Pharmaceutics

23 pages, 6102 KiB

Open AccessArticle

The Anti-Glioblastoma Effects of Novel Liposomal Formulations Loaded with Cannabidiol, Celecoxib, and 2,5-Dimethylcelecoxib

by Anna Rybarczyk, Aleksandra Majchrzak-Celińska, Ludwika Piwowarczyk and Violetta Krajka-Kuźniak

Pharmaceutics 2025, 17(8), 1031; https://doi.org/10.3390/pharmaceutics17081031 - 8 Aug 2025

Abstract

Background/Objectives: Glioblastoma multiforme (GBM) therapy efficacy remains limited due to the poor blood-brain barrier-penetrating power of drugs as well as dysregulated cellular signaling pathways of tumor cells leading to drug resistance. Novel drug delivery systems such as liposome-based nanoformulations improve the bioavailability [...] Read more.

Background/Objectives: Glioblastoma multiforme (GBM) therapy efficacy remains limited due to the poor blood-brain barrier-penetrating power of drugs as well as dysregulated cellular signaling pathways of tumor cells leading to drug resistance. Novel drug delivery systems such as liposome-based nanoformulations improve the bioavailability and stability of water-insoluble drugs, while co-delivery of two anti-cancer compounds can further increase their anti-tumor effectiveness due to synergistic effects. Thus, the aim of this study was to obtain liposomal nanoformulations encapsulating cannabidiol (CBD), celecoxib (CELE), and 2,5-dimethylcelecoxib (DMC) and their combinations and to verify their anti-GBM properties. Methods: Five liposomal nanoformulations were obtained using a modified thin-film hydration technique. Two GBM cell lines and non-cancerous astrocytes were used for the biological evaluation of the tested nanoformulations. The cytotoxicity experiments were performed using the MTT assay, whereas flow cytometry-based analysis assessed the effect of the liposomes on apoptosis, cell cycle distribution, and oxidative stress. To determine the impact of the tested nanoformulations on Nrf2, Wnt/β-catenin, and NF-κB signaling pathways, qPCR, Western blot and ELISA techniques were used. Results: The findings of this study demonstrate that liposomal nanoformulations containing CBD, CELE, and DMC exhibit significant anti-GBM activity, particularly through the induction of apoptosis and oxidative stress and modulation of the key signaling pathways. Although no clear synergistic/additive effects were observed between CBD and CELE or DMC when co-loaded in nanoformulations, the combination of CBD and CELE effectively suppressed Wnt/β-catenin and NF-κB signaling and activated the Nrf2 pathway. These results support the therapeutic potential of liposome-based co-delivery of CBD and CELE in GBM therapy. However, further in vivo studies are warranted to determine these nanoformulations’ translational relevance and clinical applicability. Full article

(This article belongs to the Special Issue Advances in Bioactive Compounds and Nanotechnology: Sustainable Approaches for Pharmaceutical Applications)

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13 pages, 1069 KiB

Open AccessArticle

Cyclosporine Dissolution Test from a Lipid Dosage Form: Next Step Towards the Establishment of Release Method for Solid Lipid Microparticles

by Eliza Wolska, Patrycja Dudek and Małgorzata Sznitowska

Pharmaceutics 2025, 17(8), 1030; https://doi.org/10.3390/pharmaceutics17081030 - 8 Aug 2025

Abstract

Background: The release study is a standard tool for the development, evaluation, and control of dosage forms. In the case of traditional drug delivery systems, it is conducted in accordance with the established principles available in the European and American Pharmacopoeias or guidelines [...] Read more.

Background: The release study is a standard tool for the development, evaluation, and control of dosage forms. In the case of traditional drug delivery systems, it is conducted in accordance with the established principles available in the European and American Pharmacopoeias or guidelines proposed by registration agencies. The problem is the study of modern carriers, not yet described in compendia, which require adjustments to traditionally used methods. Objectives: The present study focuses on developing an optimal method for testing the release of cyclosporine (Cs, 0.5–4%) incorporated in solid lipid microparticles (SLM) dispersions (10%) intended for administration in the form of eye drops. This is a multicompartment lipid carrier that provides prolonged release of the active substance. Methods: Three methods of testing the release were compared: the dialysis bag method, the horizontal cells technique, and a method without a membrane. Results: During the analyses, the proper membrane was selected and the effect of the lysozyme enzyme on the release profile was analyzed. The effect of the composition of the acceptor fluid on the obtained results was also assessed. In the model without a membrane, up to 60% of the Cs was released within 30 min due to the burst effect. In horizontal chambers, no formulation released more than 14% of the Cs over 96 h, while at the same time, 60–70% of the Cs was released from the dialysis bag. Conclusions: Based on the obtained results, the dialysis bag method was selected to study the release of Cs from SLM without the need to use multicomponent artificial tear fluid as an acceptor medium. Full article

(This article belongs to the Special Issue Solid Dispersions for Drug Delivery: Development, Preparation and In Vitro/In Vivo Characterization)

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20 pages, 4142 KiB

Open AccessArticle

Repeated Administration of Guar Gum Hydrogel Containing Sesamol-Loaded Nanocapsules Reduced Skin Inflammation in Mice in an Irritant Contact Dermatitis Model

by Vinicius Costa Prado, Bruna Rafaela Fretag de Carvalho, Kauani Moenke, Amanda Maccangnan Zamberlan, Samuel Felipe Atuati, Ana Clara Perazzio Assis, Evelyne da Silva Brum, Raul Edison Luna Lazo, Andréa Inês Horn Adams, Luana Mota Ferreira, Sara Marchesan Oliveira and Letícia Cruz

Pharmaceutics 2025, 17(8), 1029; https://doi.org/10.3390/pharmaceutics17081029 - 7 Aug 2025

Abstract

Background/Objectives: Dermatitis is frequently treated with dexamethasone cutaneous application, which causes adverse effects mainly when it is chronically administered. Sesamol is a phytochemical compound known for its anti-inflammatory activity and low toxicity. Therefore, this study reports the optimization of a guar gum [...] Read more.

Background/Objectives: Dermatitis is frequently treated with dexamethasone cutaneous application, which causes adverse effects mainly when it is chronically administered. Sesamol is a phytochemical compound known for its anti-inflammatory activity and low toxicity. Therefore, this study reports the optimization of a guar gum hydrogel with enhanced physicochemical and microbiological stability, providing an effective dosage form for topical application of sesamol nanocapsules to treat irritant contact dermatitis. Methods: Nano-based hydrogel containing 1 mg/g sesamol was prepared by adding the nanocapsule suspension to form a 2.5% (w/v) guar gum dispersion. Dynamic rheological analysis indicates that the formulations exhibit a non-Newtonian flow with pseudoplastic behavior. Hydrogels were evaluated by Fourier-transformed infrared (FTIR) spectroscopy, and, following spectrum acquisition, an unsupervised chemometrics model was developed to identify crucial variables. Additionally, the physicochemical and microbiological stability of the hydrogel was evaluated over a 60-day period. Results: ATR-FTIR spectra of all hydrogels evaluated are very similar after preparation and 60 days of storage. However, it showed a slight increase in average diameter and PDI and decreased pH values after 60 days. Microbiological assessment demonstrated that the hydrogel met the requirements for the microbial count over 60 days. The dermatitis model was induced by repeated applications of croton oil in the right ears of mice. The effectiveness of the hydrogels was evaluated by assessing ear edema and migration of polymorphonuclear cells. The nano-based hydrogel exhibited anti-inflammatory properties similar to those of dexamethasone. Conclusions: Therefore, the nano-based hydrogel containing sesamol exhibits therapeutic potential for treating cutaneous inflammatory diseases. Full article

(This article belongs to the Special Issue Bio-Based Hydrogels: Sustainable and Efficient Drug Delivery Solutions)

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36 pages, 928 KiB

Open AccessReview

Reprogramming Atherosclerosis: Precision Drug Delivery, Nanomedicine, and Immune-Targeted Therapies for Cardiovascular Risk Reduction

by Paschalis Karakasis, Panagiotis Theofilis, Panayotis K. Vlachakis, Konstantinos Grigoriou, Dimitrios Patoulias, Antonios P. Antoniadis and Nikolaos Fragakis

Pharmaceutics 2025, 17(8), 1028; https://doi.org/10.3390/pharmaceutics17081028 - 7 Aug 2025

Abstract

Atherosclerosis is a progressive, multifactorial disease driven by the interplay of lipid dysregulation, chronic inflammation, oxidative stress, and maladaptive vascular remodeling. Despite advances in systemic lipid-lowering and anti-inflammatory therapies, residual cardiovascular risk persists, highlighting the need for more precise interventions. Targeted drug delivery [...] Read more.

Atherosclerosis is a progressive, multifactorial disease driven by the interplay of lipid dysregulation, chronic inflammation, oxidative stress, and maladaptive vascular remodeling. Despite advances in systemic lipid-lowering and anti-inflammatory therapies, residual cardiovascular risk persists, highlighting the need for more precise interventions. Targeted drug delivery represents a transformative strategy, offering the potential to modulate key pathogenic processes within atherosclerotic plaques while minimizing systemic exposure and off-target effects. Recent innovations span a diverse array of platforms, including nanoparticles, liposomes, exosomes, polymeric carriers, and metal–organic frameworks (MOFs), engineered to engage distinct pathological features such as inflamed endothelium, dysfunctional macrophages, oxidative microenvironments, and aberrant lipid metabolism. Ligand-based, biomimetic, and stimuli-responsive delivery systems further enhance spatial and temporal precision. In parallel, advances in in-silico modeling and imaging-guided approaches are accelerating the rational design of multifunctional nanotherapeutics with theranostic capabilities. Beyond targeting lipids and inflammation, emerging strategies seek to modulate immune checkpoints, restore endothelial homeostasis, and reprogram plaque-resident macrophages. This review provides an integrated overview of the mechanistic underpinnings of atherogenesis and highlights state-of-the-art targeted delivery systems under preclinical and clinical investigation. By synthesizing recent advances, we aim to elucidate how precision-guided drug delivery is reshaping the therapeutic landscape of atherosclerosis and to chart future directions toward clinical translation and personalized vascular medicine. Full article

(This article belongs to the Special Issue Advances in Drug Delivery Systems for the Management of Metabolic Diseases)

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19 pages, 3228 KiB

Open AccessArticle

N-Degron-Based PROTAC Targeting PLK1: A Potential Therapeutic Strategy for Cervical Cancer

by Pethaiah Gunasekaran, Sang Chul Shin, Yeon Sil Hwang, Jihyeon Lee, Yeo Kyung La, Min Su Yim, Hak Nam Kim, Tae Wan Kim, Eunjung Yang, Soo Jae Lee, Jung Min Yoon, Eunice EunKyeong Kim, Seob Jeon, Eun Kyoung Ryu and Jeong Kyu Bang

Pharmaceutics 2025, 17(8), 1027; https://doi.org/10.3390/pharmaceutics17081027 - 7 Aug 2025

Abstract

Background: Cervical cancer remains a major global health concern, with existing chemotherapy facing limited effectiveness owing to resistance. Polo-like kinase 1 (PLK1) overexpression in cervical cancer cells is a promising target for developing novel therapies to overcome chemoresistance and improve treatment efficacy. [...] Read more.

Background: Cervical cancer remains a major global health concern, with existing chemotherapy facing limited effectiveness owing to resistance. Polo-like kinase 1 (PLK1) overexpression in cervical cancer cells is a promising target for developing novel therapies to overcome chemoresistance and improve treatment efficacy. Methods: In this study, we developed a novel PROTAC, NC1, targeting PLK1 PBD via the N-end rule pathway. Results: This PROTAC effectively depleted the PLK1 protein in HeLa cells by inducing protein degradation. The crystal structure of the PBD-NC1 complex identified key PLK1 PBD binding interactions and isothermal titration calorimetry (ITC) confirmed a binding affinity of 6.06 µM between NC1 and PLK1 PBD. NC1 significantly decreased cell viability with an IC₅₀ of 5.23 µM, induced G2/M phase arrest, and triggered apoptosis in HeLa cells. In vivo, NC1 suppressed tumor growth in a HeLa xenograft mouse model. Conclusions: This research highlights the potential of N-degron-based PROTACs targeting the PLK1 protein in cancer therapies, highlighting their potential in future cervical anticancer treatment strategies. Full article

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

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24 pages, 5480 KiB

Open AccessArticle

Liposomal Co-Delivery of Acteoside, CBD, and Naringenin: A Synergistic Strategy Against Gliomas

by Jagoda Szkudlarek, Ludwika Piwowarczyk, Violetta Krajka-Kuźniak, Aleksandra Majchrzak-Celińska, Szymon Tomczak, Mikołaj Baranowski, Rafał Pietrzyk, Aneta Woźniak-Braszak and Anna Jelińska

Pharmaceutics 2025, 17(8), 1026; https://doi.org/10.3390/pharmaceutics17081026 - 7 Aug 2025

Abstract

Background/Objectives: Adult-type diffuse gliomas, including astrocytoma and glioblastoma multiforme (GBM), are brain tumors with a very poor prognosis. While current treatment options for glioma patients are not providing satisfactory outcomes, research indicates that natural compounds could serve as alternative treatments. However, their [...] Read more.

Background/Objectives: Adult-type diffuse gliomas, including astrocytoma and glioblastoma multiforme (GBM), are brain tumors with a very poor prognosis. While current treatment options for glioma patients are not providing satisfactory outcomes, research indicates that natural compounds could serve as alternative treatments. However, their low bioavailability requires nanotechnology solutions, such as liposomes. Methods: In this study, we propose the co-encapsulation of acteoside (ACT) with other natural compounds, cannabidiol (CBD) or naringenin (NG), in a cationic liposomal nanoformulation consisting of DOTAP and POPC lipids, which were prepared using the dry lipid film method. The liposomes were characterized by their physicochemical properties, including particle size, zeta potential, and polydispersity index (PDI), with additional analyses performed using ¹H Nuclear Magnetic Resonance (NMR). Furthermore, biological experiments were performed with U-87 MG astrocytoma and U-138 MG GBM cell lines and non-cancerous MRC-5 lung fibroblasts using the MTT assay and evaluating the expression of Bax and Bcl-xL to evaluate their potential as anticancer agents. Conclusions: The IC₅₀ values for the nanoformulations in U-138 MG cells at 48 h were 6 µM for ACT + CBD and 5 µM for ACT + NG. ACT and CBD or NG demonstrated a potential synergistic effect against GBM in a liposomal formulation. Notably, treatment with ACT + CBD (5 µM) and ACT + NG (5 µM) liposomal formulations significantly upregulated Bax protein level in U-138 cells at both 24 and 48 h. In parallel, ACT + CBD (5 µM) also modulated Bcl-xL protein level in both U-138 MG and U-87 MG cell lines at the same time points. The obtained nanoformulations were homogeneous and stable for 21 days, evidenced by a narrow particle size distribution, a low polydispersity index (PDI) < 0.3, and a positive zeta potential. Full article

(This article belongs to the Special Issue PLGA Micro/Nanoparticles in Drug Delivery)

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22 pages, 2122 KiB

Open AccessReview

Micro and Nano Drug Delivery Systems for the Treatment of Oral Mucositis: A Review

by Luciana Ângela Soares Maia, Tâmara Thaiane Almeida Siqueira, Carlos Alberto Arcelly Santos Bezerra, Jéssica Horana Pereira de Farias and Elquio Eleamen Oliveira

Pharmaceutics 2025, 17(8), 1025; https://doi.org/10.3390/pharmaceutics17081025 - 7 Aug 2025

Abstract

Oral mucositis (OM) is a severe inflammatory condition of the oral mucosa that is commonly associated with cancer therapies. Traditional treatments typically have limited efficacy and significant side effects, necessitating alternative approaches. Nanobased drug delivery systems (DDSs) present promising solutions, enhancing therapeutic outcomes [...] Read more.

Oral mucositis (OM) is a severe inflammatory condition of the oral mucosa that is commonly associated with cancer therapies. Traditional treatments typically have limited efficacy and significant side effects, necessitating alternative approaches. Nanobased drug delivery systems (DDSs) present promising solutions, enhancing therapeutic outcomes while minimizing side effects. This review aims to evaluate the use of nanobased DDSs to treat OM. To reach these aims, an extensive literature review was conducted using the following databases: BVS, PubMed, Scopus, and Web of Science. The search strategy included the keywords “microparticles,” “nanoparticles,” “drug delivery system,” “oral mucositis,” “therapy,” and “treatment,” combined with the Boolean operators “AND” and “OR.” After applying filters for language, relevance, full-text availability, exclusion of review articles, and removal of duplicates, a total of 32 articles were selected for analysis. Of the 32 studies included in this review, 25 employed polymeric micro- or nanosystems for the treatment of OM. Regarding the stage of investigation, 10 studies were conducted in vitro, 16 were conducted in vivo, and 6 corresponded to clinical trials. Compared with conventional drug delivery approaches, most of these studies reported improved therapeutic outcomes. These findings highlight the potential of nanosystems as innovative strategies for enhancing OM treatment. Nonetheless, challenges in large-scale manufacturing, including reproducibility and safety, and the limited number of clinical trials warrant careful consideration. Future research with larger clinical trials is essential to validate these findings and effectively guide clinical practice. Full article

(This article belongs to the Special Issue Dosage Forms in Drug Delivery: State of the Art and Future Perspectives)

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19 pages, 787 KiB

Open AccessReview

Comparison of Polynucleotide and Polydeoxyribonucleotide in Dermatology: Molecular Mechanisms and Clinical Perspectives

by Sung Tae Kim

Pharmaceutics 2025, 17(8), 1024; https://doi.org/10.3390/pharmaceutics17081024 - 7 Aug 2025

Abstract

Polynucleotide (PN) and polydeoxyribonucleotide (PDRN) are DNA-derived biopolymers increasingly recognized for their potential in dermatology. Despite their structural similarities, PN and PDRN exhibit distinct functions due to differences in polymer length and molecular weight. PN, composed of longer DNA fragments, plays a key [...] Read more.

Polynucleotide (PN) and polydeoxyribonucleotide (PDRN) are DNA-derived biopolymers increasingly recognized for their potential in dermatology. Despite their structural similarities, PN and PDRN exhibit distinct functions due to differences in polymer length and molecular weight. PN, composed of longer DNA fragments, plays a key role in extracellular matrix remodeling. Conversely, PDRN, composed of relatively shorter oligonucleotide sequences than those of PN, enhances skin condition through adenosine receptor activations and supports nucleotide synthesis via both the salvage and de novo pathways. This review provides a critical comparison of the molecular characteristics and functions of PN and PDRN with particular emphasis on their dermatological applications. By delineating their respective roles in esthetic and regenerative medicine, we aim to highlight recent advances that may guide the development of optimized treatment strategies and foster evidence-based clinical practice. Full article

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

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31 pages, 2319 KiB

Open AccessReview

Biopharming of Lactoferrin: Current Strategies and Future Prospects

by Rajaravindra Konadaka Sri, Parthasarathi Balasamudram Chandrasekhar, Architha Sirisilla, Qudrathulla Khan Quadri Mohammed, Thejasri Jakkoju, Rajith Reddy Bheemreddy, Tarun Kumar Bhattacharya, Rajkumar Ullengala and Rudra Nath Chatterjee

Pharmaceutics 2025, 17(8), 1023; https://doi.org/10.3390/pharmaceutics17081023 - 7 Aug 2025

Abstract

Lactoferrin (LF) is an 80 kDa iron-binding glycoprotein primarily found in milk, saliva, tears, and nasal secretions. LF is well known for its antibacterial and immunomodulatory effects. However, the extraction of LF from milk is inadequate for large-scale therapeutic applications, presenting a challenge [...] Read more.

Lactoferrin (LF) is an 80 kDa iron-binding glycoprotein primarily found in milk, saliva, tears, and nasal secretions. LF is well known for its antibacterial and immunomodulatory effects. However, the extraction of LF from milk is inadequate for large-scale therapeutic applications, presenting a challenge for economic mass production. Recombinant protein expression systems offer a solution to overcome this challenge and efficient production of LF. This review discusses recent progress in the translational research of LF gene transfer and biopharming, focusing on different expression systems such as bacteria, yeast, filamentous fungi, transgenic crops, and animals as well as purification methods. The optimization of expression yields, prospects for genetic engineering, and biotechnology to enhance LF production for biomedical applications are emphasized. This review systematically sourced the literature from 1987 to 2025 from leading scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar. Despite ongoing debates, progress in this field indicates a viable path towards the effective use of LF in therapeutic settings. Full article

(This article belongs to the Section Biopharmaceutics)

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41 pages, 2949 KiB

Open AccessReview

Nanocarriers Containing Curcumin and Derivatives for Arthritis Treatment: Mapping the Evidence in a Scoping Review

by Beatriz Yurie Sugisawa Sato, Susan Iida Chong, Nathalia Marçallo Peixoto Souza, Raul Edison Luna Lazo, Roberto Pontarolo, Fabiane Gomes de Moraes Rego, Luana Mota Ferreira and Marcel Henrique Marcondes Sari

Pharmaceutics 2025, 17(8), 1022; https://doi.org/10.3390/pharmaceutics17081022 - 6 Aug 2025

Abstract

Background/Objectives: Curcumin (CUR) is well known for its therapeutic properties, particularly attributed to its antioxidant and anti-inflammatory effects in managing chronic diseases such as arthritis. While CUR application for biomedical purposes is well known, the phytochemical has several restrictions given its poor water [...] Read more.

Background/Objectives: Curcumin (CUR) is well known for its therapeutic properties, particularly attributed to its antioxidant and anti-inflammatory effects in managing chronic diseases such as arthritis. While CUR application for biomedical purposes is well known, the phytochemical has several restrictions given its poor water solubility, physicochemical instability, and low bioavailability. These limitations have led to innovative formulations, with nanocarriers emerging as a promising alternative. For this reason, this study aimed to address the potential advantages of associating CUR with nanocarrier systems in managing arthritis through a scoping review. Methods: A systematic literature search of preclinical (in vivo) and clinical studies was performed in PubMed, Scopus, and Web of Science (December 2024). General inclusion criteria include using CUR or natural derivatives in nano-based formulations for arthritis treatment. These elements lead to the question: “What is the impact of the association of CUR or derivatives in nanocarriers in treating arthritis?”. Results: From an initial 536 articles, 34 were selected for further analysis (31 preclinical investigations and three randomized clinical trials). Most studies used pure CUR (25/34), associated with organic (30/34) nanocarrier systems. Remarkably, nanoparticles (16/34) and nanoemulsions (5/34) were emphasized. The formulations were primarily presented in liquid form (23/34) and were generally administered to animal models through intra-articular injection (11/31). Complete Freund’s Adjuvant (CFA) was the most frequently utilized among the various models to induce arthritis-like joint damage. The findings indicate that associating CUR or its derivatives with nanocarrier systems enhances its pharmacological efficacy through controlled release and enhanced solubility, bioavailability, and stability. Moreover, the encapsulation of CUR showed better results in most cases than in its free form. Nonetheless, most studies were restricted to the preclinical model, not providing direct evidence in humans. Additionally, inadequate information and clarity presented considerable challenges for preclinical evidence, which was confirmed by SYRCLE’s bias detection tools. Conclusions: Hence, this scoping review highlights the anti-arthritic effects of CUR nanocarriers as a promising alternative for improved treatment. Full article

(This article belongs to the Special Issue Advances in Polymer-Based Devices and Platforms for Pain Management)

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23 pages, 3665 KiB

Open AccessCommunication

Drug Repurposing for Kala-Azar

by Biljana Arsić, Budimir S. Ilić, Andreas Maier, Michael Hartung, Jovana Janjić, Jelena Milićević and Jan Baumbach

Pharmaceutics 2025, 17(8), 1021; https://doi.org/10.3390/pharmaceutics17081021 - 6 Aug 2025

Abstract

Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated [...] Read more.

Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron–ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug–target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of −9.36 and −9.10 kcal/mol, and corresponding MM-GBSA ΔG_bind values of −14.00 and −13.25 kcal/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2/TYK2–STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation. Full article

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

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15 pages, 271 KiB

Open AccessArticle

Are We Considering All the Potential Drug–Drug Interactions in Women’s Reproductive Health? A Predictive Model Approach

by Pablo Garcia-Acero, Ismael Henarejos-Castillo, Francisco Jose Sanz, Patricia Sebastian-Leon, Antonio Parraga-Leo, Juan Antonio Garcia-Velasco and Patricia Diaz-Gimeno

Pharmaceutics 2025, 17(8), 1020; https://doi.org/10.3390/pharmaceutics17081020 - 6 Aug 2025

Abstract

Background: Drug–drug interactions (DDIs) may occur when two or more drugs are taken together, leading to undesired side effects or potential synergistic effects. Most clinical effects of drug combinations have not been assessed in clinical trials. Therefore, predicting DDIs can provide better patient [...] Read more.

Background: Drug–drug interactions (DDIs) may occur when two or more drugs are taken together, leading to undesired side effects or potential synergistic effects. Most clinical effects of drug combinations have not been assessed in clinical trials. Therefore, predicting DDIs can provide better patient management, avoid drug combinations that can negatively affect patient care, and exploit potential synergistic combinations to improve current therapies in women’s healthcare. Methods: A DDI prediction model was built to describe relevant drug combinations affecting reproductive treatments. Approved drug features (chemical structure of drugs, side effects, targets, enzymes, carriers and transporters, pathways, protein–protein interactions, and interaction profile fingerprints) were obtained. A unified predictive score revealed unknown DDIs between reproductive and commonly used drugs and their associated clinical effects on reproductive health. The performance of the prediction model was validated using known DDIs. Results: This prediction model accurately predicted known interactions (AUROC = 0.9876) and identified 2991 new DDIs between 192 drugs used in different female reproductive conditions and other drugs used to treat unrelated conditions. These DDIs included 836 between drugs used for in vitro fertilization. Most new DDIs involved estradiol, acetaminophen, bupivacaine, risperidone, and follitropin. Follitropin, bupivacaine, and gonadorelin had the highest discovery rate (42%, 32%, and 25%, respectively). Some were expected to improve current therapies (n = 23), while others would cause harmful effects (n = 11). We also predicted twelve DDIs between oral contraceptives and HIV drugs that could compromise their efficacy. Conclusions: These results show the importance of DDI studies aimed at identifying those that might compromise or improve their efficacy, which could lead to personalizing female reproductive therapies. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

30 pages, 2414 KiB

Open AccessReview

Melittin-Based Nanoparticles for Cancer Therapy: Mechanisms, Applications, and Future Perspectives

by Joe Rizkallah, Nicole Charbel, Abdallah Yassine, Amal El Masri, Chris Raffoul, Omar El Sardouk, Malak Ghezzawi, Therese Abou Nasr and Firas Kreidieh

Pharmaceutics 2025, 17(8), 1019; https://doi.org/10.3390/pharmaceutics17081019 - 6 Aug 2025

Abstract

Melittin, a cytolytic peptide derived from honeybee venom, has demonstrated potent anticancer activity through mechanisms such as membrane disruption, apoptosis induction, and modulation of key signaling pathways. Melittin exerts its anticancer activity by interacting with key molecular targets, including downregulation of the PI3K/Akt [...] Read more.

Melittin, a cytolytic peptide derived from honeybee venom, has demonstrated potent anticancer activity through mechanisms such as membrane disruption, apoptosis induction, and modulation of key signaling pathways. Melittin exerts its anticancer activity by interacting with key molecular targets, including downregulation of the PI3K/Akt and NF-κB signaling pathways, and by inducing mitochondrial apoptosis through reactive oxygen species generation and cytochrome c release. However, its clinical application is hindered by its systemic and hemolytic toxicity, rapid degradation in plasma, poor pharmacokinetics, and immunogenicity, necessitating the development of targeted delivery strategies to enable safe and effective treatment. Nanoparticle-based delivery systems have emerged as a promising strategy for overcoming these challenges, offering improved tumor targeting, reduced off-target effects, and enhanced stability. This review provides a comprehensive overview of the mechanisms through which melittin exerts its anticancer effects and evaluates the development of various melittin-loaded nanocarriers, including liposomes, polymeric nanoparticles, dendrimers, micelles, and inorganic systems. It also summarizes the preclinical evidence for melittin nanotherapy across a wide range of cancer types, highlighting both its cytotoxic and immunomodulatory effects. The potential of melittin nanoparticles to overcome multidrug resistance and synergize with chemotherapy, immunotherapy, photothermal therapy, and radiotherapy is discussed. Despite promising in vitro and in vivo findings, its clinical translation remains limited. Key barriers include toxicity, manufacturing scalability, regulatory approval, and the need for more extensive in vivo validation. A key future direction is the application of computational tools, such as physiologically based pharmacokinetic modeling and artificial-intelligence-based modeling, to streamline development and guide its clinical translation. Addressing these challenges through focused research and interdisciplinary collaboration will be essential to realizing the full therapeutic potential of melittin-based nanomedicines in oncology. Overall, this review synthesizes the findings from over 100 peer-reviewed studies published between 2008 and 2025, providing an up-to-date assessment of melittin-based nanomedicine strategies across diverse cancer types. Full article

(This article belongs to the Special Issue Development of Novel Tumor-Targeting Nanoparticles, 2nd Edition)

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12 pages, 2722 KiB

Open AccessArticle

Uniform Cu-Based Metal–Organic Framework Micrometer Cubes with Synergistically Enhanced Photodynamic/Photothermal Properties for Rapid Eradication of Multidrug-Resistant Bacteria

by Xiaomei Wang, Ting Zou, Weiqi Wang, Keqiang Xu and Handong Zhang

Pharmaceutics 2025, 17(8), 1018; https://doi.org/10.3390/pharmaceutics17081018 - 6 Aug 2025

Abstract

Background/Objectives: The rapid emergence of multidrug-resistant bacterial infections demands innovative non-antibiotic therapeutic strategies. Dual-modal photoresponse therapy integrating photodynamic (PDT) and photothermal (PTT) effects offers a promising rapid antibacterial approach, yet designing single-material systems with synergistic enhancement remains challenging. This study aims to [...] Read more.

Background/Objectives: The rapid emergence of multidrug-resistant bacterial infections demands innovative non-antibiotic therapeutic strategies. Dual-modal photoresponse therapy integrating photodynamic (PDT) and photothermal (PTT) effects offers a promising rapid antibacterial approach, yet designing single-material systems with synergistic enhancement remains challenging. This study aims to develop uniform Cu-based metal–organic framework micrometer cubes (Cu-BN) for efficient PDT/PTT synergy. Methods: Cu-BN cubes were synthesized via a one-step hydrothermal method using Cu(NO₃)₂ and 2-amino-p-benzoic acid. The material’s dual-mode responsiveness to visible light (420 nm) and near-infrared light (808 nm) was characterized through UV–Vis spectroscopy, photothermal profiling, and reactive oxygen species (ROS) generation assays. Antibacterial efficacy against multidrug-resistant Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) was quantified via colony counting under dual-light irradiation. Results: Under synergistic 420 + 808 nm irradiation for 15 min, Cu-BN (200 μg/mL) achieved rapid eradication of multidrug-resistant E. coli (99.94%) and S. aureus (99.83%). The material reached 58.6 °C under dual-light exposure, significantly exceeding single-light performance. Photodynamic analysis confirmed a 78.7% singlet oxygen (¹O₂) conversion rate. This enhancement stems from PTT-induced membrane permeabilization accelerating ROS diffusion, while PDT-generated ROS sensitized bacteria to thermal damage. Conclusions: This integrated design enables spatiotemporal PDT/PTT synergy within a single Cu-BN system, establishing a new paradigm for rapid-acting, broad-spectrum non-antibiotic antimicrobials. The work provides critical insights for developing light-responsive biomaterials against drug-resistant infections. Full article

(This article belongs to the Special Issue “The Power of Light” in Biomedical and Pharmaceutics: New Approaches for Photodynamic Purposes)

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25 pages, 4393 KiB

Open AccessArticle

Development and Preclinical Evaluation of Fixed-Dose Capsules Containing Nicergoline, Piracetam, and Hawthorn Extract for Sensorineural Hearing Loss

by Lucia Maria Rus, Andrei Uncu, Sergiu Parii, Alina Uifălean, Simona Codruța Hegheș, Cristina Adela Iuga, Ioan Tomuță, Ecaterina Mazur, Diana Șepeli, Irina Kacso, Fliur Macaev, Vladimir Valica and Livia Uncu

Pharmaceutics 2025, 17(8), 1017; https://doi.org/10.3390/pharmaceutics17081017 - 5 Aug 2025

Abstract

Background: Fixed-dose combinations have advanced in many therapeutic areas, including otorhinolaryngology, where hearing disorders are increasingly prevalent. Objectives: The present study focuses on developing and evaluating a new capsule combining nicergoline (NIC), piracetam (PIR), and hawthorn extract (HE) for the management of sensorineural [...] Read more.

Background: Fixed-dose combinations have advanced in many therapeutic areas, including otorhinolaryngology, where hearing disorders are increasingly prevalent. Objectives: The present study focuses on developing and evaluating a new capsule combining nicergoline (NIC), piracetam (PIR), and hawthorn extract (HE) for the management of sensorineural hearing loss. Methods: The first phase methodology comprised preformulation studies (DSC, FTIR, and PXRD) to assess compatibility among active substances and excipients. Subsequently, four formulations were prepared and tested for flowability, dissolution behavior in acidic and neutral media, and stability under oxidative, thermal, and photolytic stress. Quantification of the active substances and flavonoids was performed using validated spectrophotometric and HPLC-UV methods. Results: Among the tested variants, the F1 formulation (4.5 mg NIC, 200 mg PIR, 50 mg HE, 2.5 mg magnesium stearate, 2.5 mg sodium starch glycolate, and 240.5 mg monohydrate lactose per capsule) displayed optimal technological properties, superior dissolution in acidic media, and was further selected for evaluation. The antioxidant activity of the formulation was confirmed through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, Trolox Equivalent Antioxidant Capacity (TEAC), and iron chelation tests, and was primarily attributed to the flavonoid content of the HE. Acute toxicity tests in mice and rats indicated a high safety margin (LD₅₀ > 2500 mg/kg), while ototoxicity assessments showed no adverse effects on auditory function. Conclusions: The developed formulation displayed good stability, safety, and therapeutic potential, while the applied workflow could represent a model for the development of future fixed-dose combinations. Full article

(This article belongs to the Special Issue Natural Product Pharmaceuticals, 2nd Edition)

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23 pages, 1714 KiB

Open AccessArticle

Physicochemical and Biological Properties of Quercetin-Loaded Low-Molecular-Weight Chitosan Nanoparticles Derived from Hermetia illucens Larvae and Crustacean Sources: A Comparative Study

by Anna Guarnieri, Rosanna Mallamaci, Giuseppe Trapani, Dolores Ianniciello, Carmen Scieuzo, Francesco Iannielli, Luigi Capasso, Maria Chiara Sportelli, Alessandra Barbanente, Michela Marsico, Angela De Bonis, Stefano Castellani, Patrizia Falabella and Adriana Trapani

Pharmaceutics 2025, 17(8), 1016; https://doi.org/10.3390/pharmaceutics17081016 - 5 Aug 2025

Abstract

Introduction. Larvae of the insect Hermetia illucens can represent an alternative source for low-molecular-weight chitosan (CS) production compared with CS from crustaceans (CS_crustac), making it appealing in terms of pharmaceutical applications. Hence, the performances of CS_larvae and CS_crustac [...] Read more.

Introduction. Larvae of the insect Hermetia illucens can represent an alternative source for low-molecular-weight chitosan (CS) production compared with CS from crustaceans (CS_crustac), making it appealing in terms of pharmaceutical applications. Hence, the performances of CS_larvae and CS_crustac were compared herein by investigating the in vitro features of nanoparticles (NPs) made from each polysaccharide and administered with the antioxidant quercetin (QUE). Methods. X-ray diffraction and FT-IR spectroscopy enabled the identification of each type of CS. Following the ionic gelation technique and using sulfobutylether-β-cyclodextrin as a cross-linking agent, NPs were easily obtained. Results. Physicochemical data, release studies in PBS, and the evaluation of antioxidant effects via the 1,1-diphenyl-2-picrylhydrazyl (DPPH) test were studied for both CS_larvae and CS_crustac. QUE-loaded NP sizes ranged from 180 to 547 nm, and zeta potential values were between +7.5 and +39.3 mV. In vitro QUE release in PBS was faster from QUE-CS_larvae NPs than from CS_crustac, and high antioxidant activity—according to the DPPH test—was observed for all tested NP formulations. Discussion. The agar diffusion assay, referring to Escherichia coli and Micrococcus flavus, as well as the microdilution assay, showed the best performance as antimicrobial formulations in the case of QUE-CS_larvae NPs. QUE-CS_larvae NPs can represent a promising vehicle for QUE, releasing it in a sustained manner, and, relevantly, the synergism noticed between QUE and CS_larvae resulted in a final antimicrobial product. Conclusions. New perspectives for low-molecular-weight CS are disclosed by adopting renewable sources from insects instead of the commercial CS_crustac. Full article

(This article belongs to the Section Biopharmaceutics)

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27 pages, 6602 KiB

Open AccessArticle

Extracellular Vesicle-Mediated Delivery of AntimiR-Conjugated Bio-Gold Nanoparticles for In Vivo Tumor Targeting

by Parastoo Pourali, Eva Neuhöferová, Behrooz Yahyaei, Milan Svoboda, Adéla Buchnarová and Veronika Benson

Pharmaceutics 2025, 17(8), 1015; https://doi.org/10.3390/pharmaceutics17081015 - 5 Aug 2025

Abstract

Background/Objectives: Extracellular vesicles (EVs) are involved in cell-to-cell communication and delivery of signaling molecules and represent an interesting approach in targeted therapy. This project focused on EV-mediated facilitation and cell-specific delivery of effector antimiR molecules carried by biologically produced gold nanoparticles (AuNPs). Methods: [...] Read more.

Background/Objectives: Extracellular vesicles (EVs) are involved in cell-to-cell communication and delivery of signaling molecules and represent an interesting approach in targeted therapy. This project focused on EV-mediated facilitation and cell-specific delivery of effector antimiR molecules carried by biologically produced gold nanoparticles (AuNPs). Methods: First, we loaded EVs derived from cancer cells 4T1 with AuNPs-antimiR. The AuNPs were also decorated with or without transferrin (Tf) molecules. We examined parental cell-specific delivery of the AuNPs-Tf-antimiR within monocultures as well as co-cultures in vitro. Subsequently, we used autologous EVs containing AuNPs-Tf-antimiR to target tumor cells in a xenograft tumor model in vivo. Efficacy of the antimir transfer was assessed by qPCR and apoptosis assessment. Results: In vitro, EVs loaded with AuNPs-antimiR were internalized only by the parental cells and the AuNPs-antimiR transfer was successful and effective only in EVs that were decorated with Tf. We achieved effective delivery of the antimiR molecule into cancer cells in vivo, which was proved by specific silencing of the target oncogenic miRNA as well as induction of cancer cells apoptosis. Conclusions: EVs represent an interesting and potent way for targeted cargo delivery and personalized medicine. On the other hand, there are various safety and efficacy challenges that remain to be addressed. Full article

(This article belongs to the Special Issue Cell-Mediated Delivery Systems)

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17 pages, 3969 KiB

Open AccessArticle

Evaluation of the Synthesis and Skin Penetration Pathway of Folate-Conjugated Polymeric Micelles for the Dermal Delivery of Irinotecan and Alpha-Mangostin

by Thanchanok Sirirak and Thirapit Subongkot

Pharmaceutics 2025, 17(8), 1014; https://doi.org/10.3390/pharmaceutics17081014 - 5 Aug 2025

Abstract

Background/Objectives: The present study aimed to synthesize folate-conjugated poloxamers and develop polymeric micelles for the dermal delivery of irinotecan and alpha-mangostin for the treatment of melanoma using poloxamer 188 and poloxamer 184, which have never been synthesized with folate before. Methods: [...] Read more.

Background/Objectives: The present study aimed to synthesize folate-conjugated poloxamers and develop polymeric micelles for the dermal delivery of irinotecan and alpha-mangostin for the treatment of melanoma using poloxamer 188 and poloxamer 184, which have never been synthesized with folate before. Methods: Poloxamer 188 and poloxamer 184 were synthesized with folate by esterification. The in vitro skin penetration enhancement of irinotecan- and alpha-mangostin-loaded folate-conjugated polymeric micelles was evaluated. The skin penetration pathway of folate-conjugated polymeric micelles was investigated by colocalization of multiple fluorescently labeled particles using confocal laser scanning microscopy (CLSM). Results: Folate-conjugated poloxamer 188 and poloxamer 184 were successfully synthesized. The prepared irinotecan- and alpha-mangostin-loaded folate-conjugated polymeric micelles from poloxamer 188 and poloxamer 184 had particle sizes of approximately 180 and 150 nm, respectively, indicating a positive charge with a narrow size distribution which could be easily taken up into cells. An in vitro skin penetration study revealed that folate-conjugated polymeric micelles from poloxamer 184 significantly enhanced the skin penetration of irinotecan and alpha-mangostin to a greater extent than the solution. CLSM visualization revealed that folate-conjugated polymeric micelles penetrated through the skin by the transfollicular pathway as the major penetration pathway, whereas penetration by the intercluster pathway, transcellular pathway and intercellular pathway constituted a minor pathway. Conclusions: Folate-conjugated poloxamer 184 polymeric micelles are promising candidates for the dermal delivery of anticancer drugs by the transfollicular pathway as the major skin penetration pathway. Full article

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

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21 pages, 3431 KiB

Open AccessArticle

Synthesis and Antibacterial Evaluation of an Indole Triazole Conjugate with In Silico Evidence of Allosteric Binding to Penicillin-Binding Protein 2a

by Vidyasrilekha Sanapalli, Bharat Kumar Reddy Sanapalli and Afzal Azam Mohammed

Pharmaceutics 2025, 17(8), 1013; https://doi.org/10.3390/pharmaceutics17081013 - 3 Aug 2025

Abstract

Background: Antibacterial resistance (ABR) poses a major challenge to global health, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the prominent multidrug-resistant strains. MRSA has developed resistance through the expression of Penicillin-Binding Protein 2a (PBP2a), a key transpeptidase enzyme involved in bacterial [...] Read more.

Background: Antibacterial resistance (ABR) poses a major challenge to global health, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the prominent multidrug-resistant strains. MRSA has developed resistance through the expression of Penicillin-Binding Protein 2a (PBP2a), a key transpeptidase enzyme involved in bacterial cell wall biosynthesis. Objectives: The objective was to design and characterize a novel small-molecule inhibitor targeting PBP2a as a strategy to combat MRSA. Methods: We synthesized a new indole triazole conjugate (ITC) using eco-friendly and click chemistry approaches. In vitro antibacterial tests were performed against a panel of strains to evaluate the ITC antibacterial potential. Further, a series of in silico evaluations like molecular docking, MD simulations, free energy landscape (FEL), and principal component analysis (PCA) using the crystal structure of PBP2a (PDB ID: 4CJN), in order to predict the mechanism of action, binding mode, structural stability, and energetic profile of the 4CJN-ITC complex. Results: The compound ITC exhibited noteworthy antibacterial activity, which effectively inhibited the selected strains. Binding score and energy calculations demonstrated high affinity of ITC for the allosteric site of PBP2a and significant interactions responsible for complex stability during MD simulations. Further, FEL and PCA provided insights into the conformational behavior of ITC. These results gave the structural clues for the inhibitory action of ITC on the PBP2a. Conclusions: The integrated in vitro and in silico studies corroborate the potential of ITC as a promising developmental lead targeting PBP2a in MRSA. This study demonstrates the potential usage of rational drug design approaches in addressing therapeutic needs related to ABR. Full article

(This article belongs to the Topic Design, Synthesis and Biological Evaluation of Novel Small Molecules as Multi-target Enzyme Inhibitors)

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