jaremko, Mark G. Humphrey, Abdullah M. Asiri and Mostafa A. Hussien

Pharmaceutics 2021, 13(5), 764; https://doi.org/10.3390/pharmaceutics13050764 - 20 May 2021

Cited by 16 | Viewed by 3158

Abstract

A set of copper(I) coordination compounds with general formula [CuBr(PPh₃)(dppz-R)] (dppz-R = dipyrido[3,2-a:2’,3’-c]phenazine (Cu-1), 11-nitrodipyrido[3,2-a:2’,3’-c]phenazine (Cu-2), 11-cyanodipyrido[3,2-a:2’,3’-c]phenazine (Cu-3), dipyrido[3,2-a:2’,3’-c]phenazine-11-phenone (Cu-4), 11,12-dimethyldipyrido[3,2-a:2’,3’-c]phenazine (Cu-5)) have been prepared and characterized by elemental analysis, ¹ [...] Read more.

A set of copper(I) coordination compounds with general formula [CuBr(PPh₃)(dppz-R)] (dppz-R = dipyrido[3,2-a:2’,3’-c]phenazine (Cu-1), 11-nitrodipyrido[3,2-a:2’,3’-c]phenazine (Cu-2), 11-cyanodipyrido[3,2-a:2’,3’-c]phenazine (Cu-3), dipyrido[3,2-a:2’,3’-c]phenazine-11-phenone (Cu-4), 11,12-dimethyldipyrido[3,2-a:2’,3’-c]phenazine (Cu-5)) have been prepared and characterized by elemental analysis, ¹H-NMR and ³¹P-NMR spectroscopies as well as mass spectrometry. The structure of Cu-1 was confirmed by X-ray crystallography. The effect of incorporating different functional groups on the dppz ligand on the binding into CT-DNA was evaluated by absorption spectroscopy, fluorescence quenching of EtBr-DNA adducts, and viscosity measurements. The functional groups affected the binding modes and hence the strength of binding affinities, as suggested by the changes in the relative viscosity. The differences in the quenching constants (K_sv) obtained from the fluorescence quenching assay highlight the importance of the functional groups in altering the binding sites on the DNA. The molecular docking data support the DNA-binding studies, with the sites and mode of interactions against B-DNA changing with the different functional groups. Evaluation of the anticancer activities of the five copper compounds against two different cancer cell lines (M-14 and MCF-7) indicated the importance of the functional groups on the dppz ligand on the anticancer activities. Among the five copper complexes, the cyano-containing complex (Cu-3) has the best anticancer activities. Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy)

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28 pages, 2560 KiB

Open AccessReview

Mitochondrial Targeting Involving Cholesterol-Rich Lipid Rafts in the Mechanism of Action of the Antitumor Ether Lipid and Alkylphospholipid Analog Edelfosine

by Faustino Mollinedo and Consuelo Gajate

Pharmaceutics 2021, 13(5), 763; https://doi.org/10.3390/pharmaceutics13050763 - 20 May 2021

Cited by 13 | Viewed by 3644

Abstract

The ether lipid edelfosine induces apoptosis selectively in tumor cells and is the prototypic molecule of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs. Cumulative evidence shows that edelfosine interacts with cholesterol-rich lipid rafts, endoplasmic reticulum (ER) and mitochondria. Edelfosine [...] Read more.

The ether lipid edelfosine induces apoptosis selectively in tumor cells and is the prototypic molecule of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs. Cumulative evidence shows that edelfosine interacts with cholesterol-rich lipid rafts, endoplasmic reticulum (ER) and mitochondria. Edelfosine induces apoptosis in a number of hematological cancer cells by recruiting death receptors and downstream apoptotic signaling into lipid rafts, whereas it promotes apoptosis in solid tumor cells through an ER stress response. Edelfosine-induced apoptosis, mediated by lipid rafts and/or ER, requires the involvement of a mitochondrial-dependent step to eventually elicit cell death, leading to the loss of mitochondrial membrane potential, cytochrome c release and the triggering of cell death. The overexpression of Bcl-2 or Bcl-xL blocks edelfosine-induced apoptosis. Edelfosine induces the redistribution of lipid rafts from the plasma membrane to the mitochondria. The pro-apoptotic action of edelfosine on cancer cells is associated with the recruitment of F₁F_O–ATP synthase into cholesterol-rich lipid rafts. Specific inhibition of the F_O sector of the F₁F_O–ATP synthase, which contains the membrane-embedded c-subunit ring that constitutes the mitochondrial permeability transcription pore, hinders edelfosine-induced cell death. Taking together, the evidence shown here suggests that the ether lipid edelfosine could modulate cell death in cancer cells by direct interaction with mitochondria, and the reorganization of raft-located mitochondrial proteins that critically modulate cell death or survival. Here, we summarize and discuss the involvement of mitochondria in the antitumor action of the ether lipid edelfosine, pointing out the mitochondrial targeting of this drug as a major therapeutic approach, which can be extrapolated to other alkylphospholipid analogs. We also discuss the involvement of cholesterol transport and cholesterol-rich lipid rafts in the interactions between the organelles as well as in the role of mitochondria in the regulation of apoptosis in cancer cells and cancer therapy. Full article

(This article belongs to the Special Issue Mitochondria-targeted drug delivery)

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15 pages, 1241 KiB

Open AccessReview

Targeting Mitochondrial Oncometabolites: A New Approach to Overcome Drug Resistance in Cancer

by Martina Godel, Giacomo Ortone, Dario Pasquale Anobile, Martina Pasino, Giulio Randazzo, Chiara Riganti and Joanna Kopecka

Pharmaceutics 2021, 13(5), 762; https://doi.org/10.3390/pharmaceutics13050762 - 20 May 2021

Cited by 13 | Viewed by 3125

Abstract

Drug resistance is the main obstacle for a successful cancer therapy. There are many mechanisms by which cancers avoid drug-mediated death, including alterations in cellular metabolism and apoptotic programs. Mitochondria represent the cell’s powerhouse and the connection between carbohydrate, lipid and proteins metabolism, [...] Read more.

Drug resistance is the main obstacle for a successful cancer therapy. There are many mechanisms by which cancers avoid drug-mediated death, including alterations in cellular metabolism and apoptotic programs. Mitochondria represent the cell’s powerhouse and the connection between carbohydrate, lipid and proteins metabolism, as well as crucial controllers of apoptosis, playing an important role not only in tumor growth and progression, but also in drug response. Alterations in tricarboxylic acid cycle (TCA) caused by mutations in three TCA enzymes—isocitrate dehydrogenase, succinate dehydrogenase and fumarate hydratase—lead to the accumulation of 2-hydroxyglutarate, succinate and fumarate respectively, collectively known as oncometabolites. Oncometabolites have pleiotropic effects on cancer biology. For instance, they generate a pseudohypoxic phenotype and induce epigenetic changes, two factors that may promote cancer drug resistance leading to disease progression and poor therapy outcome. This review sums up the most recent findings about the role of TCA-derived oncometabolites in cancer aggressiveness and drug resistance, highlighting possible pharmacological strategies targeting oncometabolites production in order to improve the efficacy of cancer treatment. Full article

(This article belongs to the Special Issue Mitochondria-targeted drug delivery)

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12 pages, 1671 KiB

Open AccessArticle

Endocytic Uptake of Solid Lipid Nanoparticles by the Nasal Mucosa

by Ammar S. Al Khafaji and Maureen D. Donovan

Pharmaceutics 2021, 13(5), 761; https://doi.org/10.3390/pharmaceutics13050761 - 20 May 2021

Cited by 11 | Viewed by 2820

Abstract

Nanoparticles may provide unique therapeutic opportunities when administered via the nasal cavity, yet the primary uptake and transfer pathways for these particles within the nasal mucosa are not well understood. The endocytic pathways involved in the uptake of fluorescently labeled, (Nile Red) solid [...] Read more.

Nanoparticles may provide unique therapeutic opportunities when administered via the nasal cavity, yet the primary uptake and transfer pathways for these particles within the nasal mucosa are not well understood. The endocytic pathways involved in the uptake of fluorescently labeled, (Nile Red) solid lipid nanoparticles (SLNs) of different sizes (~30, 60, and 150 nm) were studied using excised bovine olfactory and nasal respiratory tissues. Endocytic activity contributing to nanoparticle uptake was investigated using a variety of pharmacological inhibitors, but none of the inhibitors were able to completely eliminate the uptake of the SLNs. The continued uptake of nanoparticles following exposure to individual inhibitors suggests that a number of endocytic pathways work in combination to transfer nanoparticles into the nasal mucosa. Following exposure to the general metabolic inhibitors, 2,4-DNP and sodium azide, additional, non-energy-dependent pathways for nanoparticle uptake were also observed. While the smallest nanoparticles (30 nm) were the most resistant to the effects of pharmacologic inhibitors, the largest (150 nm) were still able to transfer significant amounts of the particles into the tissues. The rapid nanoparticle uptake observed demonstrates that these lipid particles are promising vehicles to accomplish both local and systemic drug delivery following nasal administration. Full article

(This article belongs to the Special Issue Lipid-Based Dispersed Systems for Drug Delivery)

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18 pages, 1350 KiB

Open AccessReview

Extracellular Vesicles as Potential Theranostic Platforms for Skin Diseases and Aging

by Hyosuk Kim, Jong Won Lee, Geonhee Han, Kwangmeyung Kim, Yoosoo Yang and Sun Hwa Kim

Pharmaceutics 2021, 13(5), 760; https://doi.org/10.3390/pharmaceutics13050760 - 20 May 2021

Cited by 10 | Viewed by 3705

Abstract

Extracellular vesicles (EVs), naturally secreted by cells, act as mediators for communication between cells. They are transported to the recipient cells along with cargoes such as nucleic acids, proteins, and lipids that reflect the changes occurring within the parent cells. Thus, EVs have [...] Read more.

Extracellular vesicles (EVs), naturally secreted by cells, act as mediators for communication between cells. They are transported to the recipient cells along with cargoes such as nucleic acids, proteins, and lipids that reflect the changes occurring within the parent cells. Thus, EVs have been recognized as potential theranostic agents for diagnosis, treatment, and prognosis. In particular, the evidence accumulated to date suggests an important role of EVs in the initiation and progression of skin aging and various skin diseases, including psoriasis, systemic lupus erythematosus, vitiligo, and chronic wounds. This review highlights recent research that investigates the role of EVs and their potential as biomarkers and therapeutic agents for skin diseases and aging. Full article

(This article belongs to the Special Issue Development and Testing of Nanotechnology-Based Delivery Systems for Topical Drug Delivery to Wounds, Skin or Mucosa)

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18 pages, 2143 KiB

Open AccessArticle

The Chronotopic™ System for Pulsatile and Colonic Delivery of Active Molecules in the Era of Precision Medicine: Feasibility by 3D Printing via Fused Deposition Modeling (FDM)

by Alice Melocchi, Marco Uboldi, Francesco Briatico-Vangosa, Saliha Moutaharrik, Matteo Cerea, Anastasia Foppoli, Alessandra Maroni, Luca Palugan, Lucia Zema and Andrea Gazzaniga

Pharmaceutics 2021, 13(5), 759; https://doi.org/10.3390/pharmaceutics13050759 - 20 May 2021

Cited by 33 | Viewed by 3827

Abstract

The pulsatile-release Chronotopic™ system was conceived of as a drug-containing core surrounded by a coat made of swellable/soluble hydrophilic polymers, the latter being able to provide a programmable lag phase prior to drug liberation. This system was also proposed in a colon-targeting configuration, [...] Read more.

The pulsatile-release Chronotopic™ system was conceived of as a drug-containing core surrounded by a coat made of swellable/soluble hydrophilic polymers, the latter being able to provide a programmable lag phase prior to drug liberation. This system was also proposed in a colon-targeting configuration, entailing a gastroresistant film to prevent early interaction of the inner coat with gastric fluids and enabling the attainment of a lag phase matching the small intestinal transit time. Over the years, various multiple-step manufacturing processes have been tested for the fabrication of the Chronotopic™ system in both its configurations. This work focused on the evaluation of 3D printing by fused deposition modeling in view of its potential towards product personalization, on demand one-step manufacturing and efficient scale down of batches. The feasibility of each part of the Chronotopic™ system was independently investigated starting from in-house made filaments, characterizing the resulting specimens for physico-technological and performance characteristics. The printing parameters identified as suitable during the set-up phase were then used to fabricate prototypes either in a single step for the pulsatile configuration or following two different fabrication approaches for the colon-targeting one. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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16 pages, 4675 KiB

Open AccessArticle

Growth Inhibitory Effects of Ester Derivatives of Menahydroquinone-4, the Reduced Form of Vitamin K₂₍₂₀₎, on All-Trans Retinoic Acid-Resistant HL60 Cell Line

by Hirofumi Yamakawa, Shuichi Setoguchi, Shotaro Goto, Daisuke Watase, Kazuki Terada, Nami Nagata-Akaho, Erina Toki, Mitsuhisa Koga, Kazuhisa Matsunaga, Yoshiharu Karube and Jiro Takata

Pharmaceutics 2021, 13(5), 758; https://doi.org/10.3390/pharmaceutics13050758 - 20 May 2021

Cited by 5 | Viewed by 2592

Abstract

The first-choice drug for acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA), frequently causes drug-resistance and some adverse effects. Thus, an effective and safe agent for ATRA-resistant APL is needed. Menaquinone-4 (MK-4, vitamin K₂₍₂₀₎), used for osteoporosis treatment, does not have [...] Read more.

The first-choice drug for acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA), frequently causes drug-resistance and some adverse effects. Thus, an effective and safe agent for ATRA-resistant APL is needed. Menaquinone-4 (MK-4, vitamin K₂₍₂₀₎), used for osteoporosis treatment, does not have serious adverse effects. It has been reported that MK-4 has growth-inhibitory effects on HL60 cells by inducing apoptosis via the activation of Bcl-2 antagonist killer 1 (BAK). However, the effect of MK-4 on ATRA-resistant APL has not been reported. Here, we show that ester derivatives of menahydroquinone-4 (MKH; a reduced form of MK-4), MKH 1,4-bis-N,N-dimethylglycinate (MKH-DMG) and MKH 1,4-bis-hemi-succinate (MKH-SUC), exerted strong growth-inhibitory effects even on ATRA-resistant HL60 (HL-60R) cells compared with ATRA and MK-4. MKH delivery after MKH-SUC treatment was higher than that after MK-4 treatment, and the results indicated apoptosis induced by BAK activation. In contrast, for MKH-DMG, reconversion to MKH was slow and apoptosis was not observed. We suggest that the ester forms, including monoesters of MKH-DMG, exhibit another mechanism independent of apoptosis. In conclusion, the MKH derivatives (MKH-SUC and MKH-DMG) inhibited not only HL60 cells but also HL-60R cells, indicating a potential to overcome ATRA resistance. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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26 pages, 6415 KiB

Open AccessReview

New Approaches in Nanomedicine for Ischemic Stroke

by Clara Correa-Paz, Andrés da Silva-Candal, Ester Polo, Jérôme Parcq, Denis Vivien, Dusica Maysinger, Beatriz Pelaz and Francisco Campos

Pharmaceutics 2021, 13(5), 757; https://doi.org/10.3390/pharmaceutics13050757 - 20 May 2021

Cited by 17 | Viewed by 4788

Abstract

Ischemic stroke, caused by the interruption of blood flow to the brain and subsequent neuronal death, represents one of the main causes of disability in developed countries. Therapeutic methods such as recanalization approaches, neuroprotective drugs, or recovery strategies have been widely developed to [...] Read more.

Ischemic stroke, caused by the interruption of blood flow to the brain and subsequent neuronal death, represents one of the main causes of disability in developed countries. Therapeutic methods such as recanalization approaches, neuroprotective drugs, or recovery strategies have been widely developed to improve the patient’s outcome; however, important limitations such as a narrow therapeutic window, the ability to reach brain targets, or drug side effects constitute some of the main aspects that limit the clinical applicability of the current treatments. Nanotechnology has emerged as a promising tool to overcome many of these drug limitations and improve the efficacy of treatments for neurological diseases such as stroke. The use of nanoparticles as a contrast agent or as drug carriers to a specific target are some of the most common approaches developed in nanomedicine for stroke. Throughout this review, we have summarized our experience of using nanotechnology tools for the study of stroke and the search for novel therapies. Full article

(This article belongs to the Special Issue Biomimetic and Functional Nanomaterials for Molecular Imaging)

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12 pages, 1786 KiB

Open AccessReview

A Review of Mathematics Determining Solute Uptake at the Blood–Brain Barrier in Normal and Pathological Conditions

by Samuel A. Sprowls, Pushkar Saralkar, Tasneem Arsiwala, Christopher E. Adkins, Kathryn E. Blethen, Vincenzo J. Pizzuti, Neal Shah, Ross Fladeland and Paul R. Lockman

Pharmaceutics 2021, 13(5), 756; https://doi.org/10.3390/pharmaceutics13050756 - 19 May 2021

Cited by 2 | Viewed by 3152

Abstract

The blood–brain barrier (BBB) limits movement of solutes from the lumen of the brain microvascular capillary system into the parenchyma. The unidirectional transfer constant, K_in, is the rate at which transport across the BBB occurs for individual molecules. Single and multiple [...] Read more.

The blood–brain barrier (BBB) limits movement of solutes from the lumen of the brain microvascular capillary system into the parenchyma. The unidirectional transfer constant, K_in, is the rate at which transport across the BBB occurs for individual molecules. Single and multiple uptake experiments are available for the determination of K_in for new drug candidates using both intravenous and in situ protocols. Additionally, the single uptake method can be used to determine K_in in heterogeneous pathophysiological conditions such as stroke, brain cancers, and Alzheimer’s disease. In this review, we briefly cover the anatomy and physiology of the BBB, discuss the impact of efflux transporters on solute uptake, and provide an overview of the single-timepoint method for determination of K_in values. Lastly, we compare preclinical K_in experimental results with human parallels. Full article

(This article belongs to the Section Drug Targeting and Design)

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16 pages, 3098 KiB

Open AccessArticle

Bio- and Hemo-Compatible Silk Fibroin PEGylated Nanocarriers for 5-Fluorouracil Chemotherapy in Colorectal Cancer: In Vitro Studies

by Ariana Hudiță, Ionuț Cristian Radu, Cătălin Zaharia, Andreea Cristina Ion, Octav Ginghină, Bianca Gălățeanu, Luminița Măruțescu, Florin Grama, Aristidis Tsatsakis, Leonid Gurevich and Marieta Costache

Pharmaceutics 2021, 13(5), 755; https://doi.org/10.3390/pharmaceutics13050755 - 19 May 2021

Cited by 10 | Viewed by 2751

Abstract

5-fluorouracil (5-FU) remains the gold standard of treatment for colorectal cancer, but its poor bioavailability and high systemic toxicity highlight the urgent need for the development of novel delivery strategies to increase the efficacy of 5-FU treatment. The present study is aimed to [...] Read more.

5-fluorouracil (5-FU) remains the gold standard of treatment for colorectal cancer, but its poor bioavailability and high systemic toxicity highlight the urgent need for the development of novel delivery strategies to increase the efficacy of 5-FU treatment. The present study is aimed to design and validate a PEGylated Silk Fibroin Nanocarrier (SF/PEG nanoparticles (NPs)) as an efficient 5-FU delivery system for potential intravenous administration. Using the human adenocarcinoma HT–29 cell line as an in vitro model for colorectal cancer, the cytotoxicity screening of the SF/PEG NPs showed that pristine nanocarriers were highly biocompatible, while the addition of 5-FU triggers a dramatic reduction in tumor cell viability, proliferation potential and mitochondrial integrity as well as a significant increase in nitric oxide production. Despite their high in vitro cytotoxicity, the 5-FU SF/PEG NPs were found hemocompatible as no impact on red blood cells hemolysis or the phagocytic activity of the granulocytes was observed. Exposure of HT–29 tumor cells and blood samples to 5-FU SF/PEG NPs augmented the tumor necrosis factor-α levels. Moreover, 5-FU SF/PEG NPs showed an impact on tumor cell migration and invasive potential as both of these processes were inhibited by the NP treatment. Full article

(This article belongs to the Special Issue Innovative Polymeric Nanocarriers and Their Drug Delivery Applications)

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20 pages, 2908 KiB

Open AccessArticle

Population Pharmacokinetic Analysis of Cefaclor in Healthy Korean Subjects

by Seung-Hyun Jeong, Ji-Hun Jang, Hea-Young Cho and Yong-Bok Lee

Pharmaceutics 2021, 13(5), 754; https://doi.org/10.3390/pharmaceutics13050754 - 19 May 2021

Cited by 11 | Viewed by 3453

Abstract

The aims of this study were: (1) to perform population pharmacokinetic analysis of cefaclor in healthy Korean subjects, and (2) to investigate possible effects of various covariates on pharmacokinetic parameters of cefaclor. Although cefaclor belongs to the cephalosporin family antibiotic that has been [...] Read more.

The aims of this study were: (1) to perform population pharmacokinetic analysis of cefaclor in healthy Korean subjects, and (2) to investigate possible effects of various covariates on pharmacokinetic parameters of cefaclor. Although cefaclor belongs to the cephalosporin family antibiotic that has been used in various indications, there have been very few population studies on factors affecting its pharmacokinetics. Therefore, this study is very important in that effective therapy could be possible through a population pharmacokinetic study that explores effective covariates related to cefaclor pharmacokinetic diversity between individuals. Pharmacokinetic results of 48 subjects with physical and biochemical parameters were used for the population pharmacokinetic analysis of cefaclor. A one-compartment with lag-time and first-order absorption/elimination was constructed as a base model and extended to include covariates that could influence between-subject variability. Creatinine clearance and body weight significantly influenced systemic clearance and distribution volume of cefaclor. Cefaclor’s final population pharmacokinetic model was validated and some of the population’s pharmacokinetic diversity could be explained. Herein, we first describe the establishment of a population pharmacokinetic model of cefaclor for healthy Koreans that might be useful for customizing cefaclor or exploring additional covariates in patients. Full article

(This article belongs to the Collection Advanced Pharmaceutical Science and Technology in Korea)

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19 pages, 45254 KiB

Open AccessReview

Recent Progress in the Design and Medical Application of In Situ Self-Assembled Polypeptide Materials

by Tian-Tian Wang, Yi-Yi Xia, Jian-Qing Gao, Dong-Hang Xu and Min Han

Pharmaceutics 2021, 13(5), 753; https://doi.org/10.3390/pharmaceutics13050753 - 19 May 2021

Cited by 18 | Viewed by 3516

Abstract

Inspired by molecular self-assembly, which is ubiquitous in natural environments and biological systems, self-assembled peptides have become a research hotspot in the biomedical field due to their inherent biocompatibility and biodegradability, properties that are afforded by the amide linkages forming the peptide backbone. [...] Read more.

Inspired by molecular self-assembly, which is ubiquitous in natural environments and biological systems, self-assembled peptides have become a research hotspot in the biomedical field due to their inherent biocompatibility and biodegradability, properties that are afforded by the amide linkages forming the peptide backbone. This review summarizes the biological advantages, principles, and design strategies of self-assembled polypeptide systems. We then focus on the latest advances in in situ self-assembly of polypeptides in medical applications, such as oncotherapy, materials science, regenerative medicine, and drug delivery, and then briefly discuss their potential challenges in clinical treatment. Full article

(This article belongs to the Special Issue Development of Micro and Nano Systems for the Drug Delivery)

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22 pages, 5363 KiB

Open AccessArticle

Toxoplasma gondii Proteasome Subunit Alpha Type 1 with Chitosan: A Promising Alternative to Traditional Adjuvant

by Zhengqing Yu, Wenxi Ding, Muhammad Tahir Aleem, Junzhi Su, Junlong Liu, Jianxun Luo, Ruofeng Yan, Lixin Xu, Xiaokai Song and Xiangrui Li

Pharmaceutics 2021, 13(5), 752; https://doi.org/10.3390/pharmaceutics13050752 - 19 May 2021

Cited by 3 | Viewed by 2445

Abstract

As an important zoonotic protozoan, Toxoplasma gondii (T. gondii) has spread around the world, leading to infections in one-third of the population. There is still no effective vaccine or medicine against T. gondii, and recombinant antigens entrapped within nanospheres have [...] Read more.

As an important zoonotic protozoan, Toxoplasma gondii (T. gondii) has spread around the world, leading to infections in one-third of the population. There is still no effective vaccine or medicine against T. gondii, and recombinant antigens entrapped within nanospheres have benefits over traditional vaccines. In the present study, we first expressed and purified T. gondii proteasome subunit alpha type 1 (TgPSA1), then encapsulated the recombinant TgPSA1 (rTgPSA1) in chitosan nanospheres (CS nanospheres, rTgPSA1/CS nanospheres) and incomplete Freund’s adjuvant (IFA, rTgPSA1/IFA emulsion). Antigens entrapped in CS nanospheres reached an encapsulation efficiency of 67.39%, and rTgPSA1/CS nanospheres showed a more stable release profile compared to rTgPSA1/IFA emulsion in vitro. In vivo, Th1-biased cellular and humoral immune responses were induced in mice and chickens immunized with rTgPSA1/CS nanospheres and rTgPSA1/IFA emulsion, accompanied by promoted production of antibodies, IFN-γ, IL-4, and IL-17, and modulated production of IL-10. Immunization with rTgPSA1/CS nanospheres and rTgPSA1/IFA emulsion conferred significant protection, with prolonged survival time in mice and significantly decreased parasite burden in chickens. Furthermore, our results also indicate that rTgPSA1/CS nanospheres could be used as a substitute for rTgPSA1/IFA emulsion, with the optimal administration route being intramuscular in mass vaccination. Collectively, the results of this study indicate that rTgPSA1/CS nanospheres represent a promising vaccine to protect animals against acute toxoplasmosis. Full article

(This article belongs to the Special Issue Nanobiotechnology Systems-Based Veterinary Formulations)

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28 pages, 1203 KiB

Open AccessReview

The Vaginal Microbiota, Bacterial Biofilms and Polymeric Drug-Releasing Vaginal Rings

by Louise Carson, Ruth Merkatz, Elena Martinelli, Peter Boyd, Bruce Variano, Teresa Sallent and Robert Karl Malcolm

Pharmaceutics 2021, 13(5), 751; https://doi.org/10.3390/pharmaceutics13050751 - 19 May 2021

Cited by 14 | Viewed by 6599

Abstract

The diversity and dynamics of the microbial species populating the human vagina are increasingly understood to play a pivotal role in vaginal health. However, our knowledge about the potential interactions between the vaginal microbiota and vaginally administered drug delivery systems is still rather [...] Read more.

The diversity and dynamics of the microbial species populating the human vagina are increasingly understood to play a pivotal role in vaginal health. However, our knowledge about the potential interactions between the vaginal microbiota and vaginally administered drug delivery systems is still rather limited. Several drug-releasing vaginal ring products are currently marketed for hormonal contraception and estrogen replacement therapy, and many others are in preclinical and clinical development for these and other clinical indications. As with all implantable polymeric devices, drug-releasing vaginal rings are subject to surface bacterial adherence and biofilm formation, mostly associated with endogenous microorganisms present in the vagina. Despite more than 50 years since the vaginal ring concept was first described, there has been only limited study and reporting around bacterial adherence and biofilm formation on rings. With increasing interest in the vaginal microbiome and vaginal ring technology, this timely review article provides an overview of: (i) the vaginal microbiota, (ii) biofilm formation in the human vagina and its potential role in vaginal dysbiosis, (iii) mechanistic aspects of biofilm formation on polymeric surfaces, (iv) polymeric materials used in the manufacture of vaginal rings, (v) surface morphology characteristics of rings, (vi) biomass accumulation and biofilm formation on vaginal rings, and (vii) regulatory considerations. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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16 pages, 10765 KiB

Open AccessReview

Next Step in Gene Delivery: Modern Approaches and Further Perspectives of AAV Tropism Modification

by Maxim A. Korneyenkov and Andrey A. Zamyatnin, Jr.

Pharmaceutics 2021, 13(5), 750; https://doi.org/10.3390/pharmaceutics13050750 - 19 May 2021

Cited by 30 | Viewed by 5200

Abstract

Today, adeno-associated virus (AAV) is an extremely popular choice for gene therapy delivery. The safety profile and simplicity of the genome organization are the decisive advantages which allow us to claim that AAV is currently among the most promising vectors. Several drugs based [...] Read more.

Today, adeno-associated virus (AAV) is an extremely popular choice for gene therapy delivery. The safety profile and simplicity of the genome organization are the decisive advantages which allow us to claim that AAV is currently among the most promising vectors. Several drugs based on AAV have been approved in the USA and Europe, but AAV serotypes’ unspecific tissue tropism is still a serious limitation. In recent decades, several techniques have been developed to overcome this barrier, such as the rational design, directed evolution and chemical conjugation of targeting molecules with a capsid. Today, all of the abovementioned approaches confer the possibility to produce AAV capsids with tailored tropism, but recent data indicate that a better understanding of AAV biology and the growth of structural data may theoretically constitute a rational approach to most effectively produce highly selective and targeted AAV capsids. However, while we are still far from this goal, other approaches are still in play, despite their drawbacks and limitations. Full article

(This article belongs to the Special Issue Adeno-Associated Virus Vectors for Gene Therapy of Eye and Other Diseases)

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10 pages, 1244 KiB

Open AccessArticle

In Vivo Follow-Up of Gene Inhibition in Solid Tumors Using Peptide-Based Nanoparticles for siRNA Delivery

by Isabel Ferreiro, Coralie Genevois, Karidia Konate, Eric Vivès, Prisca Boisguérin, Sébastien Deshayes and Franck Couillaud

Pharmaceutics 2021, 13(5), 749; https://doi.org/10.3390/pharmaceutics13050749 - 19 May 2021

Cited by 7 | Viewed by 2975

Abstract

Small interfering RNA (siRNA) exhibits a high degree of specificity for targeting selected genes. They are efficient on cells in vitro, but in vivo siRNA therapy remains a challenge for solid tumor treatment as siRNAs display difficulty reaching their intracellular target. The present [...] Read more.

Small interfering RNA (siRNA) exhibits a high degree of specificity for targeting selected genes. They are efficient on cells in vitro, but in vivo siRNA therapy remains a challenge for solid tumor treatment as siRNAs display difficulty reaching their intracellular target. The present study was designed to show the in vivo efficiency of a new peptide (WRAP5), able to form peptide-based nanoparticles (PBN) that can deliver siRNA to cancer cells in solid tumors. WRAP5:siRNA nanoparticles targeting firefly luciferase (Fluc) were formulated and assayed on Fluc-expressing U87 glioblastoma cells. The mode of action of WRAP5:siRNA by RNA interference was first confirmed in vitro and then investigated in vivo using a combination of bioluminescent reporter genes. Finally, histological analyses were performed to elucidate the cell specificity of this PBN in the context of brain tumors. In vitro and in vivo results showed efficient knock-down of Fluc expression with no toxicity. WRAP5:siFluc remained in the tumor for at least 10 days in vivo. Messenger RNA (mRNA) analyses indicated a specific decrease in Fluc mRNA without affecting tumor growth. Histological studies identified PBN accumulation in the cytoplasm of tumor cells but also in glial and neuronal cells. Through in vivo molecular imaging, our findings established the proof of concept for specific gene silencing in solid tumors. The evidence generated could be translated into therapy for any specific gene in different types of tumors without cell type specificity but with high molecular specificity. Full article

(This article belongs to the Special Issue Functional Nanocarrier Technology to Deliver siRNA for Cancer Therapy)

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19 pages, 5944 KiB

Open AccessArticle

Comparison of Different Liquid Chromatography-Based Purification Strategies for Adeno-Associated Virus Vectors

by Ruth Rieser, Johanna Koch, Greta Faccioli, Klaus Richter, Tim Menzen, Martin Biel, Gerhard Winter and Stylianos Michalakis

Pharmaceutics 2021, 13(5), 748; https://doi.org/10.3390/pharmaceutics13050748 - 18 May 2021

Cited by 24 | Viewed by 6947

Abstract

Recombinant adeno-associated virus (rAAV) vectors have evolved as one of the most promising technologies for gene therapy due to their good safety profile, high transduction efficacy, and long-term gene expression in nondividing cells. rAAV-based gene therapy holds great promise for treating genetic disorders [...] Read more.

Recombinant adeno-associated virus (rAAV) vectors have evolved as one of the most promising technologies for gene therapy due to their good safety profile, high transduction efficacy, and long-term gene expression in nondividing cells. rAAV-based gene therapy holds great promise for treating genetic disorders like inherited blindness, muscular atrophy, or bleeding disorders. There is a high demand for efficient and scalable production and purification methods for rAAVs. This is particularly true for the downstream purification methods. The current standard methods are based on multiple steps of gradient ultracentrifugation, which allow for the purification and enrichment of full rAAV particles, but the scale up of this method is challenging. Here, we explored fast, scalable, and universal liquid chromatography-based strategies for the purification of rAAVs. In contrast to the hydrophobic interaction chromatography (HIC), where a substantial amount of AAV was lost, the cation exchange chromatography (CEX) was performed robustly for multiple tested serotypes and resulted in a mixture of full and empty rAAVs with a good purity profile. For the used affinity chromatography (AC), a serotype dependence was observed. Anion exchange chromatography (AEX) worked well for the AAV8 serotype and achieved high levels of purification and a baseline separation of full and empty rAAVs. Depending on the AAV serotype, a combination of CEX and AEX or AC and AEX is recommended and holds promise for future translational projects that require highly pure and full particle-enriched rAAVs. Full article

(This article belongs to the Special Issue Adeno-Associated Virus Vectors for Gene Therapy of Eye and Other Diseases)

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28 pages, 5322 KiB

Open AccessArticle

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

by Yuran Qiu, Xiaolan Yin, Xinyi Li, Yuanhao Wang, Qiang Fu, Renhua Huang and Shaoyong Lu

Pharmaceutics 2021, 13(5), 747; https://doi.org/10.3390/pharmaceutics13050747 - 18 May 2021

Cited by 44 | Viewed by 3072

Abstract

Dual-targeting therapeutics by coadministration of allosteric and orthosteric drugs is drawing increased attention as a revolutionary strategy for overcoming the drug-resistance problems. It was further observed that the occupation of orthosteric sites by therapeutics agents has the potential to enhance allosteric ligand binding, [...] Read more.

Dual-targeting therapeutics by coadministration of allosteric and orthosteric drugs is drawing increased attention as a revolutionary strategy for overcoming the drug-resistance problems. It was further observed that the occupation of orthosteric sites by therapeutics agents has the potential to enhance allosteric ligand binding, which leads to improved potency of allosteric drugs. Epidermal growth factor receptor (EGFR), as one of the most critical anti-cancer targets belonging to the receptor tyrosine kinase family, represents a quintessential example. It was revealed that osimertinib, an ATP-competitive covalent EGFR inhibitor, remarkably enhanced the affinity of a recently developed allosteric inhibitor JBJ-04-125-02 for EGFR^L858R/T790M. Here, we utilized extensive large-scale molecular dynamics simulations and the reversed allosteric communication to untangle the detailed molecular underpinning, in which occupation of osimertinib at the orthosteric site altered the overall conformational ensemble of EGFR mutant and reshaped the allosteric site via long-distance signaling. A unique intermediate state resembling the active conformation was identified, which was further stabilized by osimertinib loading. Based on the allosteric communication pathway, we predicted a novel allosteric site positioned around K867, E868, H893, and K960 within the intermediate state. Its correlation with the orthosteric site was validated by both structural and energetic analysis, and its low sequence conservation indicated the potential for selective targeting across the human kinome. Together, these findings not only provided a mechanistic basis for future clinical application of the dual-targeting therapeutics, but also explored an innovative perception of allosteric inhibition of tyrosine kinase signaling. Full article

(This article belongs to the Special Issue Covalent Inhibitors as Selective Drug Candidates)

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11 pages, 1670 KiB

Open AccessArticle

Assessment of Mini-Tablets Coating Uniformity as a Function of Fluid Bed Coater Inlet Conditions

by Magdalena Turk, Rok Šibanc, Rok Dreu, Maja Frankiewicz and Małgorzata Sznitowska

Pharmaceutics 2021, 13(5), 746; https://doi.org/10.3390/pharmaceutics13050746 - 18 May 2021

Cited by 5 | Viewed by 2587

Abstract

This study concerned the quality of mini-tablets’ coating uniformity obtained by either the bottom spray chamber with a classical Wurster distributor (CW) or a swirl distributor (SW). Mini-tablets with a diameter of 2.0, 2.5, and 3.0 mm were coated with hypromellose using two [...] Read more.

This study concerned the quality of mini-tablets’ coating uniformity obtained by either the bottom spray chamber with a classical Wurster distributor (CW) or a swirl distributor (SW). Mini-tablets with a diameter of 2.0, 2.5, and 3.0 mm were coated with hypromellose using two different inlet air distributors as well as inlet airflow rates (130 and 156 m³/h). Tartrazine was used as a colorant in the coating layer and the coating uniformity was assessed by spectrophotometric analysis of solutions obtained after disintegration of the mini-tablets (n = 100). Higher uniformity of coating material distribution among the mini-tablets was observed in the case of SW distributor, even for the biggest mini-tablets (d = 3.0 mm), with an RSD no larger than 5.0%. Additionally, coating thickness was evaluated by colorimetric analysis (n = 1000), using a scanner method, and expressed as a hue value. A high correlation (R = 0.993) between inter-tablet variability of hue and UV-Vis results was obtained. Mini-tablets were successfully coated in a fluid bed system using both a classical Wurster distributor as well as a swirl generator. However, regardless of the mini-tablets’ diameter, better film uniformity was achieved in the case of a distributor with a swirl generator. Full article

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13 pages, 2405 KiB

Open AccessArticle

Development of Pelubiprofen Tromethamine with Improved Gastrointestinal Safety and Absorption

by Ji Yeon Park, Dong Ho Oh, Sang-Wook Park, Bo Ram Chae, Chul Woo Kim, Sang Heon Han, Hyeon Jong Shin, Soo Bin Yeom, Da Yeong Lee, Min Kyu Park, Sang-Eun Park, Jun-Bom Park and Kyung-Tae Lee

Pharmaceutics 2021, 13(5), 745; https://doi.org/10.3390/pharmaceutics13050745 - 18 May 2021

Cited by 5 | Viewed by 3680

Abstract

Pelubiprofen (PEL), which is a commercialized non-steroidal anti-inflammatory drug (NSAID), is associated with the risk of gastrointestinal (GI) adverse events following long-term exposure and has poor water-soluble properties. Here, a new pelubiprofen tromethamine (PEL-T) with improved solubility, permeability, GI safety, and absorption, compared [...] Read more.

Pelubiprofen (PEL), which is a commercialized non-steroidal anti-inflammatory drug (NSAID), is associated with the risk of gastrointestinal (GI) adverse events following long-term exposure and has poor water-soluble properties. Here, a new pelubiprofen tromethamine (PEL-T) with improved solubility, permeability, GI safety, and absorption, compared to PEL, has been developed. The nuclear magnetic resonance spectroscopy (NMR), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR) results confirmed that the PEL-T was well formed. The powder of PEL-T showed the presence of additional 6H protons at δ 3.66–3.61 in the ¹H NMR spectrum, and shifted the sharp endothermic peaks at 129 °C in DSC, and the spectrum of distinct absorption peaks in FT-IR. In addition, compared with PEL, PEL-T showed a significantly improved solubility in various media and an increased permeability coefficient (K_p) in Caco-2 cells. Furthermore, compared to PEL oral administration, PEL-T was found to significantly reduce the damaged area in an acute gastric damage rat model. The pharmacokinetic study of the PEL-T powder showed higher maximum plasma concentration (C_max) and area under the plasma concentration–time curve from 0 h to the last time point (AUC_t) than those of the PEL powder. Taken together, our data suggest that PEL-T is a recommendable candidate with enhanced gastrointestinal safety and better absorption compared with commercial PEL. Full article

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17 pages, 951 KiB

Open AccessArticle

Polymeric Micelles for the Enhanced Deposition of Hydrophobic Drugs into Ocular Tissues, without Plasma Exposure

by Ijeoma F. Uchegbu, Jan Breznikar, Alessandra Zaffalon, Uche Odunze and Andreas G. Schätzlein

Pharmaceutics 2021, 13(5), 744; https://doi.org/10.3390/pharmaceutics13050744 - 18 May 2021

Cited by 11 | Viewed by 2983

Abstract

Commercial topical ocular formulations for hydrophobic actives rely on the use of suspensions or oil in water emulsions and neither of these formulation modalities adequately promote drug penetration into ocular tissues. Using the ocular relevant hydrophobic drug, cyclosporine A (CsA), a non-irritant ocular [...] Read more.

Commercial topical ocular formulations for hydrophobic actives rely on the use of suspensions or oil in water emulsions and neither of these formulation modalities adequately promote drug penetration into ocular tissues. Using the ocular relevant hydrophobic drug, cyclosporine A (CsA), a non-irritant ocular penetration enhancer is showcased, which may be used for the formulation of hydrophobic actives. The activity of this penetration enhancer is demonstrated in a healthy rabbit model. The Molecular Envelope Technology (MET) polymer (N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan), a self-assembling, micelle-forming polymer, was used to formulate CsA into sterile filtered nanoparticulate eye drop formulations and the stability of the formulation tested. Healthy rabbits were dosed with a single dose of a MET–CsA (NM133) 0.05% formulation and ocular tissues analyzed. Optically clear NM133 formulations were prepared containing between 0.01–0.1% w/v CsA and 0.375–0.75% w/v MET polymer. NM133 0.01%, NM133 0.02% and NM133 0.05% were stable for 28 days when stored at refrigeration temperature (5–6 °C) and room temperature (16–23 °C), but there was evidence of evaporation of the formulation at 40 °C. There was no change in drug content when NM133 0.05% was stored for 387 days at 4 °C. On topical dosing to rabbits, corneal, conjunctival and scleral AUC_0–24 levels were 25,780 ng.h g⁻¹, 12,046 ng.h g⁻¹ and 5879 ng.h g⁻¹, respectively, with NM133 0.05%. Meanwhile, a similar dose of Restasis 0.05% yielded lower values of 4726 ng.h/g, 4813 ng.h/g and 1729 ng.h/g for the drug corneal, conjunctival and scleral levels, respectively. NM133 thus delivered up to five times more CsA to the ocular surface tissues when compared to Restasis. The MET polymer was non-irritant up to a concentration of 4% w/v. The MET polymer is a non-irritant ocular penetration enhancer that may be used to deliver hydrophobic drugs in optically clear topical ocular formulations. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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16 pages, 1394 KiB

Open AccessArticle

Anti-Tumor and Anti-Inflammatory Activity In Vivo of Apodanthera congestiflora Cogn. (Cucurbitaceae)

by Geovana F. G. Silvestre, Renally P. Lucena, Genil D. Oliveira, Helimarcos N. Pereira, Jhonatta A. B. Dias, Ivone A. Souza and Harley S. Alves

Pharmaceutics 2021, 13(5), 743; https://doi.org/10.3390/pharmaceutics13050743 - 18 May 2021

Cited by 4 | Viewed by 2137

Abstract

This work aimed to carry out a study of Apodanthera congestiflora by investigating its chemical composition and pharmacological potential. From the dichloromethane phase (Dic-Ac) of the A. congestiflora stems, three compounds were identified: cayaponoside C_5b (Ac-1), cabenoside C (Ac-2) and fevicordin C [...] Read more.

This work aimed to carry out a study of Apodanthera congestiflora by investigating its chemical composition and pharmacological potential. From the dichloromethane phase (Dic-Ac) of the A. congestiflora stems, three compounds were identified: cayaponoside C_5b (Ac-1), cabenoside C (Ac-2) and fevicordin C₂ glucoside (Ac-3), being last identified for the first time as a natural product. These compounds were obtained by chromatographic methods and their structures were elucidated by means of spectroscopic analysis of IR, MS and NMR. In the quantification of Dic-Ac, it was possible to observe the presence of 7% of cayaponoside C_5b. Dic-Ac showed significant toxicity for in vivo tests, with macroscopic and biochemical changes. The anti-inflammatory activity of Dic-Ac was investigated using the paw edema model. A decrease in inflammatory signs was observed in the first 5 h and the most effective dose in reducing edema with was 7.5 mg kg⁻¹ (66.6%). Anti-tumor activity of Dic-Ac was evaluated by Ehrlich’s carcinoma model, which showed inhibition rate of 78.46% at 15 mg kg⁻¹ dosage. The phytochemical investigation, together with the biological tests carried out in this study, demonstrated that A. congestiflora is a promising species in the search for therapeutics, since it contains substances with high pharmacological potential in its composition. Full article

(This article belongs to the Special Issue Prospecting for Active Compounds in Medicinal Chemistry and Pharmaceutical Technological Development)

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12 pages, 19996 KiB

Open AccessArticle

The Preparation of a Novel Poly(Lactic Acid)-Based Sustained H₂S Releasing Microsphere for Rheumatoid Arthritis Alleviation

by Yue Yu, Zhou Wang, Qian Ding, Xiangbin Yu, Qinyan Yang, Ran Wang, Yudong Fang, Wei Qi, Junyi Liao, Wei Hu and Yizhun Zhu

Pharmaceutics 2021, 13(5), 742; https://doi.org/10.3390/pharmaceutics13050742 - 18 May 2021

Cited by 11 | Viewed by 2569

Abstract

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease that mainly erodes joints and surrounding tissues, and if it is not treated in time, it can cause joint deformities and loss of function. S-propargyl-cysteine (SPRC) is an excellent endogenous hydrogen sulfide donor which [...] Read more.

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease that mainly erodes joints and surrounding tissues, and if it is not treated in time, it can cause joint deformities and loss of function. S-propargyl-cysteine (SPRC) is an excellent endogenous hydrogen sulfide donor which can relieve the symptoms of RA through the promotion of H₂S release via the CSE/H₂S pathway in vivo. However, the instant release of H₂S in vivo could potentially limit its further clinical use. To solve this problem, in this study, a SPRC-loaded poly(lactic acid) (PLA) microsphere (SPRC@PLA) was prepared, which could release SPRC in vitro in a sustained manner, and further promote sustained in vivo H₂S release. Furthermore, its therapeutical effect on RA in rats was also studied. A spherical-like SPRC@PLA was successfully prepared with a diameter of approximately 31.61 μm, yielding rate of 50.66%, loading efficiency of 6.10% and encapsulation efficiency of 52.71%. The SPRC@PLA showed significant prolonged in vitro SPRC release, to 4 days, and additionally, an in vivo H₂S release around 3 days could also be observed. In addition, a better therapeutical effect and prolonged administration interval toward RA rats was also observed in the SPRC@PLA group. Full article

(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)

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23 pages, 4093 KiB

Open AccessArticle

Toxicokinetic/Toxicodynamic Interaction Studies in Rats between the Drugs of Abuse γ-Hydroxybutyric Acid and Ketamine and Treatment Strategies for Overdose

by Nisha V. Kwatra and Marilyn E. Morris

Pharmaceutics 2021, 13(5), 741; https://doi.org/10.3390/pharmaceutics13050741 - 18 May 2021

Cited by 1 | Viewed by 3013

Abstract

γ-hydroxybutyric acid (GHB) is widely abused alone and in combination with other club drugs such as ketamine. GHB exhibits nonlinear toxicokinetics, characterized by saturable metabolism, saturable absorption and saturable renal reabsorption mediated by monocarboxylate transporters (MCTs). In this research, we characterized the effects [...] Read more.

γ-hydroxybutyric acid (GHB) is widely abused alone and in combination with other club drugs such as ketamine. GHB exhibits nonlinear toxicokinetics, characterized by saturable metabolism, saturable absorption and saturable renal reabsorption mediated by monocarboxylate transporters (MCTs). In this research, we characterized the effects of ketamine on GHB toxicokinetics/toxicodynamics (TK/TD) and evaluated the use of MCT inhibition and specific receptor antagonism as potential treatment strategies for GHB overdose in the presence of ketamine. Adult male Sprague-Dawley rats were administered GHB 600 mg/kg i.v. alone or with ketamine (6 mg/kg i.v. bolus plus 1 mg/kg/min i.v. infusion). Plasma and urine samples were collected and respiratory parameters (breathing frequency, tidal and minute volume) continuously monitored using whole-body plethysmography. Ketamine co-administration resulted in a significant decrease in GHB total and metabolic clearance, with renal clearance remaining unchanged. Ketamine prevented the compensatory increase in tidal volume produced by GHB, and this resulted in a significant decline in minute volume when compared to GHB alone. Sleep time and lethality were also increased after ketamine co-administration when compared to GHB. L-lactate and AR-C155858 (potent MCT inhibitor) treatment resulted in an increase in GHB renal and total clearance and improvement in respiratory depression. AR-C155858 administration also resulted in a significant decrease in GHB brain/plasma ratio. SCH50911 (GABA_B receptor antagonist), but not naloxone, improved GHB-induced respiratory depression in the presence of ketamine. In conclusion, ketamine ingestion with GHB can result in significant TK/TD interactions. MCT inhibition and GABA_B receptor antagonism can serve as potential treatment strategies for GHB overdose when it is co-ingested with ketamine. Full article

(This article belongs to the Collection Women in Pharmaceutics)

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15 pages, 1279 KiB

Open AccessArticle

Pharmacokinetic Drug Interaction between Tofacitinib and Voriconazole in Rats

by Ji-Sang Lee, Hyo-Sung Kim, Yong-Seob Jung, Hyeon-Gyeom Choi and So-Hee Kim

Pharmaceutics 2021, 13(5), 740; https://doi.org/10.3390/pharmaceutics13050740 - 18 May 2021

Cited by 4 | Viewed by 2875

Abstract

Fungal infections are prevalent in patients with immune diseases. Voriconazole, a triazole antifungal drug, inhibits the cytochromes CYP3A4 and CYP2C, and tofacitinib, a Janus kinase inhibitor for the treatment of rheumatoid arthritis, is metabolized by CYP3A4 and CYP2C19 in humans. Here, we investigated [...] Read more.

Fungal infections are prevalent in patients with immune diseases. Voriconazole, a triazole antifungal drug, inhibits the cytochromes CYP3A4 and CYP2C, and tofacitinib, a Janus kinase inhibitor for the treatment of rheumatoid arthritis, is metabolized by CYP3A4 and CYP2C19 in humans. Here, we investigated their interaction during simultaneous administration of both drugs to rats, either intravenously or orally. The area under the plasma concentration–time curve from time zero to time infinity (AUC) of tofacitinib was significantly greater, by 166% and 171%, respectively, and the time-averaged non-renal clearance (CL_NR) of tofacitinib was significantly slower (59.5%) than that for tofacitinib alone. An in vitro metabolism study showed non-competitive inhibition of tofacitinib metabolism in the liver and intestine by voriconazole. The concentration/apparent inhibition constant (K_i) ratios of voriconazole were greater than two, indicating that the inhibition of tofacitinib metabolism could be due to the inhibition of the CYP3A1/2 and CYP2C11 enzymes by voriconazole. The pharmacokinetics of voriconazole were not affected by the co-administration of tofacitinib. In conclusion, the significantly greater AUC and slower CL_NR of tofacitinib after intravenous and oral administration of both drugs were attributable to the non-competitive inhibition of tofacitinib metabolism via CYP3A1/2 and CYP2C11 by voriconazole in rats. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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12 pages, 2236 KiB

Open AccessArticle

Investigating the Potential of Transdermal Delivery of Avanafil Using Vitamin E-TPGS Based Mixed Micelles Loaded Films

by Abdullah A. Alamoudi, Osama A. A. Ahmed and Khalid M. El-Say

Pharmaceutics 2021, 13(5), 739; https://doi.org/10.3390/pharmaceutics13050739 - 17 May 2021

Cited by 5 | Viewed by 2197

Abstract

To avoid the first-pass metabolism of avanafil (AVA) and its altered absorption in the presence of food after oral administration, this study aimed to investigate the potential of TPGS-based mixed micelle (MM)-loaded film for transdermal delivery and the enhancement of bioavailability. A Box–Behnken [...] Read more.

To avoid the first-pass metabolism of avanafil (AVA) and its altered absorption in the presence of food after oral administration, this study aimed to investigate the potential of TPGS-based mixed micelle (MM)-loaded film for transdermal delivery and the enhancement of bioavailability. A Box–Behnken design was employed to optimize the permeation behavior of AVA from the transdermal film across the skin. The variables were the hydrophile-lipophile balance (HLB) of the surfactant (X₁), the concentration of mixed micelles (MMs) in the film (X₂), and the concentration of the permeation enhancer (X₃). The initial permeation of AVA after 1 h (Y₁), and the cumulative permeation of AVA after 24 h (Y₂) were the dependent variables. Ex vivo studies were carried out on freshly isolated rat skin to investigate the drug’s permeation potential and results were visualized using a fluorescence laser microscope. Moreover, the pharmacokinetic behavior after a single application on male Wistar rats, in comparison with films loaded with raw AVA, was evaluated. The results showed that the optimum factor levels were 9.4% for the HLB of the surfactant used, and 5.12% MMs and 2.99% penetration enhancer in the film. Imaging with a fluorescence laser microscope indicated the ability of the optimized film to deliver the payload to deeper skin layers. Furthermore, optimized AVA-loaded TPGS-micelles film showed a significant increase (p < 0.05) in the C_max of AVA and the area under the AVA plasma curve (approximately three-fold). The optimized AVA-loaded TPGS-MM film thus represents a successful delivery system for enhancing the bioavailability of AVA. Full article

(This article belongs to the Special Issue Nanotechnology-Enabled Strategies to Enhance Topical Bioavailability)

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13 pages, 3859 KiB

Open AccessArticle

Gold Nanoparticles Affect Pericyte Biology and Capillary Tube Formation

by Sasikarn Looprasertkul, Amornpun Sereemaspun, Nakarin Kitkumthorn, Kanidta Sooklert, Tewarit Sarachana and Depicha Jindatip

Pharmaceutics 2021, 13(5), 738; https://doi.org/10.3390/pharmaceutics13050738 - 17 May 2021

Cited by 5 | Viewed by 2531

Abstract

Gold nanoparticles (AuNPs) are used for diagnostic and therapeutic purposes, especially antiangiogenesis, which are accomplished via inhibition of endothelial cell proliferation, migration, and tube formation. However, no research has been performed on the effects of AuNPs in pericytes, which play vital roles in [...] Read more.

Gold nanoparticles (AuNPs) are used for diagnostic and therapeutic purposes, especially antiangiogenesis, which are accomplished via inhibition of endothelial cell proliferation, migration, and tube formation. However, no research has been performed on the effects of AuNPs in pericytes, which play vital roles in endothelial cell functions and capillary tube formation during physiological and pathological processes. Therefore, the effects of AuNPs on the morphology and functions of pericytes need to be elucidated. This study treated human placental pericytes in monoculture with 20 nm AuNPs at a concentration of 30 ppm. Ki-67 and platelet-derived growth factor receptor-β (PDGFR-β) mRNA expression was measured using real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell migration was assessed by Transwell migration assay. The fine structures of pericytes were observed by transmission electron microscopy. In addition, 30 ppm AuNP-treated pericytes and intact human umbilical vein endothelial cells were cocultured on Matrigel to form three-dimensional (3D) capillary tubes. The results demonstrated that AuNPs significantly inhibited proliferation, reduced PDGFR-β mRNA expression, and decreased migration in pericytes. Ultrastructural analysis of pericytes revealed AuNPs in late endosomes, autolysosomes, and mitochondria. Remarkably, many mitochondria were swollen or damaged. Additionally, capillary tube formation was reduced. We found that numerous pericytes on 3D capillary tubes were round and did not extend their processes along the tubes, which resulted in more incomplete tube formation in the treatment group compared with the control group. In summary, AuNPs can affect pericyte proliferation, PDGFR-β mRNA expression, migration, morphology, and capillary tube formation. The findings highlight the possible application of AuNPs in pericyte-targeted therapy for antiangiogenesis. Full article

(This article belongs to the Special Issue Biological Evaluation and Biomedical Application of Nanoparticles-Based Formulations)

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17 pages, 2461 KiB

Open AccessArticle

Chondroitin Sulfate in USA Dietary Supplements in Comparison to Pharma Grade Products: Analytical Fingerprint and Potential Anti-Inflammatory Effect on Human Osteoartritic Chondrocytes and Synoviocytes

by Antonietta Stellavato, Odile Francesca Restaino, Valentina Vassallo, Elisabetta Cassese, Rosario Finamore, Carlo Ruosi and Chiara Schiraldi

Pharmaceutics 2021, 13(5), 737; https://doi.org/10.3390/pharmaceutics13050737 - 17 May 2021

Cited by 15 | Viewed by 2501

Abstract

The biological activity of chondroitin sulfate (CS) and glucosamine (GlcN) food supplements (FS), sold in USA against osteoarthritis, might depend on the effective CS and GlcN contents and on the CS structural characteristics. In this paper three USA FS were compared to two [...] Read more.

The biological activity of chondroitin sulfate (CS) and glucosamine (GlcN) food supplements (FS), sold in USA against osteoarthritis, might depend on the effective CS and GlcN contents and on the CS structural characteristics. In this paper three USA FS were compared to two pharmaceutical products (Ph). Analyses performed by HPAE-PAD, by HPCE and by SEC-TDA revealed that the CS and GlcN titers were up to −68.8% lower than the contents declared on the labels and that CS of mixed animal origin and variable molecular weights was present together with undesired keratan sulfate. Simulated gastric and intestinal digestions were performed in vitro to evaluate the real CS amount that may reach the gut as biopolymer. Chondrocytes and synoviocytes primary cells derived from human pathological joints were used to assess: cell viability, modulation of the NF-κB, quantification of cartilage oligomeric matrix protein (COMP-2), hyaluronate synthase enzyme (HAS-1), pentraxin (PTX-3) and the secreted IL-6 and IL-8 to assess inflammation. Of the three FS tested only one (US FS1) enhanced chondrocytes viability, while all of them supported synoviocytes growth. Although US FS1 proved to be less effective than Ph as it reduced NF-kB, it could not down-regulate COMP-2; HAS-1 was up-regulated but with a lower efficacy. Inflammatory cytokines were markedly reduced by Ph while a slight decrease was only found for US-FS1. Full article

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10 pages, 627 KiB

Open AccessReview

Minicircles for Investigating and Treating Arthritic Diseases

by Yeri Alice Rim, Yoojun Nam, Narae Park and Ji Hyeon Ju

Pharmaceutics 2021, 13(5), 736; https://doi.org/10.3390/pharmaceutics13050736 - 17 May 2021

Cited by 1 | Viewed by 1987

Abstract

Gene delivery systems have become an essential component of research and the development of therapeutics for various diseases. Minicircles are non-viral vectors with promising characteristics for application in a variety of fields. With their minimal size, minicircles exhibit relatively high safety and efficient [...] Read more.

Gene delivery systems have become an essential component of research and the development of therapeutics for various diseases. Minicircles are non-viral vectors with promising characteristics for application in a variety of fields. With their minimal size, minicircles exhibit relatively high safety and efficient delivery of genes of interest into cells. Cartilage tissue lacks the natural ability to heal, making it difficult to treat osteoarthritis (OA) and rheumatoid arthritis (RA), which are the two main types of joint-related disease. Although both OA and RA affect the joint, RA is an autoimmune disease, while OA is a degenerative joint condition. Gene transfer using minicircles has also been used in many studies regarding cartilage and its diseased conditions. In this review, we summarize the cartilage-, OA-, and RA-based studies that have used minicircles as the gene delivery system. Full article

(This article belongs to the Special Issue Delivery Systems of Plasmid DNA and Messenger RNA for Advanced Therapies)

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22 pages, 27339 KiB

Open AccessArticle

Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings

by Sugandha Saboo, Pradnya Bapat, Dana E. Moseson, Umesh S. Kestur and Lynne S. Taylor

Pharmaceutics 2021, 13(5), 735; https://doi.org/10.3390/pharmaceutics13050735 - 17 May 2021

Cited by 32 | Viewed by 4581

Abstract

To reduce the dosage size of amorphous solid dispersion (ASD)-based formulations, it is of interest to devise formulation strategies that allow increased drug loading (DL) without compromising dissolution performance. The aim of this study was to explore how surfactant addition impacts drug release [...] Read more.

To reduce the dosage size of amorphous solid dispersion (ASD)-based formulations, it is of interest to devise formulation strategies that allow increased drug loading (DL) without compromising dissolution performance. The aim of this study was to explore how surfactant addition impacts drug release as a function of drug loading from a ternary ASD, using felodipine as a model poorly soluble compound. The addition of 5% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant) to felodipine-polyvinylpyrrolidone/vinyl acetate ASDs was found to facilitate rapid and congruent (i.e., simultaneous) release of drug and polymer at higher DLs relative to binary ASDs (drug and polymer only). For binary ASDs, good release was observed for DLs up to <20% DL; this increased to 35% DL with surfactant. Microstructure evolution in ASD films following exposure to 100% relative humidity was studied using atomic force microscopy coupled with nanoscale infrared imaging. The formation of discrete, spherical drug-rich domains in the presence of surfactant appeared to be linked to systems showing congruent and rapid release of drug and polymer. In contrast, a contiguous drug-rich phase was formed for systems without surfactant at higher DLs. This study supports the addition of surfactant to ASD formulations as a strategy to increase DL without compromising release. Furthermore, insights into the potential role of surfactant in altering ASD release mechanisms are provided. Full article

(This article belongs to the Special Issue Recent Progress in Solid Dispersion Technology 2.0)

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