Pharmaceutics

19 pages, 6132 KiB

Open AccessArticle

Study of the Early Effects of Chitosan Nanoparticles with Glutathione in Rats with Osteoarthrosis

by Patricia Ramírez-Noguera, Iliane Zetina Marín, Blanca Margarita Gómez Chavarin, Moisés Eduardo Valderrama, Laura Denise López-Barrera and Roberto Díaz-Torres

Pharmaceutics 2023, 15(8), 2172; https://doi.org/10.3390/pharmaceutics15082172 - 21 Aug 2023

Cited by 3 | Viewed by 1660

Abstract

Due to cartilage’s limited capacity for regeneration, numerous studies have been conducted to find new drugs that modify osteoarthrosis’s progression. Some evidence showed the capability of chitosan nanoparticles with glutathione (Np-GSH) to regulate the oxide-redox status in vitro in human chondrocytes. This work [...] Read more.

Due to cartilage’s limited capacity for regeneration, numerous studies have been conducted to find new drugs that modify osteoarthrosis’s progression. Some evidence showed the capability of chitosan nanoparticles with glutathione (Np-GSH) to regulate the oxide-redox status in vitro in human chondrocytes. This work aimed to evaluate the capacity of Np-GSH in vivo, using Wistar rats with induced surgical osteoarthritis. Radiographic, biochemical (GSH and TBARS quantification), histopathological, and immunohistochemical (Col-2 and MMP-13) analyses were performed to evaluate the progress of the osteoarthritic lesions after the administration of a single dose of Np-GSH. According to the results obtained, the GSH contained in the NPs could be vectored to chondrocytes and used by the cell to modulate the oxidative state reduction, decreasing the production of ROS and free radicals induced by agents oxidizing xenobiotics, increasing GSH levels, as well as the activity of GPx, and decreasing lipid peroxidation. These results are significant since the synthesis of GSH develops exclusively in the cell cytoplasm, and its quantity under an oxidation–reduction imbalance may be defective. Therefore, the results allow us to consider these nanostructures as a helpful study tool to reduce the damage associated with oxidative stress in various diseases such as osteoarthritis. Full article

(This article belongs to the Special Issue Development of Chitosan/Cyclodextrins in Drug Delivery Field)

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21 pages, 3750 KiB

Open AccessEditor’s ChoiceReview

An Insight on the Possible Association between Inflammatory Bowel Disease and Biologic Therapy with IL-17 Inhibitors in Psoriasis Patients

by Olguța Anca Orzan, Cristian George Țieranu, Andrei Ovidiu Olteanu, Alexandra Maria Dorobanțu, Anca Cojocaru, Mara Mădălina Mihai, Liliana Gabriela Popa, Ana Maria Gheorghiu, Călin Giurcăneanu and Ana Ion

Pharmaceutics 2023, 15(8), 2171; https://doi.org/10.3390/pharmaceutics15082171 - 21 Aug 2023

Cited by 6 | Viewed by 2308

Abstract

Psoriasis is a chronic, inflammatory, multisystemic disease which affects approximately 2–3% of the population globally, whose onset is triggered by genetic and environmental factors which activate both dendritic cells and keratinocytes, resulting in the production of proinflammatory cytokines such as tumor necrosis factor [...] Read more.

Psoriasis is a chronic, inflammatory, multisystemic disease which affects approximately 2–3% of the population globally, whose onset is triggered by genetic and environmental factors which activate both dendritic cells and keratinocytes, resulting in the production of proinflammatory cytokines such as tumor necrosis factor alpha, interleukin 17, interleukin 23, interleukin 22, and interleukin 1β. An in-depth understanding of the pathophysiology of psoriasis led to significant advances in the development of safe and efficient novel therapeutic options, with four classes of biologic therapy being approved for the management of moderate to severe psoriasis: tumor necrosis factor alpha inhibitors, interleukin 23 inhibitors, anti-interleukin 12/23 agents, anti-interleukin 17 agents, as well as small-molecule inhibitors, such as apremilast. Psoriasis is associated with comorbid conditions, namely psoriatic arthritis, cardiovascular disease, metabolic syndrome, psychiatric disorders, malignancy, as well as inflammatory bowel disease. For patients affected by both psoriasis and inflammatory bowel disease, there is a strong recommendation to avoid IL-17 inhibitors since they may play a part in the exacerbation of the gastrointestinal disease. Our aim was to perform a thorough literature review regarding the development of inflammatory bowel disease lesions in psoriasis patients treated with IL-17 inhibitors, along with a case presentation to emphasize the need for close follow-up of these patients. Full article

(This article belongs to the Special Issue Targeted Therapies for Skin Diseases)

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19 pages, 4059 KiB

Open AccessArticle

QSAR and Chemical Read-Across Analysis of 370 Potential MGMT Inactivators to Identify the Structural Features Influencing Inactivation Potency

by Guohui Sun, Peiying Bai, Tengjiao Fan, Lijiao Zhao, Rugang Zhong, R. Stanley McElhinney, T. Brian H. McMurry, Dorothy J. Donnelly, Joan E. McCormick, Jane Kelly and Geoffrey P. Margison

Pharmaceutics 2023, 15(8), 2170; https://doi.org/10.3390/pharmaceutics15082170 - 21 Aug 2023

Cited by 15 | Viewed by 2226

Abstract

O⁶-methylguanine-DNA methyltransferase (MGMT) constitutes an important cellular mechanism for repairing potentially cytotoxic DNA damage induced by guanine O⁶-alkylating agents and can render cells highly resistant to certain cancer chemotherapeutic drugs. A wide variety of potential MGMT inactivators have been [...] Read more.

O⁶-methylguanine-DNA methyltransferase (MGMT) constitutes an important cellular mechanism for repairing potentially cytotoxic DNA damage induced by guanine O⁶-alkylating agents and can render cells highly resistant to certain cancer chemotherapeutic drugs. A wide variety of potential MGMT inactivators have been designed and synthesized for the purpose of overcoming MGMT-mediated tumor resistance. We determined the inactivation potency of these compounds against human recombinant MGMT using [³H]-methylated-DNA-based MGMT inactivation assays and calculated the IC₅₀ values. Using the results of 370 compounds, we performed quantitative structure–activity relationship (QSAR) modeling to identify the correlation between the chemical structure and MGMT-inactivating ability. Modeling was based on subdividing the sorted pIC₅₀ values or on chemical structures or was random. A total of nine molecular descriptors were presented in the model equation, in which the mechanistic interpretation indicated that the status of nitrogen atoms, aliphatic primary amino groups, the presence of O-S at topological distance 3, the presence of Al-O-Ar/Ar-O-Ar/R..O..R/R-O-C=X, the ionization potential and hydrogen bond donors are the main factors responsible for inactivation ability. The final model was of high internal robustness, goodness of fit and prediction ability (R²_pr = 0.7474, Q²_Fn = 0.7375–0.7437, CCC_pr = 0.8530). After the best splitting model was decided, we established the full model based on the entire set of compounds using the same descriptor combination. We also used a similarity-based read-across technique to further improve the external predictive ability of the model (R²_pr = 0.7528, Q²_Fn = 0.7387–0.7449, CCC_pr = 0.8560). The prediction quality of 66 true external compounds was checked using the “Prediction Reliability Indicator” tool. In summary, we defined key structural features associated with MGMT inactivation, thus allowing for the design of MGMT inactivators that might improve clinical outcomes in cancer treatment. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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20 pages, 2058 KiB

Open AccessReview

Rapid Prototyping Technologies: 3D Printing Applied in Medicine

by Małgorzata Oleksy, Klaudia Dynarowicz and David Aebisher

Pharmaceutics 2023, 15(8), 2169; https://doi.org/10.3390/pharmaceutics15082169 - 21 Aug 2023

Cited by 10 | Viewed by 3249

Abstract

Three-dimensional printing technology has been used for more than three decades in many industries, including the automotive and aerospace industries. So far, the use of this technology in medicine has been limited only to 3D printing of anatomical models for educational and training [...] Read more.

Three-dimensional printing technology has been used for more than three decades in many industries, including the automotive and aerospace industries. So far, the use of this technology in medicine has been limited only to 3D printing of anatomical models for educational and training purposes, which is due to the insufficient functional properties of the materials used in the process. Only recent advances in the development of innovative materials have resulted in the flourishing of the use of 3D printing in medicine and pharmacy. Currently, additive manufacturing technology is widely used in clinical fields. Rapid development can be observed in the design of implants and prostheses, the creation of biomedical models tailored to the needs of the patient and the bioprinting of tissues and living scaffolds for regenerative medicine. The purpose of this review is to characterize the most popular 3D printing techniques. Full article

(This article belongs to the Special Issue 3D Bioprinted Scaffolds for Tissue Engineering)

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20 pages, 3649 KiB

Open AccessArticle

Enhanced Cellular Uptake and Transport of Bovine Lactoferrin Using Pectin- and Chitosan-Modified Solid Lipid Nanoparticles

by Xudong Yao, Craig Bunt, Mengyang Liu, Siew-Young Quek, John Shaw, Jillian Cornish and Jingyuan Wen

Pharmaceutics 2023, 15(8), 2168; https://doi.org/10.3390/pharmaceutics15082168 - 21 Aug 2023

Cited by 5 | Viewed by 1962

Abstract

Aim: The aim of this project is to use pectin- and chitosan-modified solid lipid nanoparticles for bovine lactoferrin to enhance its cellular uptake and transport. Methods: Solid lipid particles containing bovine lactoferrin (bLf) were formulated through the solvent evaporation technique, incorporating stearic acid [...] Read more.

Aim: The aim of this project is to use pectin- and chitosan-modified solid lipid nanoparticles for bovine lactoferrin to enhance its cellular uptake and transport. Methods: Solid lipid particles containing bovine lactoferrin (bLf) were formulated through the solvent evaporation technique, incorporating stearic acid along with either chitosan or pectin modification. bLf cellular uptake and transport were evaluated in vitro using the human adenocarcinoma cell line Caco-2 cell model. Results and Discussion: The bLf-loaded SLPs showed no significant effect on cytotoxicity and did not induce apoptosis within the eight-hour investigation. The use of confocal laser scanning microscopy confirmed that bLf follows the receptor-mediated endocytosis, whereas the primary mechanism for the cellular uptake of SLPs was endocytosis. The bLf-loaded SLPs had significantly more cellular uptake compared to bLf alone, and it was observed that this impact varied based on the time, temperature, and concentration. Verapamil and EDTA were determined to raise the apparent permeability coefficients (App) of bLf and bLf-loaded SLPs. Conclusion: This occurred because they hindered efflux by interacting with P-glycoproteins and had a penetration-enhancing influence. These findings propose the possibility of an additional absorption mechanism for SLPs, potentially involving active transportation facilitated by the P-glycoprotein transporter in Caco-2 cells. These results suggest that SLPs have the potential to be applied as effective carriers to improve the oral bioavailability of proteins and peptides. Full article

(This article belongs to the Special Issue New Technology for Prolonged Drug Release)

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16 pages, 1757 KiB

Open AccessArticle

Evaluation of Pharmacokinetic Feasibility of Febuxostat/L-pyroglutamic Acid Cocrystals in Rats and Mice

by Jeong-Eun Yu, Byoung Hoon You, Mingoo Bae, Seung Yon Han, Kiwon Jung and Young Hee Choi

Pharmaceutics 2023, 15(8), 2167; https://doi.org/10.3390/pharmaceutics15082167 - 21 Aug 2023

Cited by 1 | Viewed by 1341

Abstract

Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate F value (<49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with an improving 4-fold increase of FBX solubility. Nevertheless, the in vivo [...] Read more.

Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate F value (<49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with an improving 4-fold increase of FBX solubility. Nevertheless, the in vivo pharmacokinetic properties of FBX-PG have not been evaluated yet. Therefore, the pharmacokinetic feasibility of FBX in FBX- and FBX-PG-treated rats and mice was compared in this study. The results showed that the bioavailability (F) values of FBX were 210% and 159% in FBX-PG-treated rats and mice, respectively. The 2.10-fold greater total area under the plasma concentration–time curve from time zero to infinity (AUC_0-inf) of FBX was due to the increased absorption [i.e., 2.60-fold higher the first peak plasma concentration (C_max,1) at 15 min] and entero-hepatic circulation of FBX [i.e., 1.68-fold higher the second peak plasma concentration (C_max,2) at 600 min] in FBX-PG-treated rats compared to the FBX-treated rats. The 1.59-fold greater AUC_0-inf of FBX was due to a 1.65-fold higher C_max,1 at 5 min, and a 1.15-fold higher C_max,2 at 720 min of FBX in FBX-PG-treated mice compared to those in FBX-treated mice. FBX was highly distributed in the liver, stomach, small intestine, and lungs in both groups of mice, and the FBX distributions to the liver and lungs were increased in FBX-PG-treated mice compared to FBX-treated mice. The results suggest the FBX-PG has a suitable pharmacokinetic profile of FBX for improving its oral F value. Full article

(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs, 2nd Edition)

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36 pages, 2575 KiB

Open AccessEditor’s ChoiceReview

Drug Repurposing to Circumvent Immune Checkpoint Inhibitor Resistance in Cancer Immunotherapy

by Kenneth K. W. To and William C. Cho

Pharmaceutics 2023, 15(8), 2166; https://doi.org/10.3390/pharmaceutics15082166 - 21 Aug 2023

Cited by 2 | Viewed by 2985

Abstract

Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of [...] Read more.

Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of clinically approved drugs, with characterized pharmacological properties and known adverse effect profiles, to new indications. It has also emerged as a promising strategy to overcome drug resistance. In this review, we summarized the latest research about drug repurposing to overcome ICI resistance. Repurposed drugs work by either exerting immunostimulatory activities or abolishing the immunosuppressive tumor microenvironment (TME). Compared to the de novo drug design strategy, they provide novel and affordable treatment options to enhance cancer immunotherapy that can be readily evaluated in the clinic. Biomarkers are exploited to identify the right patient population to benefit from the repurposed drugs and drug combinations. Phenotypic screening of chemical libraries has been conducted to search for T-cell-modifying drugs. Genomics and integrated bioinformatics analysis, artificial intelligence, machine and deep learning approaches are employed to identify novel modulators of the immunosuppressive TME. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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23 pages, 1644 KiB

Open AccessReview

Advance and Challenges in the Treatment of Skin Diseases with the Transdermal Drug Delivery System

by Tingting Cheng, Zongguang Tai, Min Shen, Ying Li, Junxia Yu, Jiandong Wang, Quangang Zhu and Zhongjian Chen

Pharmaceutics 2023, 15(8), 2165; https://doi.org/10.3390/pharmaceutics15082165 - 21 Aug 2023

Cited by 23 | Viewed by 6087

Abstract

Skin diseases are among the most prevalent non-fatal conditions worldwide. The transdermal drug delivery system (TDDS) has emerged as a promising approach for treating skin diseases, owing to its numerous advantages such as high bioavailability, low systemic toxicity, and improved patient compliance. However, [...] Read more.

Skin diseases are among the most prevalent non-fatal conditions worldwide. The transdermal drug delivery system (TDDS) has emerged as a promising approach for treating skin diseases, owing to its numerous advantages such as high bioavailability, low systemic toxicity, and improved patient compliance. However, the effectiveness of the TDDS is hindered by several factors, including the barrier properties of the stratum corneum, the nature of the drug and carrier, and delivery conditions. In this paper, we provide an overview of the development of the TDDS from first-generation to fourth-generation systems, highlighting the characteristics of each carrier in terms of mechanism composition, penetration method, mechanism of action, and recent preclinical studies. We further investigated the significant challenges encountered in the development of the TDDS and the crucial significance of clinical trials. Full article

(This article belongs to the Special Issue Transdermal/Dermal Drug Delivery System)

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12 pages, 5910 KiB

Open AccessArticle

Impact of Poloxamer on Crystal Nucleation and Growth of Amorphous Clotrimazole

by Jie Zhang, Ziqing Yang, Liquan Luo, Kang Li, Taotao Zi, Junjie Ren, Lei Pan, Ziyue Wang, Zihao Wang, Minzhuo Liu and Zhihong Zeng

Pharmaceutics 2023, 15(8), 2164; https://doi.org/10.3390/pharmaceutics15082164 - 21 Aug 2023

Cited by 3 | Viewed by 1449

Abstract

Surfactants have been widely used as effective additives to increase the solubility and dissolution rates of amorphous solid dispersions (ASDs). However, they may also generate adverse effects on the physical stability of ASDs. In this study, we systematically investigated the impacts of poloxamer, [...] Read more.

Surfactants have been widely used as effective additives to increase the solubility and dissolution rates of amorphous solid dispersions (ASDs). However, they may also generate adverse effects on the physical stability of ASDs. In this study, we systematically investigated the impacts of poloxamer, a frequently used surfactant, on the crystallization of amorphous clotrimazole (CMZ). The added poloxamer significantly decreased the glass transition temperature (Tg) of CMZ and accelerated the growth of Form 1 and Form 2 crystals. It was found that the poloxamer had an accelerating effect on Form 1 and Form 2 but showed a larger accelerating effect on Form 1, which resulted from a combined effect of increased mobility and local phase separation at the crystal–liquid interface. Additionally, the added poloxamer exhibited different effects on nucleation of the CMZ polymorphs, which was more complicated than crystal growth. The nucleation rate of Form 1 was significantly increased by the added poloxamer, and the effect increased with increasing P407 content. However, for Form 2, nucleation was slightly decreased or unchanged. The nucleation of Form 2 may have been influenced by the Form 1 crystallization, and Form 2 converted to Form 1 during nucleation. This study increases our understanding of poloxamer and its impacts on the melt crystallization of drugs. Full article

(This article belongs to the Special Issue Pharmaceutical Solid Forms: From Crystal Structure to Formulation)

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12 pages, 980 KiB

Open AccessArticle

Effect of Switching to Once-Weekly Semaglutide on Non-Alcoholic Fatty Liver Disease: The SWITCH-SEMA 1 Subanalysis

by Hiroshi Nomoto, Yuka Takahashi, Yoshinari Takano, Hiroki Yokoyama, Kazuhisa Tsuchida, So Nagai, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura and Tatsuya Atsumi

Pharmaceutics 2023, 15(8), 2163; https://doi.org/10.3390/pharmaceutics15082163 - 20 Aug 2023

Cited by 2 | Viewed by 2360

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an important common comorbidity in individuals with type 2 diabetes (T2DM). Although some glucagon-like peptide-1 receptor agonists (GLP-1RAs) have beneficial effects on NAFLD, the efficacy of once-weekly semaglutide has not been established. This was a subanalysis of [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is an important common comorbidity in individuals with type 2 diabetes (T2DM). Although some glucagon-like peptide-1 receptor agonists (GLP-1RAs) have beneficial effects on NAFLD, the efficacy of once-weekly semaglutide has not been established. This was a subanalysis of the SWITCH-SEMA 1 study, a multicenter, prospective, randomized, parallel-group trial comparing switching from liraglutide or dulaglutide to once-weekly semaglutide in subjects with T2DM (SWITCH) versus continuing current GLP-1RAs (Continue) for 24 weeks. This subanalysis consisted of participants who were suspected to have NAFLD [fatty liver index (FLI) ≥ 30]. In total, 58 participants met the criteria of this subanalysis. There were no statistical differences in baseline characteristics between the SWITCH (n = 31) and Continue groups (n = 27). FLI significantly improved during treatment in the SWITCH group (68.6 to 62.7) but not in the Continue group (71.1 to 72.3) (p < 0.01). The improvement of FLI in the SWITCH group was greater in switching from dulaglutide to semaglutide and significantly correlated with older age (p = 0.016) and lower baseline FLI (p < 0.01). The multiple linear regression analysis revealed that the switch from dulaglutide was associated with an improvement in FLI (p = 0.041). Switching from conventional GLP-1RAs to once-weekly semaglutide might be beneficial for individuals with NAFLD complicated with T2DM. Full article

(This article belongs to the Special Issue Effective Therapies for Diabetes)

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27 pages, 6996 KiB

Open AccessArticle

Bovine Lactoferrin-Loaded Plasmonic Magnetoliposomes for Antifungal Therapeutic Applications

by Mélanie Pereira, Ana Rita O. Rodrigues, Leslie Amaral, Manuela Côrte-Real, Cátia Santos-Pereira and Elisabete M. S. Castanheira

Pharmaceutics 2023, 15(8), 2162; https://doi.org/10.3390/pharmaceutics15082162 - 19 Aug 2023

Cited by 2 | Viewed by 1555

Abstract

Bovine lactoferrin (bLf) is a milk-derived protein that exhibits potent broad-spectrum antifungal activity against multiple fungi. bLf is susceptible to degradation, while some of its properties depend on the tertiary structure. So, the encapsulation of bLf in stimuli-responsive therapeutic formulations provides an added [...] Read more.

Bovine lactoferrin (bLf) is a milk-derived protein that exhibits potent broad-spectrum antifungal activity against multiple fungi. bLf is susceptible to degradation, while some of its properties depend on the tertiary structure. So, the encapsulation of bLf in stimuli-responsive therapeutic formulations provides an added value to enhance its biological activities. Plasmonic magnetoliposomes (PMLs) arise as promising nanocarriers for dual hyperthermia (magneto-photothermia) and local chemotherapy, since the combination of magnetic and gold nanoparticles (NPs) in a single nanosystem (multifunctional liposomes) enables the targeting and controlled release of loaded drugs. In this work, plasmonic magnetoliposomes (PMLs) containing manganese ferrite nanoparticles (28 nm size) and gold nanoparticles (5–7.5 nm size), functionalized with 11-mercaptoundecanoic acid or octadecanethiol, were prepared and loaded with bLf. The NPs’ optical, magnetic and structural properties were measured via UV/vis/NIR absorption spectroscopy, SQUID and TEM, respectively. The Specific Absorption Rate (SAR) was calculated to assess the capabilities for magnetic and photothermal hyperthermia. Finally, the antifungal potential of bLf-loaded PMLs and their mechanism of internalization were assessed in Saccharomyces cerevisiae by counting the colony forming units and using fluorescence microscopy. The results demonstrate that PMLs are mainly internalized through an energy- and temperature-dependent endocytic process, though the contribution of a diffusion component cannot be discarded. Most notably, only bLf-loaded plasmonic magnetoliposomes display cytotoxicity with an efficiency similar to free bLf, attesting their promising potential for bLf delivery in the context of antifungal therapeutic interventions. Full article

(This article belongs to the Special Issue Stimuli-Responsive Therapeutic Formulations for Drug Release)

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18 pages, 5489 KiB

Open AccessArticle

Constructing ROS-Responsive Supramolecular Gel with Innate Antibacterial Properties

by Fen Zheng, Wei Du, Minggang Yang, Kaige Liu, Shanming Zhang, Long Xu and Yong Wen

Pharmaceutics 2023, 15(8), 2161; https://doi.org/10.3390/pharmaceutics15082161 - 19 Aug 2023

Cited by 3 | Viewed by 1599

Abstract

Bacterial infections, especially antibiotic-resistant bacterial infections, pose a significant threat to human health. Supramolecular gel with innate antibacterial properties is an advanced material for the treatment of bacterial infections, which have attracted great attention. Herein, a reactive oxygen species (ROS)-responsive innate antibacterial supramolecular [...] Read more.

Bacterial infections, especially antibiotic-resistant bacterial infections, pose a significant threat to human health. Supramolecular gel with innate antibacterial properties is an advanced material for the treatment of bacterial infections, which have attracted great attention. Herein, a reactive oxygen species (ROS)-responsive innate antibacterial supramolecular gel is developed by a bottom-up approach based on phenylalanine and hydrazide with innate antibacterial properties. The structure of gelators and intermediate products was characterized by proton nuclear magnetic resonance (¹H NMR) and a high-resolution mass spectrum (HRMS). The results of ¹H NMR and the Fourier transform infrared spectrum (FT–IR) experiment disclosed that hydrogen bonding and the π–π stacking force are the important self-assembly driving forces of gelators. The microstructure and mechanical properties of gel were studied by Scanning electron microscope (SEM) and Rheometer, respectively. An in vitro degradation experiment proved that the gelator has ROS-responsive degradation properties. The in vitro drug release experiment further manifested that antibiotic-loaded gel has ROS-responsive drug-release performances. An in vitro cytotoxicity experiment showed that the supramolecular gel has good biocompatibility and could promote cell proliferation. The in vitro antibacterial experiment proved that the supramolecular gel has excellent inherent antibacterial properties, and the antibacterial rate against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) was 98.6% and 99.1%, respectively. The ROS-responsive supramolecular gel as a novel antibacterial agent has great application prospects in treating antibiotic-resistant bacterial-infected wounds and preventing the development of bacterial resistance. Full article

(This article belongs to the Special Issue Smart Materials for Targeted Drug Delivery and Cancer Therapy)

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27 pages, 6312 KiB

Open AccessEditor’s ChoiceReview

Antibody-Drug Conjugates in Solid Tumor Oncology: An Effectiveness Payday with a Targeted Payload

by Aleksei Kondrashov, Surendra Sapkota, Aditya Sharma, Ivy Riano, Razelle Kurzrock and Jacob J. Adashek

Pharmaceutics 2023, 15(8), 2160; https://doi.org/10.3390/pharmaceutics15082160 - 19 Aug 2023

Cited by 9 | Viewed by 3995

Abstract

Antibody–drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components—an antibody, a linker molecule, and a cytotoxic agent (“payload”), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific [...] Read more.

Antibody–drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components—an antibody, a linker molecule, and a cytotoxic agent (“payload”), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific antigen, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. A variety of payloads can be used, including most frequently microtubular inhibitors (auristatins and maytansinoids), as well as topoisomerase inhibitors and alkylating agents. Finally, linkers play a critical role in the ADCs’ effect, as cleavable moieties that serve as linkers impact site-specific activation as well as bystander killing effects, an upshot that is especially important in solid tumors that often express a variety of antigens. While ADCs were initially used in hematologic malignancies, their utility has been demonstrated in multiple solid tumor malignancies, including breast, gastrointestinal, lung, cervical, ovarian, and urothelial cancers. Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Although they demonstrate utility and tolerable safety profiles, ADCs may become ineffective as tumor cells undergo evolution to avoid expressing the specific antigen being targeted. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies. Full article

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

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29 pages, 10550 KiB

Open AccessArticle

Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease

by Daria A. Belinskaia, Polina A. Voronina, Denis V. Krivorotov, Richard O. Jenkins and Nikolay V. Goncharov

Pharmaceutics 2023, 15(8), 2159; https://doi.org/10.3390/pharmaceutics15082159 - 19 Aug 2023

Cited by 2 | Viewed by 1353

Abstract

The etiology and pathogenesis of Alzheimer’s disease are multifactorial, so one of the treatment strategies is the development of the drugs that affect several targets associated with the pathogenesis of the disease. Within this roadmap, we investigated the interaction of several substituted 1,3-dihydro-2-oxo-1 [...] Read more.

The etiology and pathogenesis of Alzheimer’s disease are multifactorial, so one of the treatment strategies is the development of the drugs that affect several targets associated with the pathogenesis of the disease. Within this roadmap, we investigated the interaction of several substituted 1,3-dihydro-2-oxo-1H-benzimidazol-2-ones with their potential molecular targets: cholinesterases (ChE) and three types of the G_s-protein-coupled serotonin receptors (5-HTR) 5-HT₆, 5-HT₄ and 5-HT₇ (5-HT₄R, 5-HT₆R and 5-HT₇R, respectively). A microplate modification of the Ellman method was used for the biochemical analysis of the inhibitory ability of the drugs towards ChE. Molecular modeling methods, such as molecular docking and molecular dynamics (MD) simulation in water and the lipid bilayer, were used to study the interaction of the compounds with ChE and 5-HTR. In vitro experiments showed that the tested compounds had moderate anticholinesterase activity. With the help of molecular modeling methods, the mechanism of interaction of the tested compounds with ChE was investigated, the binding sites were described and the structural features of the drugs that determine the strength of their anticholinesterase activity were revealed. Primary in silico evaluation showed that benzimidazole–carboxamides effectively bind to 5-HT₄R and 5-HT₇R. The pool of the obtained data allows us to choose N-[2-(diethylamino)ethyl]-2-oxo-3-(tert-butyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride (compound 13) as the most promising for further experimental development. Full article

(This article belongs to the Special Issue Alzheimer's Disease: An Update on Novel Therapeutics)

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18 pages, 4662 KiB

Open AccessArticle

Modulating the Effect of β-Sitosterol Conjugated with Magnetic Nanocarriers to Inhibit EGFR and Met Receptor Cross Talk

by Shanmuga Sundari Ilangovan, Biswanath Mahanty, Venkatesan Perumal and Shampa Sen

Pharmaceutics 2023, 15(8), 2158; https://doi.org/10.3390/pharmaceutics15082158 - 19 Aug 2023

Cited by 1 | Viewed by 1597

Abstract

The cross-talk between the EGFR (Epidermal Growth Factor Receptor) and MET (Hepatocyte Growth Factor Receptor) poses a significant challenge in the field of molecular signaling. Their intricate interplay leads to dysregulation and contributes to cancer progression and therapeutic resistance. β-Sitosterol (BS), a plant [...] Read more.

The cross-talk between the EGFR (Epidermal Growth Factor Receptor) and MET (Hepatocyte Growth Factor Receptor) poses a significant challenge in the field of molecular signaling. Their intricate interplay leads to dysregulation and contributes to cancer progression and therapeutic resistance. β-Sitosterol (BS), a plant sterol with promising anticancer properties, shows increased research on its potential as a chemopreventive agent. However, significant modifications are required to deliver BS in cancer cells due to its lower efficacy. The present work aims to design a carrier-mediated delivery system specifically targeting cancer cells with EGFR and MET receptor cross-talk. Surface modification of BS was performed with superparamagnetic iron oxide nanoparticles (SPIONs), polyethylene glycol (PEG), and poly(N-isopropylacrylamide) (PNIPAM) to enhance the delivery of BS at the target site. BS was conjugated with SPIONs (BS-S), PNIPAM (BS-SP), PEG, and PNIPAM (BS-SPP) polymers, respectively, and the conjugated complexes were characterized. Results showed an increase in size, stability, and monodispersity in the following order, BS-S, BS-SP, and BS-SPP. The drug encapsulation efficiency was observed to be highest in BS-SPP (82.5%), compared to BS-S (61%) and BS-SP (74.9%). Sustained drug release was achieved in both BS-SP (82.6%) and BS-SPP (83%). The IC 50 value of BS, BS-S, BS-SP, and BS-SPP towards MCF 7 was 242 µg/mL,197 µg/mL, 168 µg/mL, and 149 µg/mL, HEPG2 was 274 µg/mL, 261 µg/mL, 233 µg/mL and 207 µg/mL and NCIH 460 was 191 µg/mL, 185 µg/mL, 175 and 164 µg/mL, indicating highest inhibition towards NCIH 460 cells. Our results conclude that β-sitosterol conjugated with SPION, PEG, and PNIPAM could be a potential targeted therapy in inhibiting EGFR and MET receptor-expressing cancer cells. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Image-Guided and Targeted Theranostic Platforms)

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23 pages, 11706 KiB

Open AccessArticle

LA67 Liposome-Loaded Thermo-Sensitive Hydrogel with Active Targeting for Efficient Treatment of Keloid via Peritumoral Injection

by Hongshuang Wan, Shuangqing Wang, Chuying Li, Bowen Zeng, Hao Wu, Chao Liu, Liqing Chen, Mingji Jin, Wei Huang, Yingda Zang, Dongming Zhang, Zhonggao Gao and Zhehu Jin

Pharmaceutics 2023, 15(8), 2157; https://doi.org/10.3390/pharmaceutics15082157 - 18 Aug 2023

Cited by 4 | Viewed by 1696

Abstract

A keloid is a benign tumor manifested as abnormal fibroplasia on the surface of the skin. Curing keloids has become a major clinical challenge, and searching for new treatments and medications has become critical. In this study, we developed a LA67 liposome-loaded thermo-sensitive [...] Read more.

A keloid is a benign tumor manifested as abnormal fibroplasia on the surface of the skin. Curing keloids has become a major clinical challenge, and searching for new treatments and medications has become critical. In this study, we developed a LA67 liposome-loaded thermo-sensitive hydrogel (LA67-RL-Gel) with active targeting for treating keloids via peritumoral injection and explored the anti-keloid mechanism. Firstly, Arg-Gly-Asp (RGD) peptide-modified liposomes (LA67-RL) loaded with LA67 were prepared with a particle size of 105.9 nm and a Zeta potential of −27.4 mV, and an encapsulation efficiency of 89.6 ± 3.7%. We then constructed a thermo-sensitive hydrogel loaded with LA67-RL by poloxamer 407 and 188. The formulation was optimized through the Box–Behnken design, where the impact of the proportion of the ingredients on the quality of the hydrogel was evaluated entirely. The optimal formulation was 20.7% P407 and 2.1% P188, and the gelation time at 37 °C was 9.5 s. LA67-RL-Gel slowly released 92.2 ± 0.8% of LA67 at pH 6.5 PBS for 72 h. LA67-RL-Gel increased adhesion with KF cells; increased uptake; promoted KF cells apoptosis; inhibited cell proliferation; reduced α-SMA content; decreased collagen I, collagen III, and fibronectin deposition; inhibited angiogenesis; and modulated the keloid microenvironment, ultimately exerting anti-keloid effects. In summary, this simple, low-cost, and highly effective anti-keloid liposome hydrogel provides a novel approach for treating keloids and deserves further development. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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27 pages, 12088 KiB

Open AccessReview

Harnessing the Potential of Biosurfactants for Biomedical and Pharmaceutical Applications

by Chiara Ceresa, Letizia Fracchia, Andrea Chiara Sansotera, Mayri Alejandra Díaz De Rienzo and Ibrahim M. Banat

Pharmaceutics 2023, 15(8), 2156; https://doi.org/10.3390/pharmaceutics15082156 - 18 Aug 2023

Cited by 18 | Viewed by 3707

Abstract

Biosurfactants (BSs) are microbial compounds that have emerged as potential alternatives to chemical surfactants due to their multifunctional properties, sustainability and biodegradability. Owing to their amphipathic nature and distinctive structural arrangement, biosurfactants exhibit a range of physicochemical properties, including excellent surface activity, efficient [...] Read more.

Biosurfactants (BSs) are microbial compounds that have emerged as potential alternatives to chemical surfactants due to their multifunctional properties, sustainability and biodegradability. Owing to their amphipathic nature and distinctive structural arrangement, biosurfactants exhibit a range of physicochemical properties, including excellent surface activity, efficient critical micelle concentration, humectant properties, foaming and cleaning abilities and the capacity to form microemulsions. Furthermore, numerous biosurfactants display additional biological characteristics, such as antibacterial, antifungal and antiviral effects, and antioxidant, anticancer and immunomodulatory activities. Over the past two decades, numerous studies have explored their potential applications, including pharmaceuticals, cosmetics, antimicrobial and antibiofilm agents, wound healing, anticancer treatments, immune system modulators and drug/gene carriers. These applications are particularly important in addressing challenges such as antimicrobial resistance and biofilm formations in clinical, hygiene and therapeutic settings. They can also serve as coating agents for surfaces, enabling antiadhesive, suppression, or eradication strategies. Not least importantly, biosurfactants have shown compatibility with various drug formulations, including nanoparticles, liposomes, micro- and nanoemulsions and hydrogels, improving drug solubility, stability and bioavailability, and enabling a targeted and controlled drug release. These qualities make biosurfactants promising candidates for the development of next-generation antimicrobial, antibiofilm, anticancer, wound-healing, immunomodulating, drug or gene delivery agents, as well as adjuvants to other antibiotics. Analysing the most recent literature, this review aims to update the present understanding, highlight emerging trends, and identify promising directions and advancements in the utilization of biosurfactants within the pharmaceutical and biomedical fields. Full article

(This article belongs to the Section Biopharmaceutics)

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16 pages, 8102 KiB

Open AccessArticle

Piezodynamic Eradication of Both Gram-Positive and Gram-Negative Bacteria by Using a Nanoparticle Embedded Polymeric Membrane

by Chan Chen, Shubham Roy, Jingjing Wang, Xiafen Lu, Siyi Li, Hao Yang, Minggang Cheng, Bing Guo and Yuzhong Xu

Pharmaceutics 2023, 15(8), 2155; https://doi.org/10.3390/pharmaceutics15082155 - 17 Aug 2023

Cited by 4 | Viewed by 1494

Abstract

Nowadays, bacterial infection is regarded as a serious threat to humankind, which needs to be taken care of. The emergence of antibiotic resistance and multidrug resistance (MDR) is rendering this situation more troublesome. However, several alternative treatment regimens have aided such diseases quite [...] Read more.

Nowadays, bacterial infection is regarded as a serious threat to humankind, which needs to be taken care of. The emergence of antibiotic resistance and multidrug resistance (MDR) is rendering this situation more troublesome. However, several alternative treatment regimens have aided such diseases quite well in the recent past, among which dynamic antibacterial therapies combat this situation quite well. Among various dynamic therapies, piezodynamic therapy is a very recent avenue, in which mechanical stimuli have been exploited to treat bacterial infections. Herein, piezo-active bismuth ferrite-loaded poly(vinylidene fluoride-co-hexafluoropropylene) polymer has been utilized to eradicate gram-positive bacteria (E. faecalis) and gram-negative bacteria (E. coli). The sample has been designed in a free-standing membrane form, which, under soft ultrasound (~10 kHz), generates reactive radicals to ablate bacteria. Initially, the structure and morphology of the membrane have been substantiated by using X-ray diffraction and scanning electron microscopy methods; besides, Fourier transform infrared spectrum of the sample depicts a tremendously high value of polarizability and further confirms the piezo-activity of the membrane. More than 99% of E. coli and E. faecalis have been successfully eradicated within 30 min of ultrasound. Moreover, the solid-state structure and hydrophobic nature of the membrane help us to reuse it in a cyclic manner, which is possibly reported herein for the very first time. This novel membrane could be deployed in healthcare systems and pigment industries and could be exploited as a self-cleaning material. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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20 pages, 5422 KiB

Open AccessArticle

Comparative Evaluation of the Powder and Tableting Properties of Regular and Direct Compression Hypromellose from Different Vendors

by Nihad Mawla, Maen Alshafiee, John Gamble, Mike Tobyn, Lande Liu, Karl Walton, Barbara R. Conway, Peter Timmins and Kofi Asare-Addo

Pharmaceutics 2023, 15(8), 2154; https://doi.org/10.3390/pharmaceutics15082154 - 17 Aug 2023

Cited by 3 | Viewed by 2297

Abstract

Hypromellose, a widely used polymer in the pharmaceutical industry, is available in several grades, depending on the percentage of substitution of the methoxyl and hydroxypropyl groups and molecular weight, and in various functional forms (e.g., suitable for direct compression tableting). These differences can [...] Read more.

Hypromellose, a widely used polymer in the pharmaceutical industry, is available in several grades, depending on the percentage of substitution of the methoxyl and hydroxypropyl groups and molecular weight, and in various functional forms (e.g., suitable for direct compression tableting). These differences can affect their physicomechanical properties, and so this study aims to characterise the particle size and mechanical properties of HPMC K100M polymer grades from four different vendors. Eight polymers (CR and DC grades) were analysed using scanning electron microscopy (SEM) and light microscopy automated image analysis particle characterisation to examine the powder’s particle morphology and particle size distribution. Bulk density, tapped density, and true density of the materials were also analysed. Flow was determined using a shear cell tester. Flat-faced polymer compacts were made at five different compression forces and the mechanical properties of the compacts were evaluated to give an indication of the powder’s capacity to form a tablet with desirable strength under specific pressures. The results indicated that the CR grades of the polymers displayed a smaller particle size and better mechanical properties compared to the DC grade HPMC K100M polymers. The DC grades, however, had better flow properties than their CR counterparts. The results also suggested some similarities and differences between some of the polymers from the different vendors despite the similarity in substitution level, reminding the user that care and consideration should be given when substitution is required. Full article

(This article belongs to the Collection Feature Papers in Pharmaceutical Technology)

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11 pages, 1975 KiB

Open AccessArticle

A Machine Learning Approach to Qualitatively Evaluate Different Granulation Phases by Acoustic Emissions

by Ruwen Fulek, Selina Ramm, Christian Kiera, Miriam Pein-Hackelbusch and Ulrich Odefey

Pharmaceutics 2023, 15(8), 2153; https://doi.org/10.3390/pharmaceutics15082153 - 17 Aug 2023

Viewed by 1299

Abstract

Wet granulation is a frequent process in the pharmaceutical industry. As a starting point for numerous dosage forms, the quality of the granulation not only affects subsequent production steps but also impacts the quality of the final product. It is thus crucial and [...] Read more.

Wet granulation is a frequent process in the pharmaceutical industry. As a starting point for numerous dosage forms, the quality of the granulation not only affects subsequent production steps but also impacts the quality of the final product. It is thus crucial and economical to monitor this operation thoroughly. Here, we report on identifying different phases of a granulation process using a machine learning approach. The phases reflect the water content which, in turn, influences the processability and quality of the granule mass. We used two kinds of microphones and an acceleration sensor to capture acoustic emissions and vibrations. We trained convolutional neural networks (CNNs) to classify the different phases using transformed sound recordings as the input. We achieved a classification accuracy of up to 90% using vibrational data and an accuracy of up to 97% using the audible microphone data. Our results indicate the suitability of using audible sound and machine learning to monitor pharmaceutical processes. Moreover, since recording acoustic emissions is contactless, it readily complies with legal regulations and presents Good Manufacturing Practices. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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22 pages, 2692 KiB

Open AccessEditor’s ChoiceReview

Exploring the Antioxidant Potential of Gellan and Guar Gums in Wound Healing

by Gianina Dodi, Rosina E. Sabau, Bianca E.-B. Crețu and Ioannis Gardikiotis

Pharmaceutics 2023, 15(8), 2152; https://doi.org/10.3390/pharmaceutics15082152 - 17 Aug 2023

Cited by 10 | Viewed by 2296

Abstract

It is acknowledged that the presence of antioxidants boosts the wound-healing process. Many biopolymers have been explored over the years for their antioxidant potential in wound healing, but limited research has been performed on gum structures and their derivatives. This review aims to [...] Read more.

It is acknowledged that the presence of antioxidants boosts the wound-healing process. Many biopolymers have been explored over the years for their antioxidant potential in wound healing, but limited research has been performed on gum structures and their derivatives. This review aims to evaluate whether the antioxidant properties of gellan and guar gums and wound healing co-exist. PubMed was the primary platform used to explore published reports on the antioxidant wound-healing interconnection, wound dressings based on gellan and guar gum, as well as the latest review papers on guar gum. The literature search disclosed that some wound-healing supports based on gellan gum hold considerable antioxidant properties, as evident from the results obtained using different antioxidant assays. It has emerged that the antioxidant properties of guar gum are overlooked in the wound-healing field, in most cases, even if this feature improves the healing outcome. This review paper is the first that examines guar gum vehicles throughout the wound-healing process. Further research is needed to design and evaluate customized wound dressings that can scavenge excess reactive oxygen species, especially in clinical practice. Full article

(This article belongs to the Special Issue The Study of Plant Compounds in Antioxidant Activity and Anticancer Activity)

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18 pages, 2212 KiB

Open AccessReview

Advancing Treatment Strategies: A Comprehensive Review of Drug Delivery Innovations for Chronic Inflammatory Respiratory Diseases

by Junming Wang, Pengfei Wang, Yiru Shao and Daikun He

Pharmaceutics 2023, 15(8), 2151; https://doi.org/10.3390/pharmaceutics15082151 - 17 Aug 2023

Cited by 1 | Viewed by 3512

Abstract

Chronic inflammatory respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, present ongoing challenges in terms of effective treatment and management. These diseases are characterized by persistent inflammation in the airways, leading to structural changes and compromised lung function. [...] Read more.

Chronic inflammatory respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, present ongoing challenges in terms of effective treatment and management. These diseases are characterized by persistent inflammation in the airways, leading to structural changes and compromised lung function. There are several treatments available for them, such as bronchodilators, immunomodulators, and oxygen therapy. However, there are still some shortcomings in the effectiveness and side effects of drugs. To achieve optimal therapeutic outcomes while minimizing systemic side effects, targeted therapies and precise drug delivery systems are crucial to the management of these diseases. This comprehensive review focuses on the role of drug delivery systems in chronic inflammatory respiratory diseases, particularly nanoparticle-based drug delivery systems, inhaled corticosteroids (ICSs), novel biologicals, gene therapy, and personalized medicine. By examining the latest advancements and strategies in these areas, we aim to provide a thorough understanding of the current landscape and future prospects for improving treatment outcomes in these challenging conditions. Full article

(This article belongs to the Special Issue Drug Delivery in Chronic Inflammatory Respiratory Diseases)

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17 pages, 2385 KiB

Open AccessReview

Biopolymer-Based Nanosystems: Potential Novel Carriers for Kidney Drug Delivery

by Hao Li, Wenni Dai, Li Xiao, Lin Sun and Liyu He

Pharmaceutics 2023, 15(8), 2150; https://doi.org/10.3390/pharmaceutics15082150 - 17 Aug 2023

Cited by 3 | Viewed by 2201

Abstract

Kidney disease has become a serious public health problem throughout the world, and its treatment and management constitute a huge global economic burden. Currently, the main clinical treatments are not sufficient to cure kidney diseases. During its development, nanotechnology has shown unprecedented potential [...] Read more.

Kidney disease has become a serious public health problem throughout the world, and its treatment and management constitute a huge global economic burden. Currently, the main clinical treatments are not sufficient to cure kidney diseases. During its development, nanotechnology has shown unprecedented potential for application to kidney diseases. However, nanotechnology has disadvantages such as high cost and poor bioavailability. In contrast, biopolymers are not only widely available but also highly bioavailable. Therefore, biopolymer-based nanosystems offer new promising solutions for the treatment of kidney diseases. This paper reviews the biopolymer-based nanosystems that have been used for renal diseases and describes strategies for the specific, targeted delivery of drugs to the kidney as well as the physicochemical properties of the nanoparticles that affect the targeting success. Full article

(This article belongs to the Special Issue Biopolymer-Based Nanosystem for Drug Delivery, 2nd Edition)

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21 pages, 6455 KiB

Open AccessArticle

Breast Milk Mesenchymal Stem Cells and/or Derived Exosomes Mitigated Adenine-Induced Nephropathy via Modulating Renal Autophagy and Fibrotic Signaling Pathways and Their Epigenetic Regulations

by Tarek Khamis, Amira Ebrahim Alsemeh, Asma Alanazi, Asmaa Monir Eltaweel, Heba M. Abdel-Ghany, Doaa M. Hendawy, Adel Abdelkhalek, Mahmoud A. Said, Heba H. Awad, Basma Hamed Ibrahim, Dina Mohamed Mekawy, Corina Pascu, Crista Florin and Ahmed Hamed Arisha

Pharmaceutics 2023, 15(8), 2149; https://doi.org/10.3390/pharmaceutics15082149 - 16 Aug 2023

Cited by 3 | Viewed by 2467

Abstract

Chronic kidney disease (CKD), a global health concern, is highly prevalent among adults. Presently, there are limited therapeutic options to restore kidney function. This study aimed to investigate the therapeutic potential of breast milk mesenchymal stem cells (Br-MSCs) and their derived exosomes in [...] Read more.

Chronic kidney disease (CKD), a global health concern, is highly prevalent among adults. Presently, there are limited therapeutic options to restore kidney function. This study aimed to investigate the therapeutic potential of breast milk mesenchymal stem cells (Br-MSCs) and their derived exosomes in CKD. Eighty adult male Sprague Dawley rats were randomly assigned to one of six groups, including control, nephropathy, nephropathy + conditioned media (CM), nephropathy + Br-MSCs, nephropathy + Br-MSCs derived exosomes (Br-MSCs-EXOs), and nephropathy + Br-MSCs + Br-MSCs-EXOs. Before administration, Br-MSCs and Br-MSCs-EXOs were isolated, identified, and labeled with PKH-26. SOX2, Nanog, and OCT3/4 expression levels in Br-MSCs and miR-29b, miR-181, and Let-7b in both Br-MSCs and Br-MSCs-EXOs were assayed. Twelve weeks after transplantation, renal function tests, oxidative stress, expression of the long non-coding RNA SNHG-7, autophagy, fibrosis, and expression of profibrotic miR-34a and antifibrotic miR-29b, miR-181, and Let-7b were measured in renal tissues. Immunohistochemical analysis for renal Beclin-1, LC3-II, and P62, Masson trichome staining, and histopathological examination of kidney tissues were also performed. The results showed that Br-MSCs expressed SOX2, Nanog, and OCT3/4, while both Br-MSCs and Br-MSCs-EXOs expressed antifibrotic miR-181, miR-29b, and Let-7b, with higher expression levels in exosomes than in Br-MSCs. Interestingly, the administration of Br-MSCs + EXOs, EXOs, and Br-MSCs improved renal function tests, reduced renal oxidative stress, upregulated the renal expression of SNHG-7, AMPK, ULK-1, Beclin-1, LC3, miR-29b, miR-181, Let-7b, and Smad-7, downregulated the renal expression of miR-34a, AKT, mTOR, P62, TGF-β, Smad-3, and Coli-1, and ameliorated renal pathology. Thus, Br-MSCs and/or their derived exosomes appear to reduce adenine-induced renal damage by secreting antifibrotic microRNAs and potentiate renal autophagy by modulating SNHG-7 expression. Full article

(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cell Extracellular Vesicles: From Active Principle to Next Generation Drug Delivery)

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16 pages, 4180 KiB

Open AccessArticle

The Influence of Wet Granulation Parameters on the Compaction Behavior and Tablet Strength of a Hydralazine Powder Mixture

by Oliver Macho, Ľudmila Gabrišová, Adam Guštafík, Kristian Jezso, Martin Juriga, Juraj Kabát and Jaroslav Blaško

Pharmaceutics 2023, 15(8), 2148; https://doi.org/10.3390/pharmaceutics15082148 - 16 Aug 2023

Cited by 4 | Viewed by 2119

Abstract

The aim of this paper was to describe the influence of high-shear wet granulation process parameters on tablet tensile strength and compaction behavior of a powder mixture and granules containing hydralazine. The hydralazine powder mixture and eight types of granules were compacted into [...] Read more.

The aim of this paper was to describe the influence of high-shear wet granulation process parameters on tablet tensile strength and compaction behavior of a powder mixture and granules containing hydralazine. The hydralazine powder mixture and eight types of granules were compacted into tablets and evaluated using the Heckel, Kawakita and Adams analyses. The granules were created using two types of granulation liquid (distilled water and aqueous solution of polyvinylpyrrolidone), at different impeller speeds (500 and 700 rpm) and with different wet massing times (without wet massing and for 2 min). Granulation resulted in improved compressibility, reduced dustiness and narrower particle-size distribution. A significant influence of wet massing time on parameters from the Kawakita and Adams analysis was found. Wet massing time had an equally significant effect on tablet tensile strength, regardless of the granulation liquid used. Granules formed with the same wet massing time showed the same trends in tabletability graphs. Tablets created using a single-tablet press (batch compaction) and an eccentric tablet press showed opposite values of tensile strength. Tablets from granules with a higher bulk density showed lower strength during batch compaction and, conversely, higher strength during eccentric tableting. Full article

(This article belongs to the Special Issue Pharmaceutical Tablets: Tablet Surface Preparation and Analysis Methods)

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20 pages, 3786 KiB

Open AccessArticle

The Influence of the Intergranular Superdisintegrant Performance on New Drotaverine Orodispersible Tablet Formulations

by Robert-Alexandru Vlad, Cezara Pintea, Diana-Andreea Chirteș, Paula Antonoaea, Emöke Margit Rédai, Nicoleta Todoran, Magdalena Bîrsan and Adriana Ciurba

Pharmaceutics 2023, 15(8), 2147; https://doi.org/10.3390/pharmaceutics15082147 - 16 Aug 2023

Cited by 3 | Viewed by 1648

Abstract

The main objective of this study consists in establishing the influence of the intergranular superdisintegrant on the specific properties of drotaverine hydrochloride fast-dissolving granules (DROT-FDGs) and orodispersible tablets (DROT-ODTs). The orodispersible tablets were obtained by the compression of the FDGs and excipient mixture [...] Read more.

The main objective of this study consists in establishing the influence of the intergranular superdisintegrant on the specific properties of drotaverine hydrochloride fast-dissolving granules (DROT-FDGs) and orodispersible tablets (DROT-ODTs). The orodispersible tablets were obtained by the compression of the FDGs and excipient mixture with an eccentric tableting machine. To develop DROT-ODTs, two types of superdisintegrant excipients in different concentrations (water-soluble soy polysaccharides (SSP) (1%, 5%) and water-insoluble soy polysaccharides—Emcosoy^® STS IP (EMCS) (1%, 3%, 5%)) were used, resulting in five formulations (D1–D5). The DROT-FDGs and the DROT-ODTs were subjected to pharmacotechnical and analytical evaluation. All the orodispersible tablets obtained respect the quality requirements in terms of friability (less than 1%), crushing strength (ranging between 52 N for D2 and 125.5 N for D3), and disintegration time (<180 s). The in vitro release of drotaverine from ODTs showed that all formulations presented amounts of active substance released greater than 85% at 10 min. The main objective, developing 30 mg DROT-ODTs for children aged between 6 and 12 years by incorporating the API in FDGs, was successfully achieved. Full article

(This article belongs to the Special Issue Carbohydrate-Based Carriers for Drug Delivery)

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16 pages, 10935 KiB

Open AccessArticle

Polymeric Microspheres Designed to Carry Crystalline Drugs at Their Surface or Inside Cavities and Dimples

by Meitong Shen, Ling Zheng and Leo H. Koole

Pharmaceutics 2023, 15(8), 2146; https://doi.org/10.3390/pharmaceutics15082146 - 15 Aug 2023

Viewed by 1552

Abstract

Injectable polymer microparticles with the ability to carry and release pharmacologically active agents are attracting more and more interest. This study is focused on the chemical synthesis, characterization, and preliminary exploration of the utility of a new type of injectable drug-releasing polymer microparticle. [...] Read more.

Injectable polymer microparticles with the ability to carry and release pharmacologically active agents are attracting more and more interest. This study is focused on the chemical synthesis, characterization, and preliminary exploration of the utility of a new type of injectable drug-releasing polymer microparticle. The particles feature a new combination of structural and physico-chemical properties: (i) their geometry deviates from the spherical in the sense that the particles have a cavity; (ii) the particles are porous and can therefore be loaded with crystalline drug formulations; drug crystals can reside at both the particle’s surfaces and inside cavities; (iii) the particles are relatively dense since the polymer network contains covalently bound iodine (approximately 10% by mass); this renders the drug-loaded particles traceable (localizable) by X-ray fluoroscopy. This study presents several examples. First, the particles were loaded with crystalline voriconazole, which is a potent antifungal drug used in ophthalmology to treat fungal keratitis (infection/inflammation of the cornea caused by penetrating fungus). Drug loading as high as 10% by mass (=mass of immobilized drug/(mass of the microparticle + mass of immobilized drug) × 100%) could be achieved. Slow local release of voriconazole from these particles was observed in vitro. These findings hold promise regarding new approaches to treat fungal keratitis. Moreover, this study can help to expand the scope of the transarterial chemoembolization (TACE) technique since it enables the use of higher drug loadings (thus enabling higher local drug concentration or extended therapy duration), as well as application of hydrophobic drugs that cannot be used in combination with existing TACE embolic particles. Full article

(This article belongs to the Special Issue Controlled Crystallization of Active Pharmaceutical Ingredients, 2nd Edition)

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20 pages, 11414 KiB

Open AccessArticle

Enhanced Cartilage and Subchondral Bone Repair Using Carbon Nanotube-Doped Peptide Hydrogel–Polycaprolactone Composite Scaffolds

by Jiayi Lv, Yilun Wu, Zhicheng Cao, Xu Liu, Yuzhi Sun, Po Zhang, Xin Zhang, Kexin Tang, Min Cheng, Qingqiang Yao and Yishen Zhu

Pharmaceutics 2023, 15(8), 2145; https://doi.org/10.3390/pharmaceutics15082145 - 15 Aug 2023

Cited by 1 | Viewed by 1749

Abstract

A carbon nanotube-doped octapeptide self-assembled hydrogel (FEK/C) and a hydrogel-based polycaprolactone PCL composite scaffold (FEK/C₃-S) were developed for cartilage and subchondral bone repair. The composite scaffold demonstrated modulated microstructure, mechanical properties, and conductivity by adjusting CNT concentration. In vitro evaluations showed [...] Read more.

A carbon nanotube-doped octapeptide self-assembled hydrogel (FEK/C) and a hydrogel-based polycaprolactone PCL composite scaffold (FEK/C₃-S) were developed for cartilage and subchondral bone repair. The composite scaffold demonstrated modulated microstructure, mechanical properties, and conductivity by adjusting CNT concentration. In vitro evaluations showed enhanced cell proliferation, adhesion, and migration of articular cartilage cells, osteoblasts, and bone marrow mesenchymal stem cells. The composite scaffold exhibited good biocompatibility, low haemolysis rate, and high protein absorption capacity. It also promoted osteogenesis and chondrogenesis, with increased mineralization, alkaline phosphatase (ALP) activity, and glycosaminoglycan (GAG) secretion. The composite scaffold facilitated accelerated cartilage and subchondral bone regeneration in a rabbit knee joint defect model. Histological analysis revealed improved cartilage tissue formation and increased subchondral bone density. Notably, the FEK/C₃-S composite scaffold exhibited the most significant cartilage and subchondral bone formation. The FEK/C₃-S composite scaffold holds great promise for cartilage and subchondral bone repair. It offers enhanced mechanical support, conductivity, and bioactivity, leading to improved tissue regeneration. These findings contribute to the advancement of regenerative strategies for challenging musculoskeletal tissue defects. Full article

(This article belongs to the Special Issue Functional Peptide-Based Biomaterials for Biomedical Applications)

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15 pages, 2665 KiB

Open AccessArticle

Molecular Imaging Investigations of Polymer-Coated Cerium Oxide Nanoparticles as a Radioprotective Therapeutic Candidate

by Philip Reed McDonagh, Sundaresan Gobalakrishnan, Christopher Rabender, Vimalan Vijayaragavan and Jamal Zweit

Pharmaceutics 2023, 15(8), 2144; https://doi.org/10.3390/pharmaceutics15082144 - 15 Aug 2023

Cited by 3 | Viewed by 1558

Abstract

Cerium oxide nanoparticles (CONPs) have a unique surface redox chemistry that appears to selectively protect normal tissues from radiation induced damage. Our prior research exploring the biocompatibility of polymer-coated CONPs found further study of poly-acrylic acid (PAA)-coated CONPs was warranted due to improved [...] Read more.

Cerium oxide nanoparticles (CONPs) have a unique surface redox chemistry that appears to selectively protect normal tissues from radiation induced damage. Our prior research exploring the biocompatibility of polymer-coated CONPs found further study of poly-acrylic acid (PAA)-coated CONPs was warranted due to improved systemic biodistribution and rapid renal clearance. This work further explores PAA-CONPs’ radioprotective efficacy and mechanism of action related to tumor microenvironment pH. An ex vivo TUNEL assay was used to measure PAA-CONPs’ protection of the irradiated mouse colon in comparison to the established radioprotector amifostine. [¹⁸F]FDG PET imaging of spontaneous colon tumors was utilized to determine the effects of PAA-CONPs on tumor radiation response. In vivo MRI and an ex vivo clonogenic assay were used to determine pH effects on PAA-CONPs’ radioprotection in irradiated tumor-bearing mice. PAA-CONPs showed excellent radioprotective efficacy in the normal colon that was equivalent to uncoated CONPs and amifostine. [¹⁸F]FDG PET imaging showed PAA-CONPs do not affect tumor response to radiation. Normalization of tumor pH allowed some radioprotection of tumors by PAA-CONPs, which may explain their lack of tumor radioprotection in the acidic tumor microenvironment. Overall, PAA-CONPs meet the criteria for clinical application as a radioprotective therapeutic agent and are an excellent candidate for further study. Full article

(This article belongs to the Special Issue Advanced Bio-Hybrid Materials for Drug Delivery Systems - New Trends and Perspectives)

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11 pages, 3354 KiB

Open AccessArticle

Antiemetic Drugs Compatibility Evaluation with Paediatric Parenteral Nutrition Admixtures

by Szymon Tomczak, Maciej Chmielewski, Jagoda Szkudlarek and Anna Jelińska

Pharmaceutics 2023, 15(8), 2143; https://doi.org/10.3390/pharmaceutics15082143 - 15 Aug 2023

Cited by 3 | Viewed by 1496

Abstract

Chemotherapy-induced nausea and vomiting are defined as the most common of side effects of treatment and, at the same time, are very difficult to accept for patients’, frequently causing changes in the therapy regimen, significantly reducing its effectiveness. Thus, an antiemetic prophylactic is [...] Read more.

Chemotherapy-induced nausea and vomiting are defined as the most common of side effects of treatment and, at the same time, are very difficult to accept for patients’, frequently causing changes in the therapy regimen, significantly reducing its effectiveness. Thus, an antiemetic prophylactic is essential to the provision of such a therapy for the patient. Pharmacotherapy often includes various drugs, including antiemetics, with the administration of such drugs by injection through two separate catheters being the preferred method. However, the co-administration of drugs and parenteral nutrition admixtures (PNAs) requires the consideration of compatibility, stability and potential negative interactions. To meet the purposes of clinical pharmacy, a compatibility test of ondansetron, dexamethasone and hydrocortisone with paediatric PNAs was conducted. PNAs differ in the composition of amino acid source (Primene^® or Aminoplasmal Paed^® 10%) and the type of injectable lipid emulsion (Lipidem^® 200 mg/mL, Clinoleic^® 20%, SMOFlipid^® 200 mg/mL, Intralipid^® 20%). An in vitro evaluation was performed in a static way as a simulated co-administration through a Y-site. The drug PNA ratios were determined based on the extreme infusion rates contained in the characteristics of medicinal products. All calculations were performed for a hypothetical patient aged 7 years weighing 24 kg. As a result of this study, it can be concluded that all tested PNAs showed the required stability in the range of parameters such as pH, osmolality, turbidity, zeta potential, MDD and homogeneity. The co-administration of antiemetic drugs does not adversely affect lipid emulsion stability. This combination was consistently compatible during the evaluation period. Full article

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

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Pharmaceutics, Volume 15, Issue 8 (August 2023) – 158 articles

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