Pharmaceutics

14 pages, 328 KiB

Open AccessArticle

Understanding the Toxicity Profile of Approved ADCs

by Pablo Ballestín, Alfonso López de Sá, Cristina Díaz-Tejeiro, Lucía Paniagua-Herranz, Adrián Sanvicente, Igor López-Cade, Pedro Pérez-Segura, Carlos Alonso-Moreno, Cristina Nieto-Jiménez and Alberto Ocaña

Pharmaceutics 2025, 17(2), 258; https://doi.org/10.3390/pharmaceutics17020258 - 14 Feb 2025

Abstract

Background: Antibody–drug conjugates (ADCs) represent a novel therapeutic class that combines an antibody against a tumor-associated antigen (TAA), a payload, and a linker that binds these two components. Serious adverse events (SAEs), particularly those of grade 3 (G3) or higher, frequently contribute to [...] Read more.

Background: Antibody–drug conjugates (ADCs) represent a novel therapeutic class that combines an antibody against a tumor-associated antigen (TAA), a payload, and a linker that binds these two components. Serious adverse events (SAEs), particularly those of grade 3 (G3) or higher, frequently contribute to the abandonment of ADCs during clinical development. Methods: In this study, we analyzed the toxicity profiles of all approved ADCs, aiming to uncover correlations between their safety profiles and the specific characteristics of their components. Results: In our analysis, dose reductions, dose delays, treatment discontinuations, and ≥G3 toxicities were not significantly different across payload types. Similarly, no association was found between the payload mechanism of action and ≥G3 toxicities, including anemia, neutropenia, febrile neutropenia, thrombocytopenia, and diarrhea. By exploring the specific toxicities of ADCs observed by organ, we identified that most were related to the payload mechanism of action, like the ≥G3 diarrhea observed in 10% of patients treated with sacituzumab govitecan (the payload SN-38 is the active metabolite of irinotecan), and very few were related to the presence of the TAA in normal tissue (presence of Nectin-4 in skin and ≥G3 rash toxicity in 14% of patients treated with enfortumab vedotin). In line with this, no major differences in ≥G3 toxicities were identified in studies with different levels of the TAA (trastuzumab deruxtecan in Destiny Breast Studies with different HER2 expression levels). Conclusions: Our analysis reveals that most ADC toxicities are driven by the payload’s effects on non-transformed tissues; however, a detailed analysis of each ADC component should be taken into consideration. Full article

(This article belongs to the Section Clinical Pharmaceutics)

32 pages, 2894 KiB

Open AccessReview

Extracellular Vesicle-Based Strategies for Tumor Immunotherapy

by Luksika Jiramonai, Xing-Jie Liang and Mengliang Zhu

Pharmaceutics 2025, 17(2), 257; https://doi.org/10.3390/pharmaceutics17020257 - 14 Feb 2025

Abstract

Immunotherapy is one of the most promising approaches for cancer management, as it utilizes the intrinsic immune response to target cancer cells. Normally, the human body uses its immune system as a defense mechanism to detect and eliminate foreign objects, including cancer cells. [...] Read more.

Immunotherapy is one of the most promising approaches for cancer management, as it utilizes the intrinsic immune response to target cancer cells. Normally, the human body uses its immune system as a defense mechanism to detect and eliminate foreign objects, including cancer cells. However, cancers develop a ‘switch off’ mechanism, known as immune checkpoint proteins, to evade immune surveillance and suppress immune activation. Therefore, significant efforts have been made to develop the strategies for stimulating immune responses against cancers. Among these, the use of extracellular vesicles (EVs) to enhance the anti-tumor immune response has emerged as a particularly promising approach in cancer management. EVs possess several unique properties that elevate the potency in modulating immune responses. This review article provides a comprehensive overview of recent advances in this field, focusing on the strategic usage of EVs to overcome tumor-induced immune tolerance. We discuss the biogenesis and characteristics of EVs, as well as their potential applications in medical contexts. The immune mechanisms within the tumor microenvironment and the strategies employed by cancers to evade immune detection are explored. The roles of EVs in regulating the tumor microenvironment and enhancing immune responses for immunotherapy are also highlighted. Additionally, this article addresses the challenges and future directions for the development of EV-based nanomedicine approaches, aiming to improve cancer immunotherapy outcomes with greater precision and efficacy while minimizing off-target effects. Full article

(This article belongs to the Special Issue Nanomedicines for Overcoming Tumor Immunotherapy Tolerance)

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23 pages, 1040 KiB

Open AccessReview

Recent Advances in Studying In Vitro Drug Permeation Across Mucosal Membranes

by Juan Song, Zizhao Xu, Lingxiao Xie and Jie Shen

Pharmaceutics 2025, 17(2), 256; https://doi.org/10.3390/pharmaceutics17020256 - 14 Feb 2025

Abstract

Transmucosal drug products, such as aerosols, films, semisolids, suppositories, and tablets, have been developed for the treatment of various human diseases and conditions. Transmucosal drug absorption is highly influenced by the biological structures of the mucosa and the physiological environment specific to the [...] Read more.

Transmucosal drug products, such as aerosols, films, semisolids, suppositories, and tablets, have been developed for the treatment of various human diseases and conditions. Transmucosal drug absorption is highly influenced by the biological structures of the mucosa and the physiological environment specific to the administration route (e.g., nasal, rectal, and vaginal). Over the last few decades, in vitro permeation testing (IVPT) using animal tissues or in vitro cell cultures have been utilized as a cost-effective and efficient tool for evaluating drug release and permeation behavior, assisting in formulation development and quality control of transmucosal drug delivery systems. This review summarizes the key mucosal permeation barriers associated with representative transmucosal administration routes, as well as considerations for IVPT method development. It highlights various IVPT methods, including vertical diffusion cell, flow-through diffusion cell, Ussing chamber, and transwell systems. Additionally, future perspectives are discussed, such as the use of optical methods to study in vitro drug permeation and the development of in vitro–in vivo correlation (IVIVC) for transmucosal drug development. The potential of IVPT as part of in vitro bioequivalence assessment strategies for locally acting transmucosal drug products is also highlighted. Full article

(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)

28 pages, 11504 KiB

Open AccessArticle

Phytoactive-Loaded Lipid Nanocarriers for Simvastatin Delivery: A Drug Repositioning Strategy Against Lung Cancer

by Rocío Gambaro, Cecilia Y. Chain, Sebastian Scioli-Montoto, Ailin Moreno, Cristián Huck-Iriart, María Esperanza Ruiz, José S. Cisneros, Diego G. Lamas, Julia Tau, Stephan Gehring, Germán A. Islan and Boris Rodenak-Kladniew

Pharmaceutics 2025, 17(2), 255; https://doi.org/10.3390/pharmaceutics17020255 - 14 Feb 2025

Abstract

Background/Objectives: Drug repurposing explores new applications for approved medications, such as simvastatin (SV), a lipid-lowering drug that has shown anticancer potential but is limited by solubility and side effects. This study aims to enhance SV delivery and efficacy against lung cancer cells using [...] Read more.

Background/Objectives: Drug repurposing explores new applications for approved medications, such as simvastatin (SV), a lipid-lowering drug that has shown anticancer potential but is limited by solubility and side effects. This study aims to enhance SV delivery and efficacy against lung cancer cells using bioactive lipid nanoparticles formulated with plant-derived monoterpenes as both nanostructuring agents and anticancer molecules. Methods: Lipid nanoparticles were produced by ultrasonication and characterized for morphology, size, zeta potential, and polydispersity index (PDI). Monoterpenes (linalool-LN-, limonene, 1,8-cineole) or Crodamol^® were used as liquid lipids. Encapsulation efficiency (EE), release profiles, stability, biocompatibility, protein adsorption, cytotoxicity, and anticancer effects were evaluated. Results: The nanoparticles exhibited high stability, size: 94.2 ± 0.9–144.0 ± 2.6 nm, PDI < 0.3, and zeta potential: −4.5 ± 0.7 to −16.3 ± 0.8 mV. Encapsulation of SV in all formulations enhanced cytotoxicity against A549 lung cancer cells, with NLC/LN/SV showing the highest activity and being chosen for further investigation. Sustained SV release over 72 h and EE > 95% was observed for NLC/LN/SV. SAXS/WAXS analysis revealed that LN altered the crystallographic structure of nanoparticles. NLC/LN/SV demonstrated excellent biocompatibility and developed a thin serum protein corona in vitro. Cellular studies showed efficient uptake by A549 cells, G0/G1 arrest, mitochondrial hyperpolarization, reactive oxygen species production, and enhanced cell death compared to free SV. NLC/LN/SV more effectively inhibited cancer cell migration than free SV. Conclusions: NLC/LN/SV represents a promising nanocarrier for SV repurposing, combining enhanced anticancer activity, biocompatibility, and sustained stability for potential lung cancer therapy. Full article

(This article belongs to the Special Issue Natural Nanoparticle for Cancer Diagnosis and Treatment, 2nd Edition)

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25 pages, 9926 KiB

Open AccessArticle

A Novel Natural Penetration Enhancer for Transdermal Drug Delivery: In Vitro/In Vivo Evaluation and Penetration Enhancement Mechanism

by Nanxi Zhao, Jiale Hao, Yucong Zhao, Bingqian Zhao, Jiayu Lin, Jian Song, Manli Wang and Zheng Luo

Pharmaceutics 2025, 17(2), 254; https://doi.org/10.3390/pharmaceutics17020254 - 14 Feb 2025

Abstract

Objectives: This study aimed to identify and develop a novel, safe, and effective transdermal penetration enhancer derived from the leaves of Perilla frutescens (L.) Britt, and to explore the underlying mechanisms of its penetration enhancement effects. Methods: To evaluate the safety [...] Read more.

Objectives: This study aimed to identify and develop a novel, safe, and effective transdermal penetration enhancer derived from the leaves of Perilla frutescens (L.) Britt, and to explore the underlying mechanisms of its penetration enhancement effects. Methods: To evaluate the safety profile of the penetration enhancer, both skin irritation tests and histopathological analyses were conducted. The transdermal enhancement capabilities of the penetration enhancer were assessed in vitro using five model drugs. Furthermore, to gain insights into the penetration enhancement mechanism of this novel penetration enhancer, a range of analytical methods were used, including a spectroscopic technique, differential scanning calorimetry, micro-optical techniques, and molecular docking simulations. Results: Perilla essential oil contained 93.70% perilla ketone (PEK), which exhibited a safety profile superior to that of azone. PEK significantly increased the cumulative skin permeation of all the model drugs (p < 0.05). PEK exhibited the most obvious impact on puerarin penetration, with quantitative enhancement ratios of 2.96 ± 0.07 and 3.39 ± 0.21 at concentrations of 3% and 5% (w/v), respectively. A strong correlation between the enhancement effect of PEK and the physicochemical properties of the drugs was observed. Mechanistic studies revealed that PEK facilitates drug distribution from the solution phase to the stratum corneum (SC). Conclusions: PEK, seldom discussed in former studies, was observed to show extensive penetration enhancement effects by inducing conformational changes in SC lipids and disrupting the tightly ordered bilayer arrangement of lipids. These findings highlight the potential of PEK as a promising and safe natural transdermal penetration enhancer. Full article

(This article belongs to the Special Issue Pharmaceutical Excipients: Impact on Efficiency, Stability, and Solubility in Formulation)

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12 pages, 2735 KiB

Open AccessArticle

PET Imaging of CD206 Macrophages in Bleomycin-Induced Lung Injury Mouse Model

by Volkan Tekin, Yujun Zhang, Clayton Yates, Jesse Jaynes, Henry Lopez, Charles Garvin, Benjamin M. Larimer and Suzanne E. Lapi

Pharmaceutics 2025, 17(2), 253; https://doi.org/10.3390/pharmaceutics17020253 - 14 Feb 2025

Abstract

Background/Objectives: The identification of inflammatory mediators and the involvement of CD206 macrophages in anti-inflammatory responses, along with the synthesis of fibrotic mediators, are crucial for the diagnosis and treatment of Idiopathic Pulmonary Fibrosis (IPF). Methods: In this study, the assessment of [...] Read more.

Background/Objectives: The identification of inflammatory mediators and the involvement of CD206 macrophages in anti-inflammatory responses, along with the synthesis of fibrotic mediators, are crucial for the diagnosis and treatment of Idiopathic Pulmonary Fibrosis (IPF). Methods: In this study, the assessment of ⁶⁸Ga-labeled linear and cyclic forms of the RP832c peptide, which demonstrate a specific affinity for CD206 macrophages, was performed to evaluate efficacy for CD206 imaging through PET/CT, biodistribution studies, and CD206 staining in a bleomycin-induced lung injury mouse model (BLM). This model serves as a representative framework for inflammation and fibrosis. Results: The findings reveal significant peak PET/CT signals (SUV means), ID/gram values, and CD206 staining scores in lung tissues at one week post bleomycin instillation, likely due to the heightened expression of CD206 in the bleomycin-induced lung injury model. In contrast, the healthy mice exhibited no detectable CD206 staining, lower PET signals, and reduced radiopharmaceutical accumulation in lung tissues at the same timepoint. Conclusions: These findings suggest that both linear and cyclic [⁶⁸Ga]Ga-RP832c may function as promising PET imaging agents for CD206 macrophages, and thereby a strategy to non-invasively explore the role of macrophages during fibrogenesis. Full article

(This article belongs to the Special Issue Advances in Radiopharmaceuticals for Disease Diagnoses and Therapy)

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14 pages, 1537 KiB

Open AccessArticle

Effects of Sex and Cross-Sex Hormone Treatment on Renal MCT/SMCT Expression Following Prepubertal Gonadectomy

by Annie Lee, Qing Zhang, Hao Wei and Melanie A. Felmlee

Pharmaceutics 2025, 17(2), 252; https://doi.org/10.3390/pharmaceutics17020252 - 14 Feb 2025

Abstract

Background: Kidney proton- and sodium-dependent monocarboxylate transporters (MCT/SMCT) are involved in the renal reabsorption of substrates, and thus factors involved in their regulation may have pharmacokinetic implications. Previous studies have demonstrated sex hormone-dependent regulation of MCTs and SMCTs in tissues involved in drug [...] Read more.

Background: Kidney proton- and sodium-dependent monocarboxylate transporters (MCT/SMCT) are involved in the renal reabsorption of substrates, and thus factors involved in their regulation may have pharmacokinetic implications. Previous studies have demonstrated sex hormone-dependent regulation of MCTs and SMCTs in tissues involved in drug disposition. The present study evaluates the impact of puberty on renal MCT/SMCT expression with ovariectomy and castration conducted before puberty, removing the initial exposure to sex hormones. Methods: Male and female rats were castrated or ovariectomized before puberty (4 weeks of age), and subsequently treated with testosterone, 17β-estradiol, progesterone, or both 17β-estradiol and progesterone for 21 days starting at 10 weeks of age. MCT1, CD147, and SMCT1 membrane-bound kidney expression were quantified by Western blot. Results: SMCT1 and CD147 expression were significantly higher in OVX and CST rats treated with testosterone, and testosterone plasma concentrations showed a significant positive correlation with MCT1, SMCT1, and CD147 expression. CD147 expression was significantly downregulated in OVX rats treated with estrogen, compared to placebo controls, and estrogen plasma concentrations were significantly negatively correlated with CD147 expression. Conclusions: Sex and cross-sex hormone treatment altered MCT1, CD147, and SMCT1 expression when gonadectomy was conducted before puberty. The magnitude and direction of the expression differences differed when compared to animals that underwent gonadectomy after puberty, suggesting that sex hormone exposure during puberty plays a key role in MCT1/SMCT1 renal expression. Further studies are needed to elucidate the underlying mechanisms for the differential regulation of MCTs/SMCTs when gonadectomy occurs before or after puberty. Full article

(This article belongs to the Special Issue New Insights into Transporters in Drug Development)

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14 pages, 3645 KiB

Open AccessArticle

Toward the Optimal Choice of Gelled Vehicles for Oral Drug Administration in Dysphagic Patients

by Serena Logrippo, Roberta Ganzetti, Matteo Sestili, Diego Romano Perinelli, Marco Cespi and Giulia Bonacucina

Pharmaceutics 2025, 17(2), 251; https://doi.org/10.3390/pharmaceutics17020251 - 14 Feb 2025

Abstract

Background/Objectives: Thickened waters are commonly used for dysphagic patients to ensure hydration, facilitate safer swallowing, and administer oral therapies, yet their impact on drug dissolution remains unclear. This study aims to investigate how thickening agents, viscosity, and solid oral dosage form (SODF) [...] Read more.

Background/Objectives: Thickened waters are commonly used for dysphagic patients to ensure hydration, facilitate safer swallowing, and administer oral therapies, yet their impact on drug dissolution remains unclear. This study aims to investigate how thickening agents, viscosity, and solid oral dosage form (SODF) formulations influence drug release in gelled vehicles. Methods: Twelve commercially available thickened waters, including both ready-to-use products and powders for extemporaneous preparation, were used to disperse crushed sodium pravastatin tablets. The resulting preparations were evaluated for their rheological properties and dissolution performance. Results: Thickened water products vary in consistency, with starch-based thickeners providing more consistent results than gum-based ones. Pravastatin release profiles closely matched the original tablets with starch thickeners, while gum-based thickeners showed greater variability, primarily influenced by viscosity. Conclusions: These findings emphasize the importance of selecting the appropriate thickening agent for controlling drug release in thickened water products, highlighting the need to balance patient compliance with the potential impact on drug release during product development. Full article

(This article belongs to the Special Issue Extemporaneous Formulations: Filling the Gap in the Pharmaceutical Industry with Personalized Medicines)

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21 pages, 1248 KiB

Open AccessReview

Clinical Pharmacology of Bulevirtide: Focus on Known and Potential Drug–Drug Interactions

by Martina Billi, Sara Soloperto, Stefano Bonora, Antonio D’Avolio and Amedeo De Nicolò

Pharmaceutics 2025, 17(2), 250; https://doi.org/10.3390/pharmaceutics17020250 - 14 Feb 2025

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Abstract

Background: Hepatitis D virus (HDV) is a defective virus requiring co-infection with hepatitis B virus (HBV) to replicate, occurring in 5% of HBV+ patients. Bulevirtide (BLV) is now the first-in-class specific anti-HDV agent, inhibiting HDV binding to NTCP, with good tolerability and good [...] Read more.

Background: Hepatitis D virus (HDV) is a defective virus requiring co-infection with hepatitis B virus (HBV) to replicate, occurring in 5% of HBV+ patients. Bulevirtide (BLV) is now the first-in-class specific anti-HDV agent, inhibiting HDV binding to NTCP, with good tolerability and good virological and biochemical response rates. Currently, little is known about its pharmacokinetic/pharmacodynamic (PK/PD), as well as potential drug-drug interaction (DDI) profile. In this work we provide a systematic review of the current knowledge on these aspects. Methods: A literature review of PK, PD and DDI profiles of BLV was conducted from Pubmed and EMA websites. Experimentally tested interactions and hypothetical mechanisms of interaction were evaluated, mostly focusing on usually co-administered anti-infective agents and other drugs interacting on NTCP. Results: BLV shows non-linear PK, due to target-mediated drug disposition, so its PK as well as PD is expected to be influenced by interactions of other drugs with NTCP, while it is not substrate of CYPs and ABC transporters. In-vivo investigated DDIs showed no clinically relevant interactions, but a weak inhibitory effect was suggested on CYP3A4 in a work when used at high doses (10 mg instead of 2 mg). In vitro, a weak inhibitory effect on OATP transporters was observed, but at much higher concentrations than the ones expected in vivo. Conclusions: The drug-drug interaction potential of BLV can be considered generally very low, particularly at the currently approved dose of 2 mg/day. Some attention should be paid to the coadministration of drugs with known binding and/or inhibition of NTCP. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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35 pages, 5990 KiB

Open AccessReview

Gels as Promising Delivery Systems: Physicochemical Property Characterization and Recent Applications

by Enzhao Wang, Zhaoying Qi, Yuzhou Cao, Ruixiang Li, Jing Wu, Rongshuang Tang, Yi Gao, Ruofei Du and Minchen Liu

Pharmaceutics 2025, 17(2), 249; https://doi.org/10.3390/pharmaceutics17020249 - 14 Feb 2025

Viewed by 67

Abstract

Gels constitute a versatile class of materials with considerable potential for applications in both technical and medical domains. Physicochemical property characterization is a critical evaluation method for gels. Common characterization techniques include pH measurement, structural analysis, mechanical property assessment, rheological analysis, and phase [...] Read more.

Gels constitute a versatile class of materials with considerable potential for applications in both technical and medical domains. Physicochemical property characterization is a critical evaluation method for gels. Common characterization techniques include pH measurement, structural analysis, mechanical property assessment, rheological analysis, and phase transition studies, among others. While numerous research articles report characterization results, few reviews comprehensively summarize the appropriate numerical ranges for these properties. This lack of standardization complicates harmonized evaluation methods and hinders direct comparisons between different gels. To address this gap, it is essential to systematically investigate characterization methods and analyze data from the extensive body of literature on gels. In this review, we provide a comprehensive summary of general characterization methods and present a detailed analysis of gel characterization data to support future research and promote standardized evaluation protocols. Full article

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

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23 pages, 4808 KiB

Open AccessReview

Microneedle-Mediated Treatment of Obesity

by Huanhuan Pan, Wanshan Hu, Chunxian Zhou, Jubo Jian, Jing Xu, Chao Lu, Guilan Quan, Chuanbin Wu, Xin Pan and Tingting Peng

Pharmaceutics 2025, 17(2), 248; https://doi.org/10.3390/pharmaceutics17020248 - 13 Feb 2025

Viewed by 213

Abstract

Obesity has become a major public health threat, as it can cause various complications such as diabetes, cardiovascular disease, sleep apnea, cancer, and osteoarthritis. The primary anti-obesity therapies include dietary control, physical exercise, surgical interventions, and drug therapy; however, these treatments often have [...] Read more.

Obesity has become a major public health threat, as it can cause various complications such as diabetes, cardiovascular disease, sleep apnea, cancer, and osteoarthritis. The primary anti-obesity therapies include dietary control, physical exercise, surgical interventions, and drug therapy; however, these treatments often have poor therapeutic efficacy, significant side effects, and unavoidable weight rebound. As a revolutionized transdermal drug delivery system, microneedles (MNs) have been increasingly used to deliver anti-obesity therapeutics to subcutaneous adipose tissue or targeted absorption sites, significantly enhancing anti-obese effects. Nevertheless, there is still a lack of a review to comprehensively summarize the latest progress of MN-mediated treatment of obesity. This review provides an overview of the application of MN technology in obesity, focusing on the delivery of various therapeutics to promote the browning of white adipose tissue (WAT), suppress adipogenesis, and improve metabolic function. In addition, this review presents detailed examples of the integration of MN technology with iontophoresis (INT) or photothermal therapy (PTT) to promote drug penetration into deeper dermis and exert synergistic anti-obese effects. Furthermore, the challenges and prospects of MN technology used for obesity treatment are also discussed, which helps to guide the design and optimization of MNs. Overall, this review provides insight into the development and clinical translation of MN technology for the treatment of obesity. Full article

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

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23 pages, 1775 KiB

Open AccessArticle

Assessment of Cell Viability in Drug Therapy: IC50 and Other New Time-Independent Indices for Evaluating Chemotherapy Efficacy

by Marta Sánchez-Díez, Paula Romero-Jiménez, Nicolás Alegría-Aravena, Clara E. Gavira-O’Neill, Elena Vicente-García, Josefa Quiroz-Troncoso, Raquel González-Martos, Carmen Ramírez-Castillejo and Juan Manuel Pastor

Pharmaceutics 2025, 17(2), 247; https://doi.org/10.3390/pharmaceutics17020247 - 13 Feb 2025

Viewed by 278

Abstract

Background/Objectives: Cell viability assays play a crucial role in cancer research and the development of effective treatments. Evaluating the efficacy of conventional treatments across different tumor profiles is essential for understanding patient resistance to chemotherapy and relapse. The IC50 index has been [...] Read more.

Background/Objectives: Cell viability assays play a crucial role in cancer research and the development of effective treatments. Evaluating the efficacy of conventional treatments across different tumor profiles is essential for understanding patient resistance to chemotherapy and relapse. The IC50 index has been commonly used as a guide in these assays. The idea behind the IC50 index is to compare cell proliferation under treatment with respect to a control population exposed to the same treatment. The index requires normalization to a control and is time dependent. These aspects are disadvantages, as small variations yield different results. In this article, we propose a new method to analyze cell viability assays. Methods: This method involves calculating the effective growth rate for both control (untreated) cells and cells exposed to a range of drug doses for short times, during which exponential proliferation can be assumed. The concentration dependence of the effective growth rate gives a real estimate of the treatment on cell proliferation. A curve fit of the effective growth rate related to concentration yields the concentration corresponding to a given effective growth rate. Results: We use this estimation to calculate the IC50 index and introduce two new parameters (ICr0 and ICrmed) to compare treatment efficacy under different culture conditions or cell lines. Conclusions: In summary, this study presents a new method to analyze cell viability assays and introduces two more precise parameters, improving the comparison and evaluation of efficacy under different conditions. Full article

(This article belongs to the Special Issue Biotechnology Applications and Innovative Approaches for Cancer Prevention and Treatment (BIO-APP))

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19 pages, 17773 KiB

Open AccessArticle

Novel Peptide-Modified Zeolitic Imidazolate Framework-8 Nanoparticles with pH-Sensitive Release of Doxorubicin for Targeted Treatment of Colorectal Cancer

by Liming Gong, Heming Zhao, Liqing Chen, Yanhong Liu, Hao Wu, Chao Liu, Jing Feng, Chenfei Liu, Congcong Xiao, Qiming Wang, Mingji Jin, Zhonggao Gao, Wei Huang and Youyan Guan

Pharmaceutics 2025, 17(2), 246; https://doi.org/10.3390/pharmaceutics17020246 - 13 Feb 2025

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Abstract

Background: Colorectal cancer (CRC) is one of the common malignant tumors. Chemotherapeutic agents represented by doxorubicin (DOX) are common adjuvant therapies for patients with advanced CRC. However, DOX suffers from dose-dependent cardiotoxicity and myelosuppression due to a lack of targeting and specificity, [...] Read more.

Background: Colorectal cancer (CRC) is one of the common malignant tumors. Chemotherapeutic agents represented by doxorubicin (DOX) are common adjuvant therapies for patients with advanced CRC. However, DOX suffers from dose-dependent cardiotoxicity and myelosuppression due to a lack of targeting and specificity, which severely limits its clinical application. Methods: Herein, we constructed a zeolitic imidazolate framework-8 (ZIF-8) modified by a novel peptide (LT peptide) to deliver the chemotherapeutic drug doxorubicin (DOX) for the targeted treatment of CRC. Results: In this study, LT-PEG@DOX@ZIF-8 nanoparticles were prepared by a simple method with suitable particle size and zeta potential, which were also capable of pH-responsive drug release. In vitro assays exhibited that LT-PEG@DOX@ZIF-8 nanoparticles were effectively taken up by C26 cells, significantly inhibited cell proliferation, and induced apoptosis. Furthermore, in mice models with colorectal tumors, LT-PEG@DOX@ZIF-8 nanoparticles also displayed specific tumor aggregation and exerted anti-tumor effects to prolong the survival of the mice. Conclusions: In conclusion, LT-PEG@DOX@ZIF-8 provides a promising strategy for the delivery of DOX to effectively treat CRC. Full article

(This article belongs to the Special Issue Innovative Nanoplatforms for Enhanced Gene Delivery and Therapeutic Applications)

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36 pages, 3932 KiB

Open AccessReview

Innovations in Cancer Therapy: Endogenous Stimuli-Responsive Liposomes as Advanced Nanocarriers

by Jazmín Torres, Johanna Karina Valenzuela Oses, Antonio María Rabasco-Álvarez, María Luisa González-Rodríguez and Mónica Cristina García

Pharmaceutics 2025, 17(2), 245; https://doi.org/10.3390/pharmaceutics17020245 - 13 Feb 2025

Viewed by 304

Abstract

Recent advancements in nanotechnology have revolutionized cancer therapy—one of the most pressing global health challenges and a leading cause of death—through the development of liposomes (L), lipid-based nanovesicles known for their biocompatibility and ability to encapsulate both hydrophilic and lipophilic drugs. More recent [...] Read more.

Recent advancements in nanotechnology have revolutionized cancer therapy—one of the most pressing global health challenges and a leading cause of death—through the development of liposomes (L), lipid-based nanovesicles known for their biocompatibility and ability to encapsulate both hydrophilic and lipophilic drugs. More recent innovations have led to the creation of stimuli-responsive L that release their payloads in response to specific endogenous or exogenous triggers. Dual- and multi-responsive L, which react to multiple stimuli, offer even greater precision, improving therapeutic outcomes while reducing systemic toxicity. Additionally, these smart L can adjust their physicochemical properties and morphology to enable site-specific targeting and controlled drug release, enhancing treatment efficacy while minimizing adverse effects. This review explores the latest advancements in endogenous stimuli-responsive liposomal nanocarriers, as well as dual- and multi-responsive L that integrate internal and external triggers, with a focus on their design strategies, mechanisms, and applications in cancer therapy. Full article

(This article belongs to the Special Issue Lipid Nanostructures as Drug Carriers for Cancer Therapy)

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23 pages, 8634 KiB

Open AccessReview

Recent Advances in Glutathione Depletion-Enhanced Porphyrin-Based nMOFs for Photodynamic Therapy

by Bin Gong, Qiuyun Zhang, Jiayi Chen, Yijie Qu, Xuanxuan Luo, Weiqi Wang and Xiaohua Zheng

Pharmaceutics 2025, 17(2), 244; https://doi.org/10.3390/pharmaceutics17020244 - 12 Feb 2025

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Abstract

Photodynamic therapy has established itself as a clinical treatment for certain superficial cancers by converting oxygen into cytotoxic singlet oxygen to eradicate cancer cells. Porphyrin-based nanoscale metal–organic frameworks have emerged as promising photosensitive platforms due to their ability to prevent the hydrophobic aggregation [...] Read more.

Photodynamic therapy has established itself as a clinical treatment for certain superficial cancers by converting oxygen into cytotoxic singlet oxygen to eradicate cancer cells. Porphyrin-based nanoscale metal–organic frameworks have emerged as promising photosensitive platforms due to their ability to prevent the hydrophobic aggregation quenching of porphyrin molecules and enhance accumulation at the tumor site, thereby becoming a focal point in photodynamic materials research. However, the elevated levels of glutathione and other reductive substances within cancer cells can alleviate the oxidative stress induced by singlet oxygen from the photodynamic therapy process, thus protecting intracellular biomolecular structures from damage. Consequently, it is crucial to design functionalized nanoplatforms that integrate glutathione depletion with porphyrin-based metal–organic frameworks to significantly boost photodynamic therapy efficacy. Moreover, the excess glutathione within cells can disrupt the structure of porphyrin-based metal–organic frameworks, which not only increases the capacity of porphyrin molecules to generate singlet oxygen upon light exposure but also aids in the recovery of their fluorescence imaging capabilities. Additionally, this specificity minimizes the photosensitizing harm of porphyrin-based metal–organic frameworks to other normal tissues. This review compiles recent advancements in developing porphyrin-based metal–organic frameworks for enhanced phototherapy through glutathione depletion. It aims to promote the further application of porphyrin-based metal–organic frameworks in phototherapy and provide valuable insights for preclinical applications. By highlighting strategies that improve therapeutic outcomes while maintaining safety profiles, this summary seeks to advance the development of more effective and targeted cancer treatments. Full article

(This article belongs to the Special Issue Advanced Nanomaterials for Drug Delivery, 2nd Edition)

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27 pages, 2964 KiB

Open AccessArticle

Tailored Intranasal Albumin Caged Selegiline-α Synuclein siRNA Liposome with Improved Efficiency in Parkinson’s Model

by Ahmed A. Katamesh, Hend Mohamed Abdel-Bar, Mohammed Khaled Bin Break, Shimaa M. Hassoun, Gehad Mohammed Subaiea, Amr Radwan and Hadel A. Abo El-Enin

Pharmaceutics 2025, 17(2), 243; https://doi.org/10.3390/pharmaceutics17020243 - 12 Feb 2025

Viewed by 330

Abstract

Background/Objectives: Parkinson’s disease (PD) is a progressive neuro-degenerative disorder characterized by α-synuclein aggregation, which promotes neuronal death and accelerates neurodegeneration. Small interfering RNA (siRNA) can reduce α-synuclein levels, but its therapeutic potential is limited by poor stability and delivery challenges. Similarly, Selegiline (Sel), [...] Read more.

Background/Objectives: Parkinson’s disease (PD) is a progressive neuro-degenerative disorder characterized by α-synuclein aggregation, which promotes neuronal death and accelerates neurodegeneration. Small interfering RNA (siRNA) can reduce α-synuclein levels, but its therapeutic potential is limited by poor stability and delivery challenges. Similarly, Selegiline (Sel), a monoamine oxidase-B (MAO-B) inhibitor, has low bioavailability, restricting its effectiveness. This study aims to develop an intranasal (IN) albumin-coated liposomal system (C-Lip_Sel-siSNCA2) for the co-delivery of Sel and α-synuclein-targeting siRNA (siSNCA2) to enhance brain targeting and therapeutic efficacy. Methods: Liposomes were prepared using the ethanol injection method and optimized via D-optimal design for size, charge, and encapsulation efficiency (EE%). The optimized formulation was coated with human serum albumin (HSA) and characterized for stability, cellular uptake, and gene silencing. In vivo pharmacokinetics and pharmacodynamics were assessed in a rotenone-induced PD rat model to evaluate the motor function, biochemical markers, and brain-targeting efficiency. Results: Optimized liposomes had a particle size of 113.5 ± 6.8 nm, zeta potential of 6.2 ± 0.8 mV, and high EE% (Sel: 92.35%; siRNA: 78.66%). Albumin coating increased size to 136.5 ± 10.3 nm and shifted zeta potential to −13.5 ± 1.4 mV, enhancing stability and targeting. IN administration achieved a 3-fold increase in brain area under the concentration-time curve (AUC) versus intravenous delivery. In PD rats, C-Lip_Sel-siSNCA2 improved motor and non-motor functions, restored dopamine levels, enhanced catalase activity, and reduced MAO-B levels, mitigating dopamine degradation and α-synuclein aggregation. Conclusions: This non-invasive, dual-action nanoplatform offers a targeted therapy for PD, combining siRNA gene silencing and MAO-B inhibition, with the potential for clinical translation in neurodegenerative diseases. Full article

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

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13 pages, 3020 KiB

Open AccessArticle

C24 Ceramide Lipid Nanoparticles for Skin Wound Healing

by Ji-Hye Lee, Jin-Hyun Kim, Tong-Il Hyeon, Khee-Tae Min, Se-Young Lee, Han-Chul Ko, Hong-Seok Choi, Kuk-Youn Ju, Young-Seok Cho and Tae-Jong Yoon

Pharmaceutics 2025, 17(2), 242; https://doi.org/10.3390/pharmaceutics17020242 - 12 Feb 2025

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Abstract

Background/Objectives: C24 ceramide plays a crucial role in skin regeneration and wound healing; however, its hydrophobic nature limits its application in therapeutic formulations. This study aims to enhance the bioavailability and efficacy of C24 ceramide by developing ceramide-based lipid nanoparticles (C24-LNP) and [...] Read more.

Background/Objectives: C24 ceramide plays a crucial role in skin regeneration and wound healing; however, its hydrophobic nature limits its application in therapeutic formulations. This study aims to enhance the bioavailability and efficacy of C24 ceramide by developing ceramide-based lipid nanoparticles (C24-LNP) and evaluate their impact on skin regeneration and wound healing. Methods: C24-LNP was synthesized and characterized for aqueous stability and bioavailability. In vitro experiments were conducted to assess its effects on keratinocyte proliferation and migration. Molecular biological analysis examined key signaling pathways, including AKT and ERK1/2 phosphorylation. Additionally, an in vivo mouse wound model was utilized to evaluate wound healing efficacy, with histological analysis performed to assess epidermal and dermal regeneration. Results: C24-LNP exhibited improved aqueous stability and bioavailability compared to free C24 ceramide. In vitro studies demonstrated that C24-LNP significantly promoted keratinocyte proliferation and migration. Molecular analysis revealed activation of the AKT and ERK1/2 signaling pathways, which are critical for cell growth and skin regeneration. In vivo wound healing experiments showed that C24-LNP accelerated wound closure compared to the control group. Histological analysis confirmed enhanced epidermal and dermal regeneration, leading to improved structural and functional skin repair. Conclusion: The lipid nanoparticle formulation of C24 ceramide effectively increases its bioavailability and enhances its therapeutic efficacy in skin regeneration and wound healing. C24-LNP presents a scalable and cost-effective alternative to traditional growth factor-based therapies, offering significant potential for clinical applications in wound care and dermatological treatments. Full article

(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)

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23 pages, 3549 KiB

Open AccessArticle

Efavirenz Repurposing Challenges: A Novel Nanomicelle-Based Antiviral Therapy Against Mosquito-Borne Flaviviruses

by Sofía Maldonado, Pedro Fuentes, Ezequiel Bernabeu, Facundo Bertera, Javier Opezzo, Eduardo Lagomarsino, Hyun J. Lee, Fleming Martínez Rodríguez, Marcelo R. Choi, María Jimena Salgueiro, Elsa B. Damonte, Christian Höcht, Marcela A. Moretton, Claudia S. Sepúlveda and Diego A. Chiappetta

Pharmaceutics 2025, 17(2), 241; https://doi.org/10.3390/pharmaceutics17020241 - 12 Feb 2025

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Abstract

Background/Objective: World Health Organization latest statistics state that 17% of infectious diseases are transmitted by vectors, causing more than 700,000 deaths each year. Particularly, dengue (DENV), Zika (ZIKV) and yellow fever (YFV) viral infections have generated international awareness due to their epidemic proportion [...] Read more.

Background/Objective: World Health Organization latest statistics state that 17% of infectious diseases are transmitted by vectors, causing more than 700,000 deaths each year. Particularly, dengue (DENV), Zika (ZIKV) and yellow fever (YFV) viral infections have generated international awareness due to their epidemic proportion and risks of international spread. In this framework, the repositioning strategy of Efavirenz (EFV) represents a key clinical feature to improve different antiviral therapies. Therefore, the development of Soluplus^®-based nanomicelles (NMs) loaded with EFV (10 mg/mL) for optimized oral pharmacotherapy against ZIKV, DENV and YFV infections was investigated. Methods: EFV-NMs were obtained by an acetone diffusion technique. Micellar size and in vitro micellar interaction with mucin were assessed by dynamic light scattering. In vitro cytocompatibility was investigated in A549 and Vero cells and micellar in vitro antiviral activity against ZIKV, DENV and YFV was evaluated. In vivo oral bioavailability and histological studies were assessed in Wistar rats. Results: EFV encapsulation within Soluplus^® NMs increased the drug’s apparent aqueous solubility up to 4803-fold with a unimodal micellar size distribution and a micellar size of ~90 nm at 25 and 37 °C. Micellar in vitro interaction with mucin was also assessed in a pH range of 1.2–7.5 and its storage micellar physicochemical stability at 4 °C was confirmed over 2 years. In vitro cytocompatibility assays in A549 and Vero cells confirmed that EFV micellar dispersions resulted in safe nanoformulations. Interestingly, EFV-loaded NMs exhibited significantly higher in vitro antiviral activity compared with EFV solution for all the tested flaviviruses. In addition, the selectivity index (SI) values reveal that EFV-loaded NMs exhibited considerably more biological efficacy compared to EFV solution in A549 and Vero cell lines and for each viral infection (SI > 10). Further, the drug pharmacokinetics parameters were enhanced after the oral administration of EFV-loaded NMs, being biocompatible by not causing damage in the gastrointestinal segments. Conclusions: Overall, our EFV nanoformulation highlighted its potential as a novel drug delivery platform for optimized ZIKV, DENV and YFV antiviral therapy. Full article

(This article belongs to the Special Issue Cutting-Edge Drug Delivery and Nanomedicine: Innovations in Hybrid Systems, Theranostics and Targeted Therapies)

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19 pages, 3262 KiB

Open AccessReview

An Insight to Nanoliposomes as Smart Radiopharmaceutical Delivery Tools for Imaging Atherosclerotic Plaques: Positron Emission Tomography Applications

by Reabetswe Sebatana, Kahwenga D. Kudzai, Allan Magura, Amanda Mdlophane, Jan Rijn Zeevaart, Mike Sathekge, Maryke Kahts, Sipho Mdanda and Bwalya Angel Witika

Pharmaceutics 2025, 17(2), 240; https://doi.org/10.3390/pharmaceutics17020240 - 12 Feb 2025

Viewed by 370

Abstract

Atherosclerosis is a chronic progressive disease which is known to cause acute cardiovascular events as well as cerebrovascular events with high mortality. Unlike many other diseases, atherosclerosis is often diagnosed only after an acute or fatal event. At present, the clinical problems of [...] Read more.

Atherosclerosis is a chronic progressive disease which is known to cause acute cardiovascular events as well as cerebrovascular events with high mortality. Unlike many other diseases, atherosclerosis is often diagnosed only after an acute or fatal event. At present, the clinical problems of atherosclerosis mainly involve the difficulty in confirming the plaques or identifying the stability of the plaques in the early phase. In recent years, the development of nanotechnology has come with various advantages including non-invasive imaging enhancement, which can be studied for the imaging of atherosclerosis. For targeted imaging and atherosclerosis treatment, nanoliposomes provide enhanced stability, drug administration, extended circulation, and less toxicity. This review discusses the current advances in the development of tailored liposomal nano-radiopharmaceutical-based techniques and their applications to atherosclerotic plaque diagnosis. This review further highlights liposomal nano-radiopharmaceutical localisation and biodistribution—key processes in the pathophysiology of atherosclerosis. Finally, this review discusses the direction and future of liposomal nano-radiopharmaceuticals as a potential clinical tool for the assessment and diagnosis of atherosclerotic plaque. Full article

(This article belongs to the Special Issue Targeted Nanoradiopharmaceuticals as a Molecular Approach for Theranostic Applications)

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24 pages, 5579 KiB

Open AccessArticle

Uptake and Inhibition of P-Glycoprotein-Mediated Efflux Evaluation of Encapsulated Methotrexate Chitosan and Hypromellose Phthalate Nanoparticles for Potential Glioblastoma Treatment

by Valéria de Moura Leite Naves, Rafaela Franco Dias Bruzadelli, Marisa Ionta, Maria Palmira Daflon Gremião, Liliane Neves Pedreiro, Gislaine Ribeiro Pereira and Flávia Chiva Carvalho

Pharmaceutics 2025, 17(2), 239; https://doi.org/10.3390/pharmaceutics17020239 - 12 Feb 2025

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Abstract

Background: Methotrexate (MTX), a folic acid antagonist used in chemotherapy, faces limitations due to cancer cell resistance, high toxicity, and low bioavailability. Objective: This study developed nanoparticles (NPs) of chitosan (QS) and hydroxypropylmethylcellulose phthalate (HPMCP) to encapsulate MTX for potential effect investigation on [...] Read more.

Background: Methotrexate (MTX), a folic acid antagonist used in chemotherapy, faces limitations due to cancer cell resistance, high toxicity, and low bioavailability. Objective: This study developed nanoparticles (NPs) of chitosan (QS) and hydroxypropylmethylcellulose phthalate (HPMCP) to encapsulate MTX for potential effect investigation on glioblastoma cell targeting and P-gp efflux inhibition. Method: NPs were produced by the polyelectrolyte complexation method and were characterized by DLS, PDI, DSC, FTIR, PXRD, MEV, drug release profile, and an in vitro mucoadhesion test. Cell viability, flow cytometry, and LSCM using U251MG (glioblastoma) and CCD 1059Sk (fibroblasts) cells were used to evaluate glioblastoma and the P-gp efflux effect. Results: NPPM29 (QS3:1) showed 91.72% encapsulation efficiency, a mean diameter of 452.6 nm, and a zeta potential of +22.5 mV. DSC, FTIR, and PXRD confirmed the QS-HPMCP supramolecular interaction. Liquid falling mucoadhesion tests demonstrated strong retention of NPPM29 (84%) compared to free MTX (10.5%). In vitro release studies indicated controlled drug release at pH 7.4. Cytotoxicity assays in U251MG revealed enhanced efficacy of NPPM29 (IC₅₀ = 68.79 µg/mL) compared to free MTX (IC₅₀ = 80.54 µg/mL), with minimal impact on fibroblasts, confirming tumor specificity. Flow cytometry and LSCM confirmed improved cellular internalization and P-gp inhibition. Conclusions: These findings highlight the potential of MTX-QS-HPMCP-NPs for glioblastoma therapy. Full article

(This article belongs to the Special Issue Methotrexate-Based Drug Delivery Systems: Advances in Disease Treatment)

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33 pages, 2566 KiB

Open AccessReview

Advances in Oral Biomacromolecule Therapies for Metabolic Diseases

by Qiuxia Jiao, Yuan Huang, Jinhan He and Yining Xu

Pharmaceutics 2025, 17(2), 238; https://doi.org/10.3390/pharmaceutics17020238 - 12 Feb 2025

Viewed by 440

Abstract

Metabolic diseases like obesity and diabetes are on the rise, and therapies with biomacromolecules (such as proteins, peptides, antibodies, and oligonucleotides) play a crucial role in their treatment. However, these drugs are traditionally injected. For patients with chronic diseases (e.g., metabolic diseases), long-term [...] Read more.

Metabolic diseases like obesity and diabetes are on the rise, and therapies with biomacromolecules (such as proteins, peptides, antibodies, and oligonucleotides) play a crucial role in their treatment. However, these drugs are traditionally injected. For patients with chronic diseases (e.g., metabolic diseases), long-term injections are accompanied by inconvenience and low compliance. Oral administration is preferred, but the delivery of biomacromolecules is challenging due to gastrointestinal barriers. In this article, we introduce the available biomacromolecule drugs for the treatment of metabolic diseases. The gastrointestinal barriers to oral drug delivery and strategies to overcome these barriers are also explored. We then discuss strategies for alleviating metabolic defects, including glucose metabolism, lipid metabolism, and energy metabolism, with oral biomacromolecules such as insulin, glucagon-like peptide-1 receptor agonists, proprotein convertase subtilisin/kexin type 9 inhibitors, fibroblast growth factor 21 analogues, and peptide YY analogues. Full article

(This article belongs to the Special Issue New Strategies to Improve Oral Drug Delivery for Disease Treatment)

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14 pages, 2555 KiB

Open AccessArticle

Quantifying Heart Rate Changes After Delta-9-Tetrahydrocannabinol Administration Using a PBPK-PD Model in Healthy Adults

by Lixuan Qian and Zhu Zhou

Pharmaceutics 2025, 17(2), 237; https://doi.org/10.3390/pharmaceutics17020237 - 12 Feb 2025

Viewed by 302

Abstract

Background: As cannabis becomes legal in several U.S. states, the risk of THC-induced tachycardia increases. This study aimed to develop and verify a physiologically based pharmacokinetic–pharmacodynamic (PBPK-PD) model to assess the impact of THC and its active metabolite, 11-hydroxy-THC (11-OH-THC), on the [...] Read more.

Background: As cannabis becomes legal in several U.S. states, the risk of THC-induced tachycardia increases. This study aimed to develop and verify a physiologically based pharmacokinetic–pharmacodynamic (PBPK-PD) model to assess the impact of THC and its active metabolite, 11-hydroxy-THC (11-OH-THC), on the heart rate of healthy adults. Methods: A PBPK-PD model for intravenous (IV) 11-OH-THC administration was first developed. Secondly, a PBPK-PD model for IV THC, combined with the metabolized 11-OH-THC, was established, verified, and validated. Direct PD models driven by the plasma, brain, and heart concentrations of THC and 11-OH-THC predicted using our previously verified PBPK model were tested for model development. Finally, the risks of tachycardia at a rest condition from various doses of oral and inhaled THC were simulated for 500 individuals aged 18–65 years, with a sex ratio of 1:1 and a baseline heart rate of 70 beats per minute. Results: The PD model was best described by a direct nonlinear E_max model driven by the sum of the total THC and 11-OH-THC concentrations in their effect compartments linked to their heart compartments. In 42 simulated dosing regimens with THC doses ranging from 2 to 69.4 mg, 97% of the observed heart rates or heart rate changes following THC administration fell within the 5th to 95th percentiles of the model-predicted values. Similarly, for two simulated 11-OH-THC IV doses, 93% of the observations fell within this range. Simulations indicated that half of the simulated population would experience tachycardia at doses of 60 mg and 15 mg of THC for oral and inhaled administration, respectively. The simulated risks of tachycardia based on specific conditions should be interpreted with caution. Conclusions: Our verified PBPK-PD model successfully describes the heart rate changes in healthy adults after IV, oral, and inhaled THC administration. This model provides a tool to predict the effects of THC and its primary metabolite on heart rates, offering valuable insights for assessing the risk of tachycardia in both clinical and recreational cannabis use. Full article

(This article belongs to the Special Issue Mechanism-Based Pharmacokinetic and Pharmacodynamic Modeling)

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21 pages, 754 KiB

Open AccessReview

Pharmacokinetics of Non-Psychotropic Phytocannabinoids

by Mariana Lacerda, Andreia Carona, Sara Castanheira, Amílcar Falcão, Joana Bicker and Ana Fortuna

Pharmaceutics 2025, 17(2), 236; https://doi.org/10.3390/pharmaceutics17020236 - 12 Feb 2025

Viewed by 364

Abstract

Cannabinoids are widely recognized for their potential therapeutic effects, making them significant and valuable candidates for medical research and applications across various fields. This review aims to analyze the pharmacokinetics of Cannabidiol (CBD), Cannabigerol (CBG), and Cannabichromene (CBC), along with their corresponding acidic [...] Read more.

Cannabinoids are widely recognized for their potential therapeutic effects, making them significant and valuable candidates for medical research and applications across various fields. This review aims to analyze the pharmacokinetics of Cannabidiol (CBD), Cannabigerol (CBG), and Cannabichromene (CBC), along with their corresponding acidic forms, Cannabidiolic acid (CBDA), Cannabigerolic acid (CBGA), and Cannabichromenic acid (CBCA). Among these cannabinoids, CBD is the most extensively studied. Nevertheless, research involving all the mentioned cannabinoids has shown that their pharmacokinetic parameters are highly variable, depending significantly on factors such as dose, formulation, route of administration, and diet. Furthermore, challenges such as brain penetration and first-pass metabolism have been highlighted. In conclusion, this review demonstrates significant progress in understanding the pharmacokinetics of non-psychotropic cannabinoids. However, it also underscores the need for further research, particularly on CBG, CBC, and their respective acidic forms, with the most significant gap being in clinical investigations. Expanding these studies is essential to facilitate their optimized use in medical treatments. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug–Drug Interactions of Novel Psychotropic Drugs)

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14 pages, 2885 KiB

Open AccessArticle

New Eye Drop Formulation Based on Desonide and Xanthan Gum in Dry Eye Disease: Nonclinical Studies

by Santa Viola, Luca Rosario La Rosa, Giuseppe De Pasquale, Manuela Santonocito, Donato Spina, Ilenia Abbate, Francesco Giuliano, Maria Cristina Curatolo, Maria Grazia Mazzone and Cristina Zappulla

Pharmaceutics 2025, 17(2), 235; https://doi.org/10.3390/pharmaceutics17020235 - 12 Feb 2025

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Abstract

Background/Objectives: A novel ophthalmic formulation, XanterDES, containing 0.2% xanthan gum and 0.025% desonide sodium phosphate (DES), was developed to alleviate ocular surface discomfort and irritation. This study aimed to evaluate its pharmacodynamic properties and to characterize its rheological behavior and mucoadhesive characteristics, compared [...] Read more.

Background/Objectives: A novel ophthalmic formulation, XanterDES, containing 0.2% xanthan gum and 0.025% desonide sodium phosphate (DES), was developed to alleviate ocular surface discomfort and irritation. This study aimed to evaluate its pharmacodynamic properties and to characterize its rheological behavior and mucoadhesive characteristics, compared to another formulation containing 0.2% hyaluronic acid and 0.001% hydrocortisone (HYD). Methods: A rabbit (New Zealand White) model of LPS-induced uveitis was used to test different concentrations of DES on ocular markers of inflammation. The efficacy of XanterDES and HYD on induced dry eye was evaluated by assessing tear volume and corneal damage in C57BL/6 mice exposed to a controlled environmental chamber. The rheological and mucoadhesive properties of XanterDES and HYD were assessed using a HAAKE RheoStress RS600 rheometer and a TA-XT2 texture analyzer, respectively. Results: In the uveitis model, unlike DES 0.25%, a low concentration of 0.025% DES showed a significant inhibitory activity localized to the eye surface and effectively reduced corneal edema. In the dry eye model, XanterDES demonstrated superior efficacy compared to HYD, effectively preventing both tear volume reduction and corneal damage. XanterDES also demonstrated pseudoplastic and enhanced mucoadhesive properties compared to HYD. Conclusions: The ancillary anti-inflammatory effects of a low dose of DES combined with the biophysical properties of xanthan gum are supportive of a favorable therapeutic profile, promoting the maintenance or restoration of ocular surface homeostasis while minimizing the risk of adverse effects typically associated with standard-dose corticosteroids. The comparison with another low-dose corticosteroid highlights the superiority of XanterDES in pharmacodynamic and biophysical performance. Full article

(This article belongs to the Special Issue Unveiling New Insights and Treatment Options for Ocular Surface Diseases)

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11 pages, 1574 KiB

Open AccessArticle

CLEC3A-Derived Antimicrobial Peptides Reduce Staphylococcus aureus Bacterial Counts in an In Vivo Biomaterial-Associated Infection Mouse Model

by Denise Meinberger, Gabriele Hermes, Bent Brachvogel, Gerhard Sengle, Dzemal Elezagic, Annika Roth, Johannes Ruthard, Thomas Streichert and Andreas R. Klatt

Pharmaceutics 2025, 17(2), 234; https://doi.org/10.3390/pharmaceutics17020234 - 12 Feb 2025

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Abstract

Background/Objectives: Biomaterials are an essential part of healthcare for both diagnostic and therapeutic procedures. Although some biomaterials possess antimicrobial properties, introducing biomaterial into the body may lead to infections due to bacterial adhesion on their surfaces and still poses a major clinical problem. [...] Read more.

Background/Objectives: Biomaterials are an essential part of healthcare for both diagnostic and therapeutic procedures. Although some biomaterials possess antimicrobial properties, introducing biomaterial into the body may lead to infections due to bacterial adhesion on their surfaces and still poses a major clinical problem. Peptides derived from the human cartilage-specific C-type lectin domain family 3 member A (CLEC3A) show a potent antimicrobial effect. In addition, coating titanium, a commonly used prosthetic material, with the CLEC3A-derived AMPs HT-47 and WRK-30 greatly reduces the number of adherent bacteria in vitro. The aim of this study was to evaluate the effectiveness of CLEC3A-derived peptides HT-47 and WRK-30 in reducing bacterial adhesion and mitigating infection in vivo in a murine biomaterial-associated infection model. Methods: To do so, an in vivo mouse infection model was used, where titanium plates—either uncoated or coated with chimeric CLEC3A-derived peptides TiBP-HT-47 and TiBP-WRK-30—were implanted subcutaneously into mice. This was followed by the introduction of Staphylococcus aureus bacterial cultures to induce a biomaterial-associated infection. After 24 h, the titanium plates, surrounding tissue, and mice blood samples were investigated. Results: CLEC3A-coated titanium plates lead to a significantly lower bacterial count than uncoated ones. Additionally, they prevent the infection from spreading to the surrounding tissue. Moreover, mice with CLEC3A-coated implants display lower IL-6 serum levels and therefore decreased systemic inflammation. Conclusions: In conclusion, in this biomaterial-associated infection mouse-model, CLEC3A-derived peptides show in vivo antimicrobial activity by reducing bacterial burden on biomaterial and wound tissue and decreasing systemic inflammation, making them promising candidates for clinical applications. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Their Potential Pharmaceutical Applications)

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15 pages, 2919 KiB

Open AccessArticle

Toxicity, Half-Life and Antitumor Activity of Phenyl 4-(2-Oxo-3-alkylimidazolidin-1-yl)benzenesulfonates as Novel Antimitotic CYP1A1-Targeted Prodrugs in Female Mouse Models

by Atziri Corin Chavez Alvarez, Chahrazed Bouzriba, Vincent Ouellette, Mathieu Gagné-Boulet, Alexandre Patenaude, Sylvie Pilote, René C.-Gaudreault, Chantale Simard and Sébastien Fortin

Pharmaceutics 2025, 17(2), 233; https://doi.org/10.3390/pharmaceutics17020233 - 11 Feb 2025

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Abstract

Background/Objectives: Chemoresistance of breast cancers (BCs) is a major impediment to current chemotherapeutics that urges the development of new drugs and new therapeutic approaches. To that end, phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were recently prepared to fulfill some of the unmet needs with classic [...] Read more.

Background/Objectives: Chemoresistance of breast cancers (BCs) is a major impediment to current chemotherapeutics that urges the development of new drugs and new therapeutic approaches. To that end, phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were recently prepared to fulfill some of the unmet needs with classic chemotherapeutics. PAIB-SOs are prodrugs bioactivated into potent antimitotics by the cytochrome P450 1A1 (CYP1A1), which is a frequent enzyme in resistant BC cells, but mostly missing in normal cells. Our screening program studies of PAIB-SO chemolibraries selected three prototypical PAIB-SOs as antimitotic prodrugs amenable for studies using BC animal models. Methods: Healthy female CD1^® IGS mice were treated with three prototypical PAIB-SOs, namely CEU-835, -934, and -938, for the determination of their toxicity and half-lives. Moreover, MCF7 tumor-bearing CD1-Foxn1^nu Nude female mice were treated with the three prototypical PAIB-SOs for the determination of their antitumor activity. Results: Herein, we show that multi-intravenous administrations of CEU-835, -934, and -938 at their maximal solubilities are well tolerated in healthy female CD1^® IGS mice, as depicted by the evaluation of distress behaviors, organ necropsy, total blood cell count, and histology. Moreover, the half-life of CEU-835, -934, and -938 administered intravenously in healthy CD1^® IGS female mice were 8.1, 23.2, and 21.5 h, respectively. Finally, their intravenous administrations of CEU-934 and -938 decreased MCF7 tumor growth as efficiently as paclitaxel in MCF7 tumor-bearing CD1-Foxn1^nu Nude mouse model. Conclusions: overall, our study demonstrated for the first time that pentyl-bearing PAIB-SOs are new CYP1A1-dependent prodrugs efficiently decrease breast cancer tumor growth, and show no side effects at their pharmacological concentration in mouse models. Full article

(This article belongs to the Special Issue Prodrugs and Molecular Hybrids as Innovative Strategies in Medicinal Chemistry)

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26 pages, 3377 KiB

Open AccessArticle

Intravenous Nanoemulsions Loaded with Phospholipid Complex of a Novel Pyrazoloquinolinone Ligand for Enhanced Brain Delivery

by Tijana Stanković, Tanja Ilić, Branka Divović Matović, Milos Petkovic, Vladimir Dobričić, Ivan Jančić, Biljana Bufan, Kristina Jezdić, Jelena Đoković, Ivana Pantelić, Danijela Randjelović, Dishary Sharmin, James M. Cook, Miroslav M. Savić and Snežana Savić

Pharmaceutics 2025, 17(2), 232; https://doi.org/10.3390/pharmaceutics17020232 - 11 Feb 2025

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Abstract

Background/Objectives: The novel pyrazoloquinolinone ligand CW-02-79 shows a unique profile of selective binding to σ2 receptors, but its poor solubility in both water and lipids makes its research and development a burdensome task. We aimed to develop a phospholipid-complex-based nanoemulsion formulation containing [...] Read more.

Background/Objectives: The novel pyrazoloquinolinone ligand CW-02-79 shows a unique profile of selective binding to σ2 receptors, but its poor solubility in both water and lipids makes its research and development a burdensome task. We aimed to develop a phospholipid-complex-based nanoemulsion formulation containing CW-02-79 suitable for intravenous administration in preclinical research. Methods: The decorated and undecorated nanoemulsions were formulated and subjected to detailed physiochemical characterization. The delivery and exposure to CW-02-79 from selected nanoemulsions were examined in the in vitro blood–brain barrier model based on human-induced pluripotent stem-cell-derived microvascular endothelial cells, astrocytes, and pericytes, and in vivo neuropharmacokinetic study in rats, respectively. Results: The developed biocompatible nanoemulsions loaded with a CW-02-79—phospholipid complex at a mass ratio of 1:10 exhibited a small droplet size and narrow size distribution, with satisfactory physicochemical stability during steam sterilization and short-term storage at 25 °C. The analysis of protein binding interactions revealed that the PEGylated nanoemulsions had fewer observable interactions compared to the undecorated nanoemulsions, especially when 0.2% DSPE-PEG2000 and 0.1% DSPE-PEG2000-mannose were combined. An in vitro BBB study demonstrated that a substantial part of CW-02-79 present in the applied nanoemulsion is able to permeate the barrier. The quantification of CW-02-79 in plasma/brain homogenate and calculated pharmacokinetic parameters confirmed good systemic and brain availability after intravenous administration. There were subtle differences in the pharmacokinetic parameters in favor of a dual surface-functionalized nanoemulson containing the glucose transporter-1-targeting ligand (mannose). Conclusions: The developed and characterized nanoemulsions enable substantial brain exposure to CW-02-79 as a prerequisite for a pharmacologically and clinically relevant selective modulation of σ2 receptors. Full article

(This article belongs to the Special Issue Engineering and Characterisation of Novel Nanomedicine Formulations, 2nd Edition)

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18 pages, 3570 KiB

Open AccessArticle

Development, Safety, and Therapeutic Evaluation of Voriconazole-Loaded Zein–Pectin–Hyaluronic Acid Nanoparticles Using Alternative In Vivo Models for Efficacy and Toxicity

by Margani Taise Fin, Kelvin Sousa dos Santos, Marcos William de Lima Gualque, Rafaela Cristine dos Santos, Natália Cristina Morici Aoki, Marcos Ereno Auler, Ana Marisa Fusco-Almeida, Maria José Soares Mendes-Gianinni and Rubiana Mara Mainardes

Pharmaceutics 2025, 17(2), 231; https://doi.org/10.3390/pharmaceutics17020231 - 11 Feb 2025

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Abstract

Background/Objectives: Fungal infections caused by Candida species remain a significant clinical challenge, exacerbated by limitations in current antifungal therapies, including toxicity and poor bioavailability. This study aimed to develop and evaluate voriconazole-loaded zein–pectin–hyaluronic acid nanoparticles (ZPHA-VRC NPs) as a novel drug delivery [...] Read more.

Background/Objectives: Fungal infections caused by Candida species remain a significant clinical challenge, exacerbated by limitations in current antifungal therapies, including toxicity and poor bioavailability. This study aimed to develop and evaluate voriconazole-loaded zein–pectin–hyaluronic acid nanoparticles (ZPHA-VRC NPs) as a novel drug delivery system to enhance efficacy and reduce toxicity. Alternative in vitro and in vivo models were utilized to assess the safety and therapeutic potential of the nanoparticles. Methods: ZPHA-VRC NPs were prepared using a nanoprecipitation method and characterized for particle size, polydispersity index, zeta potential, and encapsulation efficiency. Antifungal activity was assessed via MIC assays against Candida albicans, C. krusei, and C. parapsilosis. Cytotoxicity was evaluated on Vero cells, while in vivo toxicity and efficacy were assessed using Galleria mellonella and Caenorhabditis elegans models. The therapeutic efficacy was further evaluated in an infected Caenorhabditis elegans model using survival and health scores. Results: ZPHA-VRC nanoparticles exhibited favorable physicochemical properties, including a particle size of approximately 192 nm, a polydispersity index of 0.079, a zeta potential of −24 mV, and an encapsulation efficiency of 34%. The nanoparticles retained antifungal activity comparable to free voriconazole while significantly reducing cytotoxicity. In vivo studies using G. mellonella and C. elegans demonstrated that ZPHA-VRC NPs markedly improved survival rates, reduced fungal burden, and enhanced health scores in infected models, outperforming the free drug. Additionally, the nanoparticles exhibited a superior safety profile, minimizing systemic toxicity while maintaining therapeutic efficacy. Conclusions: ZPHA-VRC NPs offer a safer and more effective delivery system for VRC, addressing the limitations of conventional formulations. The integration of alternative efficacy and safety models highlights their value in preclinical research. Full article

(This article belongs to the Special Issue Alternative Animal Models for Nanoparticle-Based Drug Delivery: Efficacy and Toxicity Assessment)

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16 pages, 2698 KiB

Open AccessArticle

Exploring the Anticancer Potential of NO-Donor Oxadiazole Assemblies Against Malignant Pleural Mesothelioma

by Irina A. Stebletsova, Alexander A. Larin, Egor M. Matnurov, Ivan V. Ananyev, Maria V. Babak and Leonid L. Fershtat

Pharmaceutics 2025, 17(2), 230; https://doi.org/10.3390/pharmaceutics17020230 - 10 Feb 2025

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Abstract

Background: Nitric oxide (NO) has been linked to the pathogenesis of asbestos-related pleural diseases, including an extremely aggressive cancer called malignant pleural mesothelioma (MPM). Given that MPM cells are characterized by a higher expression of NO synthases and elevated NO production relative to [...] Read more.

Background: Nitric oxide (NO) has been linked to the pathogenesis of asbestos-related pleural diseases, including an extremely aggressive cancer called malignant pleural mesothelioma (MPM). Given that MPM cells are characterized by a higher expression of NO synthases and elevated NO production relative to normal cells, the use of NO-donor compounds could potentially saturate the cancerous cells with NO, triggering their death. Methods: We developed a novel class of NO prodrugs by merging two NO-releasing components, 1,2,5-oxadiazole 2-oxides (furoxans) and 1,2,4-oxadiazoles, and studied their NO-releasing characteristics in a time-dependent manner using the Griess assay. The cytotoxicity against two human MPM cell lines and non-cancerous lung fibroblasts was evaluated using a colorimetric MTT assay. Results: All compounds exhibited excellent NO-donating properties, surpassing the capacity of two reference NO donor compounds, 3-carbamoyl-4-(hydroxymethyl)furoxan (CAS-1609) and 4-ethoxy-3-phenylsulphonylfuroxan (CHF-2363), by at least 1.5–3 times. All oxadiazole hybrids demonstrated high cytotoxicity against MPM cell lines in a low micromolar range, comparable or higher than the cytotoxicity of the standard-of-care drug cisplatin. Conclusions: Notably, the novel compounds displayed a markedly greater selectivity towards cancerous cells than cisplatin when compared with non-cancerous lung fibroblasts, aligning with the intended design. Full article

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

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22 pages, 1489 KiB

Open AccessReview

Bioadhesive Nanoparticles in Topical Drug Delivery: Advances, Applications, and Potential for Skin Disorder Treatments

by Rashed M. Almuqbil and Bandar Aldhubiab

Pharmaceutics 2025, 17(2), 229; https://doi.org/10.3390/pharmaceutics17020229 - 10 Feb 2025

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Abstract

Skin disorders are the fourth most common cause of all diseases, which affect nearly one-third of the world’s population. Topical drug delivery can be effective in treating a range of skin disorders, including microbial infections, skin cancer, dermatitis, burn injury, wounds, and psoriasis. [...] Read more.

Skin disorders are the fourth most common cause of all diseases, which affect nearly one-third of the world’s population. Topical drug delivery can be effective in treating a range of skin disorders, including microbial infections, skin cancer, dermatitis, burn injury, wounds, and psoriasis. Bioadhesive nanoparticles (BNPs) can serve as an efficient topical drug delivery system as they can serve dual purposes as bioadhesives and nanocarriers, which can mediate targeted drug delivery, prolong retention time, and deepen drug penetration through skin layers. There is an increasing demand for BNP-based applications in medicine because of their various advantages, including biodegradability, flexibility, biocompatibility, and enhanced adhesive strength. A number of BNPs have already been developed and evaluated as potential topical drug delivery systems. In addition, a range of studies have already been carried out to evaluate the potential of BNPs in the treatment of various skin disorders, including atopic dermatitis, irritant contact dermatitis, skin cancer, psoriasis, microbial infections, wounds, and severe burn injuries. This review article is timely and unique, because it provides an extensive and unique summary of the recent advances of BNPs in the treatment of wide-ranging skin disorders. Moreover, this review also provides a useful discussion on the bioadhesion mechanism and various biopolymers that can be used to prepare BNPs. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems for the Treatment of Skin Disorders)

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Pharmaceutics, Volume 17, Issue 2 (February 2025) – 120 articles

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