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Pharmaceutics
Volume 17
Issue 7
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Pharmaceutics, Volume 17, Issue 7 (July 2025) – 146 articles

Cover Story (view full-size image): Cell membranes maintain cellular integrity, regulate the transport of substances, and facilitate intercellular communication. Their complex, heterogeneous structure, composed of a lipid bilayer embedded with proteins, directly impacts biological functions. A better understanding of biological membrane composition and physical features might inspire new therapeutic strategies for many pathologies, like cancer. After describing the physico-chemical characteristics of natural membranes, this review provides an overview of the literature works reporting the rational design of drug delivery systems mimicking vesicles naturally secreted by cells. This insight may aid in the development of innovative and efficient platforms for targeted delivery. View this paper
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22 pages, 1375 KB  
Review
Polymorphic Transformations of Pharmaceutical Materials Induced by Mechanical Milling: A Review
by Mathieu Guerain and Jean-François Willart
Pharmaceutics 2025, 17(7), 946; https://doi.org/10.3390/pharmaceutics17070946 - 21 Jul 2025
Viewed by 472
Abstract
A review of the literature on polymorphic transformations by milling on pharmaceutical materials was carried out. The available information on 18 pharmaceutical materials was compiled. In particular, when data are available, the starting and final crystalline forms, their enantiotropic or monotropic relationship, the [...] Read more.
A review of the literature on polymorphic transformations by milling on pharmaceutical materials was carried out. The available information on 18 pharmaceutical materials was compiled. In particular, when data are available, the starting and final crystalline forms, their enantiotropic or monotropic relationship, the glass transition temperature of the compound and its melting temperature, the experimental observation of a transient or partial amorphization of compounds, and the transformation kinetics make it possible to suggest a two-step transformation mechanism. First, an amorphization occurs under milling of the starting polymorphic form. Secondly, a recrystallization of the amorphous form occurs towards the final form. The observed transformation kinetics are due to the fact that the recrystallization of the amorphous material towards the final form depends on the accidental formation of a cluster of this form during milling. Moreover, the observation of the transient amorphous form depends on the relative position of the glass transition temperature of the material with respect to the milling temperature. This mechanism seems to be independent of the enantiotropic or monotropic character of the polymorphic forms involved in the transformation. Full article
(This article belongs to the Collection Feature Papers in Pharmaceutical Technology)
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20 pages, 15716 KB  
Article
Dual-Action Tocilizumab-Conjugated Cisplatin Nanoparticles Overcome Chemoresistance and Metastasis in Non-Small-Cell Lung Cancer
by Yin Wang, Fanyu Wu, Tan Yang, Bin Li, Han Wang, Peng Ye and Weijie Li
Pharmaceutics 2025, 17(7), 945; https://doi.org/10.3390/pharmaceutics17070945 - 21 Jul 2025
Viewed by 614
Abstract
Background/Objectives: Cisplatin remains a cornerstone chemotherapeutic agent for non-small-cell lung cancer (NSCLC) treatment, yet its clinical utility is substantially limited by acquired resistance and the inadequate suppression of tumor metastasis. Emerging evidence implicates interleukin 6 (IL-6) as a critical mediator of chemoresistance through [...] Read more.
Background/Objectives: Cisplatin remains a cornerstone chemotherapeutic agent for non-small-cell lung cancer (NSCLC) treatment, yet its clinical utility is substantially limited by acquired resistance and the inadequate suppression of tumor metastasis. Emerging evidence implicates interleukin 6 (IL-6) as a critical mediator of chemoresistance through cancer stem cell (CSC) enrichment and metastasis promotion via epithelial–mesenchymal transition (EMT) induction, ultimately contributing to cisplatin therapy failure. This study sought to address these challenges by designing a nanoplatform with two innovative aims: (1) to achieve active tumor targeting through binding to the IL-6 receptor (IL-6R), and (2) to concurrently inhibit IL-6-mediated chemoresistance signaling pathways. Methods: A lipid–polymer hybrid nanoparticle (LPC) encapsulating cisplatin was synthesized and subsequently surface-functionalized with tocilizumab (TCZ), a monoclonal antibody that targets IL-6R. The therapeutic efficacy of this TCZ-modified nanoparticle (LPC-TCZ) was assessed through a series of in vitro and in vivo experiments, focusing on the inhibition of EMT, expression of CSC markers, tumor growth, and metastasis. Results: Systematic in vitro and in vivo evaluations revealed that LPC-TCZ synergistically attenuated both EMT progression and CSC marker expression through the targeted blockade of IL-6/STAT3 signaling. This multimodal therapeutic strategy demonstrated superior tumor growth inhibition and metastatic suppression compared to conventional cisplatin monotherapy. Conclusions: Our findings establish a nanotechnology-enabled approach to potentiate cisplatin efficacy by simultaneously countering chemoresistance mechanisms and metastatic pathways in NSCLC management. Full article
(This article belongs to the Section Biologics and Biosimilars)
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24 pages, 4254 KB  
Review
Zein-Based Nanocarriers: Advances in Oral Drug Delivery
by Yuxin Liu, Dongyu An, Xiangjian Meng, Shiming Deng and Guijin Liu
Pharmaceutics 2025, 17(7), 944; https://doi.org/10.3390/pharmaceutics17070944 - 21 Jul 2025
Viewed by 778
Abstract
Oral administration remains the preferred drug delivery route but faces formidable gastrointestinal barriers, including enzymatic degradation, solubility limitations, and poor epithelial absorption. Zein-based nanocarriers (ZBNs), derived from maize prolamin, provide a transformative platform to address these challenges. This review synthesizes recent advances in [...] Read more.
Oral administration remains the preferred drug delivery route but faces formidable gastrointestinal barriers, including enzymatic degradation, solubility limitations, and poor epithelial absorption. Zein-based nanocarriers (ZBNs), derived from maize prolamin, provide a transformative platform to address these challenges. This review synthesizes recent advances in ZBNs’ design, highlighting their intrinsic advantages: structural stability across pH gradients, self-assembly versatility, and a surface functionalization capacity. Critically, we detail how engineered ZBNs overcome key barriers, such as enzymatic/chemical protection via hydrophobic encapsulation, the enhanced mucus penetration or adhesion through surface engineering, and improved epithelial transport via ligand conjugation. Applications demonstrate their efficacy in stabilizing labile therapeutics, enhancing the solubility of BCS Class II/IV drugs, enabling pH-responsive release, and significantly boosting oral bioavailability. Remaining challenges in scalability and translational predictability warrant future efforts toward multifunctional systems, bio-interfacial modeling, and continuous manufacturing. This work positions ZBNs as a potential platform for the oral delivery of BCS Class II–IV drugs’ in the biopharmaceutics classification system. Full article
(This article belongs to the Special Issue Recent Advances in Peptide and Protein-Based Drug Delivery Systems)
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12 pages, 1498 KB  
Article
Long-Term Effect of Semaglutide on the Glomerular Filtration Rate Slope in High-Risk Patients with Diabetic Nephropathy: Analysis in Real-World Clinical Practice
by Enrique Luna, Álvaro Álvarez, Jorge Rodriguez-Sabiñón, Juan Villa, Teresa Giraldo, Maria Victoria Martín, Eva Vázquez, Noemi Fernández, Belén Ruiz, Guadalupe Garcia-Pino, Coral Martínez, Lilia Azevedo, Rosa María Diaz, Nicolas Roberto Robles and Guillermo Gervasini
Pharmaceutics 2025, 17(7), 943; https://doi.org/10.3390/pharmaceutics17070943 - 21 Jul 2025
Viewed by 657
Abstract
Background: Semaglutide, a GLP-1 receptor agonist, has shown promising nephroprotective effects in clinical trials, though real-world data on its long-term impact on renal function in high-risk diabetic nephropathy patients remain scarce. Methods: We conducted a multicenter, retrospective observational study involving 156 patients with [...] Read more.
Background: Semaglutide, a GLP-1 receptor agonist, has shown promising nephroprotective effects in clinical trials, though real-world data on its long-term impact on renal function in high-risk diabetic nephropathy patients remain scarce. Methods: We conducted a multicenter, retrospective observational study involving 156 patients with type 2 diabetes and chronic kidney disease (CKD) treated with subcutaneous semaglutide between 2019 and 2023. Inclusion required an eGFR > 15 mL/min/1.73 m2 or albuminuria > 30 mg/g and at least two years of follow-up. The primary outcome was the change in eGFR slope after semaglutide initiation. Subgroup analyses were performed based on baseline eGFR, albuminuria, and SGLT2i co-treatment. Results: In the whole study population, the median eGFR slope significantly improved from −3.29 (IQR 7.54) to −0.79 (IQR 6.01) mL/min/1.73 m2/year post-treatment (p < 0.001). Multiple linear regression showed a hazard ratio for the effect of semaglutide on the eGFR slope of 4.06 (2.43–5.68), p < 0.001. In patients with baseline eGFR < 60 mL/min/1.73 m2, the slope improved from −3.77 to −1.01 (p < 0.0001), while patients on concurrent SGLT2i therapy saw slope changes from −2.96 to −0.37 (p < 0.0001). Patients with albuminuria 30–1000 mg/g also improved from −2.96 to −0.04 (p < 0.0001); however, those > 1000 mg/g did not show a significant change (p = 0.184). Semaglutide also reduced BMI (p = 0.04), HbA1c (p = 0.002), triglycerides (p = 0.001), CRP (p = 0.003), and GGT values (p = 0.004). Conclusions: In real-world practice, semaglutide significantly attenuated renal function decline in high-risk diabetic patients, particularly those with advanced CKD or concurrent SGLT2i therapy. These findings support its nephroprotective role beyond glycemic control. Full article
(This article belongs to the Special Issue Optimizing Drug Therapy in Kidney Diseases: Effectiveness and Safety)
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4 pages, 147 KB  
Editorial
Advances in Nano-Drug Delivery for Tumor Microenvironment and Drug Resistance—Insights from the Special Issue “Nano-Drug Delivery Systems for Targeting the Tumor Microenvironment and Simultaneously Overcoming Drug Resistance Properties”
by Patrícia M. A. Silva and Odília Queirós
Pharmaceutics 2025, 17(7), 942; https://doi.org/10.3390/pharmaceutics17070942 - 21 Jul 2025
Viewed by 359
Abstract
Cancer continues to pose a major global health burden [...] Full article
(This article belongs to the Special Issue Nano-Drug Delivery Systems for Targeting the Tumor Microenvironment and Simultaneously Overcoming Drug Resistance Properties)
19 pages, 2402 KB  
Article
Wound Healing Effects of New Cream Formulations with Herbal Ingredients
by Derya Algül, Ertuğrul Kılıç, Ferda Özkan and Yasemin Yağan Uzuner
Pharmaceutics 2025, 17(7), 941; https://doi.org/10.3390/pharmaceutics17070941 - 21 Jul 2025
Viewed by 720
Abstract
Aim: To prepare two different kinds of wound care creams containing plant extracts and examine their effectiveness in comparison with a placebo cream and a commercial wound care cream, Madecassol®. Methods: The two cream formulations were developed using the [...] Read more.
Aim: To prepare two different kinds of wound care creams containing plant extracts and examine their effectiveness in comparison with a placebo cream and a commercial wound care cream, Madecassol®. Methods: The two cream formulations were developed using the same placebo cream (PC) as base cream. One formulation contained balsam of oriental sweet gum, or Levant storax, named as Levant Storax Cream (LSC); the other contained oil of Calendula, extract of St. John’s Wort, aescin (an extract of horse chestnut), and freeze-dried powder from Aloe vera (L.) Burm. f. leaf juice, designated as Complex Cream (CC). In the characterization of the creams, organoleptic properties, pH, viscosity, size distribution, and zeta potential of oil globules were measured. Furthermore, the stability of the creams was assessed under different environmental conditions. In vitro studies were performed by using an excisional wound model in rats to assess the potential of the creams for stimulating wound healing. The efficacy of LSC and CC was compared with a commercial reference cream, Madecassol® (M), and the placebo control. The study was also designed with a negative control group of rats that were not treated but handled the same way as the other treatment groups. The wound contraction rate, total skin thickness recovery, and results of histopathological parameter examinations were used to compare the effectiveness of the treatments. Results: The stability of formulated creams confirmed that they were stable for the duration of the study. In vivo studies showed that rats treated with LSC achieved the highest wound healing rates when compared with the other groups. A better response was recorded for the CC-treated population when compared to both control and placebo groups, but there was no significant difference seen in healing score between CC and M groups. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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34 pages, 6295 KB  
Article
ROS/Enzyme Dual-Responsive Drug Delivery System for Targeted Colorectal Cancer Therapy: Synergistic Chemotherapy, Anti-Inflammatory, and Gut Microbiota Modulation
by Xin Zhang, Ruonan Lian, Bingbing Fan, Lei Meng, Pengxia Zhang, Yu Zhang and Weitong Sun
Pharmaceutics 2025, 17(7), 940; https://doi.org/10.3390/pharmaceutics17070940 - 21 Jul 2025
Viewed by 601
Abstract
Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, driven by chronic inflammation, gut microbiota dysbiosis, and complex tumor microenvironment interactions. Current therapies are limited by systemic toxicity and poor tumor accumulation. This study aimed to develop a ROS/enzyme dual-responsive oral [...] Read more.
Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, driven by chronic inflammation, gut microbiota dysbiosis, and complex tumor microenvironment interactions. Current therapies are limited by systemic toxicity and poor tumor accumulation. This study aimed to develop a ROS/enzyme dual-responsive oral drug delivery system, KGM-CUR/PSM microspheres, to achieve precise drug release in CRC and enhance tumor-specific drug accumulation, which leverages high ROS levels in CRC and the β-mannanase overexpression in colorectal tissues. Methods: In this study, we synthesized a ROS-responsive prodrug polymer (PSM) by conjugating polyethylene glycol monomethyl ether (mPEG) and mesalazine (MSL) via a thioether bond. CUR was then encapsulated into PSM using thin-film hydration to form tumor microenvironment-responsive micelles (CUR/PSM). Subsequently, konjac glucomannan (KGM) was employed to fabricate KGM-CUR/PSM microspheres, enabling targeted delivery for colorectal cancer therapy. The ROS/enzyme dual-response properties were confirmed through in vitro drug release studies. Cytotoxicity, cellular uptake, and cell migration were assessed in SW480 cells. In vivo efficacy was evaluated in AOM/DSS-induced CRC mice, monitoring tumor growth, inflammatory markers (TNF-α, IL-1β, IL-6, MPO), and gut microbiota composition. Results: In vitro drug release studies demonstrated that KGM-CUR/PSM microspheres exhibited ROS/enzyme-responsive release profiles. CUR/PSM micelles demonstrated significant anti-CRC efficacy in cytotoxicity assays, cellular uptake studies, and cell migration assays. In AOM/DSS-induced CRC mice, KGM-CUR/PSM microspheres significantly improved survival and inhibited CRC tumor growth, and effectively reduced the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6) and myeloperoxidase (MPO). Histopathological and microbiological analyses revealed near-normal colon architecture and microbial diversity in the KGM-CUR/PSM group, confirming the system’s ability to disrupt the “inflammation-microbiota-tumor” axis. Conclusions: The KGM-CUR/PSM microspheres demonstrated a synergistic enhancement of anti-tumor efficacy by inducing apoptosis, alleviating inflammation, and modulating the intestinal microbiota, which offers a promising stimuli-responsive drug delivery system for future clinical treatment of CRC. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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10 pages, 2328 KB  
Article
Vertical Hot-Melt Extrusion: The Next Challenge in Innovation
by Maël Gallas, Ghouti Medjahdi, Pascal Boulet and Victoire de Margerie
Pharmaceutics 2025, 17(7), 939; https://doi.org/10.3390/pharmaceutics17070939 - 21 Jul 2025
Viewed by 478
Abstract
Background/Objectives: Hot-melt extrusion (HME) has become a key technology in pharmaceutical formulation, particularly for enhancing the solubility of poorly soluble Active Pharmaceutical Ingredients (APIs). While horizontal HME is widely adopted, vertical HME remains underexplored despite its potential benefits in footprint reduction, feeding efficiency, [...] Read more.
Background/Objectives: Hot-melt extrusion (HME) has become a key technology in pharmaceutical formulation, particularly for enhancing the solubility of poorly soluble Active Pharmaceutical Ingredients (APIs). While horizontal HME is widely adopted, vertical HME remains underexplored despite its potential benefits in footprint reduction, feeding efficiency, temperature control, and integration into continuous manufacturing. This study investigates vertical HME as an innovative approach in order to optimize drug polymer interactions and generate stable amorphous dispersions with controlled release behavior. Methods: Extrusion trials were conducted using a vertical hot-melt extruder developed by Rondol Industrie (Nancy, France). Acetylsalicylic acid (ASA) supplied by Seqens (Écully, France) was used as a model API and processed with Soluplus® and Kollidon® 12 PF (BASF, Ludwigshafen, Germany). Various process parameters (temperature, screw speed, screw profile) were explored. The extrudates were characterized by powder X-ray diffraction (PXRD) and small-angle X-ray scattering (SAXS) to evaluate crystallinity and microstructure. In vitro dissolution tests were performed under sink conditions using USP Apparatus II to assess drug release profiles. Results: Vertical HME enabled the formation of homogeneous amorphous solid dispersions. PXRD confirmed the absence of residual crystallinity, and SAXS revealed nanostructural changes in the polymer matrix influenced by drug loading and thermal input. In vitro dissolution demonstrated enhanced drug release rates compared to crystalline ASA, with good reproducibility. Conclusions: Vertical HME provides a compact, cleanable, and modular platform that supports the development of stable amorphous dispersions with controlled release. It represents a robust and versatile solution for pharmaceutical innovation, with strong potential for cost-efficient continuous manufacturing and industrial-scale adoption. Full article
(This article belongs to the Special Issue Advances in Hot Melt Extrusion Technology)
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20 pages, 19986 KB  
Article
In Situ Targeting RGD-Modified Cyclodextrin Inclusion Complex/Hydrogel Hybrid System for Enhanced Glioblastoma Therapy
by Xiaofeng Yuan, Zhenhua Wang, Pengcheng Qiu, Zhenhua Tong, Bingwen Wang, Yingjian Sun, Xue Sun, Lu Sui, Haiqiang Jia, Jiajun Wang, Haifeng Tang and Weiliang Ye
Pharmaceutics 2025, 17(7), 938; https://doi.org/10.3390/pharmaceutics17070938 - 20 Jul 2025
Viewed by 407
Abstract
Background/Objectives: Glioblastoma (GBM) remains the most aggressive primary brain tumor, characterized by high malignancy, recurrence rate, and dismal prognosis, thereby demanding innovative therapeutic strategies. In this study, we report a novel in situ targeting inclusion complex hydrogel hybrid system (DOX/RGD-CD@Gel) that integrates [...] Read more.
Background/Objectives: Glioblastoma (GBM) remains the most aggressive primary brain tumor, characterized by high malignancy, recurrence rate, and dismal prognosis, thereby demanding innovative therapeutic strategies. In this study, we report a novel in situ targeting inclusion complex hydrogel hybrid system (DOX/RGD-CD@Gel) that integrates doxorubicin (DOX) with RGD-conjugated cyclodextrin (RGD-CD) and a thermosensitive hydrogel for enhanced GBM therapy. Methods: The DOX/RGD-CD@Gel system was prepared by conjugating doxorubicin (DOX) with RGD-modified cyclodextrin (RGD-CD) and embedding it into a thermosensitive hydrogel. The drug delivery and antitumor efficacy of this system were evaluated in vitro and in vivo. Results: In vitro and in vivo evaluations demonstrated that DOX/RGD-CD@Gel significantly enhanced cytotoxicity compared to free DOX or DOX/CD formulations. The targeted delivery system effectively promoted apoptosis and inhibited cell proliferation and metastasis in GBM cells. Moreover, the hydrogel-based system exhibited prolonged drug retention in the brain, as evidenced by its temperature- and pH-responsive release characteristics. In a GBM mouse model, DOX/RGD-CD@Gel significantly suppressed tumor growth and improved survival rates. Conclusions: This study presents a paradigm of integrating a targeted inclusion complex with a thermosensitive hydrogel, offering a safe and efficacious strategy for localized GBM therapy with potential translational value. Full article
(This article belongs to the Section Drug Targeting and Design)
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45 pages, 4112 KB  
Review
Recent Advances in Nanotechnology-Based Approaches for Ferroptosis Therapy and Imaging Diagnosis in Pancreatic Cancer
by Xiaoyan Yang, Wangping Luo, Yining Wang, Yongzhong Du and Risheng Yu
Pharmaceutics 2025, 17(7), 937; https://doi.org/10.3390/pharmaceutics17070937 - 20 Jul 2025
Viewed by 768
Abstract
Pancreatic cancer is a highly lethal malignant tumor characterized by challenges in early diagnosis and limited therapeutic options, leading to an exceptionally low clinical cure rate. With the advent of novel cancer treatment paradigms, ferroptosis—a form of iron-dependent regulated cell death driven by [...] Read more.
Pancreatic cancer is a highly lethal malignant tumor characterized by challenges in early diagnosis and limited therapeutic options, leading to an exceptionally low clinical cure rate. With the advent of novel cancer treatment paradigms, ferroptosis—a form of iron-dependent regulated cell death driven by lipid peroxidation—has emerged as a promising therapeutic strategy, particularly for tumors harboring RAS mutations. However, the poor bioavailability and insufficient tumor-targeting capabilities of conventional drugs constrain the efficacy of ferroptosis-based therapies. Recent advancements in nanotechnology and imaging-guided treatments offer transformative solutions through targeted drug delivery, real-time monitoring of treatment efficacy, and multimodal synergistic strategies. This article aims to elucidate the mechanisms underlying ferroptosis in pancreatic cancer and to summarize the latest identified therapeutic targets for ferroptosis in this context. Furthermore, it reviews the recent progress in nanotechnology-based ferroptosis therapy for pancreatic cancer, encompassing ferroptosis monotherapy, synergistic ferroptosis therapy, and endogenous ferroptosis therapy. Subsequently, the integration of imaging-guided nanotechnology in ferroptosis therapy is summarized. Finally, this paper discusses innovative strategies, such as stroma-targeted ferroptosis therapy, immune-ferroptosis synergy, and AI-driven nanomedicine development, offering new insights and directions for future research in pancreatic cancer treatment. Full article
(This article belongs to the Special Issue Recent Advances in Nanotechnology-Based Approaches for Pharmaceutical Applications, 2nd Edition)
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39 pages, 1536 KB  
Review
Transdermal Drug Delivery Systems: Methods for Enhancing Skin Permeability and Their Evaluation
by Elena O. Bakhrushina, Marina M. Shumkova, Yana V. Avdonina, Arsen A. Ananian, Mina Babazadeh, Ghazaleh Pouya, Viktoria V. Grikh, Irina M. Zubareva, Svetlana I. Kosenkova, Ivan I. Krasnyuk, Jr. and Ivan I. Krasnyuk
Pharmaceutics 2025, 17(7), 936; https://doi.org/10.3390/pharmaceutics17070936 - 20 Jul 2025
Cited by 1 | Viewed by 2020
Abstract
Transdermal drug delivery (TDD) is an increasingly important non-invasive method for administering active pharmaceutical ingredients (APIs) through the skin barrier, offering advantages such as improved therapeutic efficacy and reduced systemic side effects. As demand increases for patient-friendly and minimally invasive treatment options, TDD [...] Read more.
Transdermal drug delivery (TDD) is an increasingly important non-invasive method for administering active pharmaceutical ingredients (APIs) through the skin barrier, offering advantages such as improved therapeutic efficacy and reduced systemic side effects. As demand increases for patient-friendly and minimally invasive treatment options, TDD has attracted substantial attention in research and clinical practice. This review summarizes recent advances enhancing skin permeability through chemical enhancers (e.g., ethanol, fatty acids, terpenes), physical (e.g., iontophoresis, microneedles, sonophoresis), and nanotechnological methods (e.g., liposomes, ethosomes, solid lipid nanoparticles, and transferosomes). A comprehensive literature analysis, including scientific publications, regulatory guidelines, and patents, was conducted to identify innovative methods and materials used to overcome the barrier properties of the stratum corneum. Special emphasis was placed on in vitro, ex vivo, and in vivo evaluation techniques for such as Franz diffusion cells for assessing drug permeation and skin interactions. The findings highlight the importance of active physical methods, passive nanostructured systems, and chemical penetration enhancers. In conclusion, integrating multiple analytical techniques is essential for the rational design and optimization of effective transdermal drug delivery systems. Full article
(This article belongs to the Special Issue Dermal and Transdermal Drug Delivery Systems)
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23 pages, 11160 KB  
Article
Modeling the Influence of CYP2C9 and ABCB1 Gene Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Losartan
by Dmitry Babaev, Elena Kutumova and Fedor Kolpakov
Pharmaceutics 2025, 17(7), 935; https://doi.org/10.3390/pharmaceutics17070935 - 20 Jul 2025
Viewed by 506
Abstract
Background/Objectives: Hypertension is a pathological condition characterized by elevated systolic and/or diastolic blood pressure. A range of pharmacotherapeutic agents are available to treat this condition and prevent complications, including the angiotensin II AT1-receptor blocker losartan. Following oral administration, losartan is exposed to a [...] Read more.
Background/Objectives: Hypertension is a pathological condition characterized by elevated systolic and/or diastolic blood pressure. A range of pharmacotherapeutic agents are available to treat this condition and prevent complications, including the angiotensin II AT1-receptor blocker losartan. Following oral administration, losartan is exposed to a variety of enzymes that facilitate its metabolism or transportation. The structural characteristics of the genes that encode the enzymes may potentially impact the pharmacokinetics and pharmacodynamics of losartan, thereby modulating its effects on the treatment process. Methods: In this study, a computational model of losartan pharmacokinetics was developed, taking into account the influence of different alleles of the CYP2C9 gene, which plays a pivotal role in losartan metabolism, and the ABCB1 gene, which is responsible for losartan transport. Results: Alterations in the modeled activities of the enzymes encoded by CYP2C9 and ABCB1 result in changes in the losartan and its metabolite profiles that are consistent with known experimental data in real patients with different CYP2C9 and ABCB1 genotypes. Conclusions: The findings of the modeling can potentially be used to personalize drug therapy for arterial hypertension. Full article
(This article belongs to the Special Issue In Vitro–In Vivo Correlation and Mechanistic Pharmacokinetic Models: Bridging Drug In Vitro Characteristics and In Vivo Behaviors)
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22 pages, 1532 KB  
Article
Novel Alkyl-Polyglucoside-Based Topical Creams Containing Basil Essential Oil (Ocimum basilicum L. Lamiaceae): Assessment of Physical, Mechanical, and Sensory Characteristics
by Ana Barjaktarević, Georgeta Coneac, Snežana Cupara, Olivera Kostić, Marina Kostić, Ioana Olariu, Vicenţiu Vlaia, Ana-Maria Cotan, Ştefania Neamu and Lavinia Vlaia
Pharmaceutics 2025, 17(7), 934; https://doi.org/10.3390/pharmaceutics17070934 - 19 Jul 2025
Viewed by 848
Abstract
Background/Objectives: Basil essential oil exhibits a wide range of biological activities, including strong antimicrobial and anti-inflammatory effects. Considering the health benefits of basil essential oil (BEO) and the favorable properties of alkyl polyglucoside emulsifiers, novel Montanov™-68-based O/W creams containing BEO were developed and [...] Read more.
Background/Objectives: Basil essential oil exhibits a wide range of biological activities, including strong antimicrobial and anti-inflammatory effects. Considering the health benefits of basil essential oil (BEO) and the favorable properties of alkyl polyglucoside emulsifiers, novel Montanov™-68-based O/W creams containing BEO were developed and characterized. Additionally, the influence of the emulsifier content on the cream’s properties was evaluated. Methods: The physicochemical properties were evaluated by organoleptic examination, physical stability test, and pH and electrical conductivity measurement. The mechanical properties were investigated by rheological, textural, and consistency analyses. In addition, a sensory evaluation protocol was applied. Results: The cream formulations containing 5% and 7% Montanov™ 68 demonstrated physical stability, with no evidence of phase separation during the observation period or following accelerated aging. The pH values remained within the acceptable range for topical use, and a gradual decrease in electrical conductivity over time was observed. The rheological analyses confirmed the non-Newtonian pseudoplastic behavior with thixotropic flow characteristics. The textural analyses demonstrated that the higher emulsifier content led to increased firmness, consistency, cohesiveness, and index of viscosity. The sensory analysis revealed differences between the alkyl polyglucoside (APG)-based cream formulations only in terms of the elasticity and stickiness. Conclusions: Although the rheological analyses suggested the better spreadability of the formulation with 5% emulsifier, this was not confirmed by the sensory analysis. However, the APG-based formulations performed significantly better than the synthetic surfactant-based formulation in terms of the absorption, stickiness, and greasiness (during and after application). These results are encouraging for the further evaluation of APG-based creams containing basil essential oil for topical application. Full article
(This article belongs to the Special Issue Novel Drug Delivery Systems for the Treatment of Skin Disorders)
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22 pages, 2224 KB  
Article
Development and Evaluation of an Anti-Inflammatory Emulsion: Skin Penetration, Physicochemical Properties, and Fibroblast Viability Assessment
by Jolita Stabrauskiene, Agnė Mazurkevičiūtė, Daiva Majiene, Rima Balanaskiene and Jurga Bernatoniene
Pharmaceutics 2025, 17(7), 933; https://doi.org/10.3390/pharmaceutics17070933 - 19 Jul 2025
Viewed by 617
Abstract
Background/Objectives. Chronic inflammatory skin disorders, such as atopic dermatitis and psoriasis, require safe and effective topical treatments. This study aimed to develop and evaluate a novel anti-inflammatory emulsion enriched with menthol, capsaicin, amino acids (glycine, arginine, histidine), and boswellic acid. Methods. Three formulations [...] Read more.
Background/Objectives. Chronic inflammatory skin disorders, such as atopic dermatitis and psoriasis, require safe and effective topical treatments. This study aimed to develop and evaluate a novel anti-inflammatory emulsion enriched with menthol, capsaicin, amino acids (glycine, arginine, histidine), and boswellic acid. Methods. Three formulations were prepared: a control (E1), a partial (E2), and a comprehensive formulation (E3). Physicochemical analyses included texture profiling, rheological behavior, pH stability, moisture content, and particle size distribution. Results. E3 demonstrated superior colloidal stability, optimal pH (5.75–6.25), and homogenous droplet size (<1 µm), indicating favorable dermal delivery potential. Ex vivo permeation studies revealed effective skin penetration of menthol and amino acids, with boswellic acid remaining primarily in the epidermis, suggesting localized action. Under oxidative stress conditions, E3 significantly improved fibroblast viability, indicating synergistic cytoprotective effects of combined active ingredients. While individual compounds showed limited or dose-dependent efficacy, their combination restored cell viability to near-control levels. Conclusions. These findings support the potential of this multi-component emulsion as a promising candidate for the topical management of inflammatory skin conditions. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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14 pages, 1925 KB  
Article
Chitosan Microparticles Coupled with MAGE-AX and CpGs as a Treatment for Murine Melanoma
by Gabriela Piñón-Zárate, Beatriz Hernández-Téllez, Ariel Ramírez-Cortés, Katia Jarquín-Yáñez, Enrique A. Sampedro-Carrillo, Miguel A. Herrera-Enríquez, Christian A. Cárdenas-Monroy and Andrés E. Castell-Rodríguez
Pharmaceutics 2025, 17(7), 932; https://doi.org/10.3390/pharmaceutics17070932 - 19 Jul 2025
Viewed by 474
Abstract
Background/Objectives: One current cancer treatment is immunotherapy, in which tumor antigens (such as MAGE) or adjuvants (such as CpGs) can be used to induce the destruction of tumor cells by the immune system; however, the therapeutic response is generally weak. Therefore, it is [...] Read more.
Background/Objectives: One current cancer treatment is immunotherapy, in which tumor antigens (such as MAGE) or adjuvants (such as CpGs) can be used to induce the destruction of tumor cells by the immune system; however, the therapeutic response is generally weak. Therefore, it is necessary to develop a strategy that increases the immune response induced by tumor antigens and CpGs. We propose the coupling of tumor antigens and adjuvants to chitosan (Cs) microparticles to improve the immune response against cancer, as these microparticles can activate the innate immune response when recognized by macrophages and dendritic cells (DCs). Methods: Cs microparticles coupled with CpGs and tumor antigens were constructed with the emulsification method; then, their morphology, in vitro biological effect on DCs, and therapeutic effect in a murine melanoma model were analyzed. Results: The Cs microparticles showed a rounded morphology and a size of approximately 5 μ; in addition, they were not cytotoxic in in vitro assays and induced the production of IFNα. Finally, in the murine model of melanoma, treatment with Cs microparticles coupled to MAGE or CpGs reduced the tumor growth rate and increased both survival and the presence of cell death areas in the tumor parenchyma in contrast to the control group. Conclusions: The results suggest that treatment with Cs microparticles coupled to tumor antigen and/or CpGs can be considered a promising strategy in the field of immunotherapy based on the use of biomaterials. Full article
(This article belongs to the Special Issue Drug Formulations Based on Chitosan and Its Derivatives for Therapeutic Applications)
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28 pages, 732 KB  
Systematic Review
Preclinical Trials of Cancer Stem Cells Targeted by Metal-Based Coordination Complexes: A Systematic Review
by Ana Caroline Mafra Bezerra, Lucas Elohim Cardoso Viana Baptista, Maria Núbia Alencar Couto and Milton Masahiko Kanashiro
Pharmaceutics 2025, 17(7), 931; https://doi.org/10.3390/pharmaceutics17070931 - 18 Jul 2025
Viewed by 768
Abstract
Background/Objective: Cancer stem cells (CSCs) are a self-renewing subpopulation within tumors that contribute to heterogeneity and resistance to conventional cancer therapies, including chemotherapy and radiotherapy. Despite growing interest in CSCs as therapeutic targets, effective compounds against these cells remain limited. This systematic [...] Read more.
Background/Objective: Cancer stem cells (CSCs) are a self-renewing subpopulation within tumors that contribute to heterogeneity and resistance to conventional cancer therapies, including chemotherapy and radiotherapy. Despite growing interest in CSCs as therapeutic targets, effective compounds against these cells remain limited. This systematic review aims to assess the potential of metal-based coordination complexes as anti-CSC agents in preclinical models. Methods: A systematic literature search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Twenty-seven original in vitro studies were included, all evaluating the cytotoxic effects of metal-based compounds on cancer cell lines enriched with CSC subpopulations. To ensure methodological rigor, all articles underwent a critical appraisal by independent reviewers who resolved discrepancies through consensus, and only studies meeting predefined quality criteria were included. Results: Several metal complexes, particularly copper-based compounds, demonstrated significant cytotoxicity toward CSCs, mainly through the induction of apoptosis. Breast cancer was the most frequently studied tumor type. Many studies reported modulation of CSC-related markers, including EPCAM, CD44, CD133, CD24, SOX2, KLF4, Oct4, NOTCH1, ALDH1, CXCR4, and HES1, suggesting effects on CSC maintenance pathways. Most studies were conducted in the United Kingdom and relied on in vitro models. Conclusions: Metal coordination complexes, especially those containing copper, show promise as therapeutic agents targeting CSCs. However, further in vivo studies and mechanistic investigations are essential to advance their translational potential. Full article
(This article belongs to the Topic Recent Advances in Anticancer Strategies, 2nd Edition)
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35 pages, 4837 KB  
Review
MicroRNA-Based Delivery Systems for Chronic Neuropathic Pain Treatment in Dorsal Root Ganglion
by Stefan Jackson, Maria Rosa Gigliobianco, Cristina Casadidio, Piera Di Martino and Roberta Censi
Pharmaceutics 2025, 17(7), 930; https://doi.org/10.3390/pharmaceutics17070930 - 18 Jul 2025
Viewed by 1213
Abstract
Neuropathic pain is a significant global clinical issue that poses substantial challenges to both public health and the economy due to its complex underlying mechanisms. It has emerged as a serious health concern worldwide. Recent studies involving dorsal root ganglion (DRG) stimulation have [...] Read more.
Neuropathic pain is a significant global clinical issue that poses substantial challenges to both public health and the economy due to its complex underlying mechanisms. It has emerged as a serious health concern worldwide. Recent studies involving dorsal root ganglion (DRG) stimulation have provided strong evidence supporting its effectiveness in alleviating chronic pain and its potential for sustaining long-term pain relief. In addition to that, there has been ongoing research with clinical evidence relating to the role of small non-coding ribonucleic acids known as microRNAs in regulating gene expressions affecting pain signals. The signal pathway involves alterations in neuronal excitation, synaptic transmission, dysregulated signaling, and subsequent pro-inflammatory response activation and pain development. When microRNAs are dysregulated in the dorsal root ganglia neurons, they polarize macrophages from anti-inflammatory M2 to inflammatory M1 macrophages causing pain signal generation. By reversing this polarization, a therapeutic activity can be induced. However, the direct delivery of these nucleotides has been challenging due to limitations such as rapid clearance, degradation, and reduction in half-life. Therefore, safe and efficient carrier vehicles are fundamental for microRNA delivery. Here, we present a comprehensive analysis of miRNA-based nano-systems for chronic neuropathic pain, focusing on their impact in dorsal root ganglia. This review provides a critical evaluation of various delivery platforms, including viral, polymeric, lipid-based, and inorganic nanocarriers, emphasizing their therapeutic potential as well as their limitations in the treatment of chronic neuropathic pain. Innovative strategies such as hybrid nanocarriers and stimulus-responsive systems are also proposed to enhance the prospects for clinical translation. Serving as a roadmap for future research, this review aims to guide the development and optimization of miRNA-based therapies for effective and sustained neuropathic pain management. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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17 pages, 2943 KB  
Article
Development of a Rapid Method for Residence Time Distribution Measurement in Twin-Screw Wet Granulation Based on Image Processing with Lab Color Space
by Jie Zhao, Geng Tian, Ying Tian and Haibin Qu
Pharmaceutics 2025, 17(7), 929; https://doi.org/10.3390/pharmaceutics17070929 - 18 Jul 2025
Viewed by 395
Abstract
Background/Objectives: In the twin-screw wet granulation (TSWG) process, accurate measurement of residence time distribution (RTD) is critical, as it characterizes material transport kinetics and mixing behavior. It plays a critical role in evaluating the homogeneity and stability of the granulation process and [...] Read more.
Background/Objectives: In the twin-screw wet granulation (TSWG) process, accurate measurement of residence time distribution (RTD) is critical, as it characterizes material transport kinetics and mixing behavior. It plays a critical role in evaluating the homogeneity and stability of the granulation process and optimizing process parameters. It is necessary to overcome the limitations arising from the complex and time-consuming procedures of conventional RTD determination methods. Methods: This study proposes a new RTD detection method based on image processing. It uses black dye as a tracer to obtain RTD curve data, and the effects of process parameters such as tracer dosage, screw speed, and feeding rate on the RTD were investigated. Results: The results show that the established method can accurately determine RTD and that the tracer dosage has no significant effect on the detection results. Further analysis revealed that the screw speed is negatively correlated with the mean residence time (MRT). As the speed increases, not only does the MRT shorten, but its distribution also decreases. Similarly, an increase in the feeding rate also leads to a decrease in the MRT and distribution, but it is worth noting that lower feeding rates are beneficial for achieving a state close to mixed flow, while excessively high feeding rates are not conducive to sufficient mixing of materials in the extruder. Conclusions: The RTD detection method provides a reliable parameter basis and theoretical guidance for the in-depth study of the TSWG process and the development of quality control strategies. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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29 pages, 4982 KB  
Article
Comprehensive Investigation of Polymorphic Stability and Phase Transformation Kinetics in Tegoprazan
by Joo Ho Lee, Ki Hyun Kim, Se Ah Ryu, Jason Kim, Kiwon Jung, Ki Sung Kang and Tokutaro Yamaguchi
Pharmaceutics 2025, 17(7), 928; https://doi.org/10.3390/pharmaceutics17070928 - 18 Jul 2025
Viewed by 673
Abstract
Background/Objectives: Tegoprazan (TPZ) is a potassium-competitive acid blocker (P-CAB) used to treat conditions such as gastroesophageal reflux disease, peptic ulcer, and Helicobacter pylori infection. It exists in three solid forms: amorphous, Polymorph A, and Polymorph B. This study investigates the molecular basis of [...] Read more.
Background/Objectives: Tegoprazan (TPZ) is a potassium-competitive acid blocker (P-CAB) used to treat conditions such as gastroesophageal reflux disease, peptic ulcer, and Helicobacter pylori infection. It exists in three solid forms: amorphous, Polymorph A, and Polymorph B. This study investigates the molecular basis of polymorph selection, focusing on conformational bias and solvent-mediated phase transformations (SMPTs). Methods: The conformational energy landscapes of two TPZ tautomers were constructed using relaxed torsion scans with the OPLS4 force field and validated by nuclear Overhauser effect (NOE)-based nuclear magnetic resonance (NMR). Hydrogen-bonded dimers were analyzed using DFT-D. Powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), solubility, and slurry tests were conducted using methanol, acetone, and water. Kinetic profiles were modeled with the Kolmogorov–Johnson–Mehl–Avrami (KJMA) equation. Results: Polymorph A was thermodynamically stable across all analyses. Both amorphous TPZ and Polymorph B converted to A in a solvent-dependent manner. Methanol induced direct A formation, while acetone showed a B → A transition. Crystallization was guided by solution conformers and hydrogen bonding. Conclusions: TPZ polymorph selection is governed by solution-phase conformational preferences, tautomerism, and solvent-mediated hydrogen bonding. DFT-D and NMR analyses showed that protic solvents favor the direct crystallization of stable Polymorph A, while aprotic solvents promote the transient formation of metastable Polymorph B. Elevated temperatures and humidity accelerate polymorphic transitions. This crystal structure prediction (CSP)-independent strategy offers a practical framework for rational polymorph control and the mitigation of disappearing polymorph risks in tautomeric drugs. Full article
(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design, 2nd Edition)
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26 pages, 1363 KB  
Review
From Structure to Function: The Promise of PAMAM Dendrimers in Biomedical Applications
by Said Alamos-Musre, Daniel Beltrán-Chacana, Juan Moyano, Valeria Márquez-Miranda, Yorley Duarte, Sebastián Miranda-Rojas, Yusser Olguín, Juan A. Fuentes, Danilo González-Nilo and María Carolina Otero
Pharmaceutics 2025, 17(7), 927; https://doi.org/10.3390/pharmaceutics17070927 - 18 Jul 2025
Viewed by 686
Abstract
PAMAM dendrimers are distinguished by their capacity for functionalization, which enhances the properties of the compounds they transport, rendering them highly versatile nanoparticles with extensive applications in the biomedical domain, including drug, vaccine, and gene delivery. These dendrimers can be internalized into cells [...] Read more.
PAMAM dendrimers are distinguished by their capacity for functionalization, which enhances the properties of the compounds they transport, rendering them highly versatile nanoparticles with extensive applications in the biomedical domain, including drug, vaccine, and gene delivery. These dendrimers can be internalized into cells through various endocytic mechanisms, such as passive diffusion, clathrin-mediated endocytosis, and caveolae-mediated endocytosis, allowing them to traverse the cytoplasm and reach intracellular targets, such as the mitochondria or nucleus. Despite the significant challenge posed by the cytotoxicity of these nanoparticles, which is contingent upon the dendrimer size, surface charge, and generation, numerous strategies have been documented to modify the dendrimer surface using polyethylene glycol and other chemical groups to temporarily mitigate their cytotoxic effects. The potential of PAMAM dendrimers in cancer therapy and other biomedical applications is substantial, owing to their ability to enhance bioavailability, pharmacokinetics, and pharmacodynamics of active ingredients within the body. This underscores the necessity for further investigation into the optimization of internalization pathways and cytotoxicity of these nanoparticles. This review offers a comprehensive synthesis of the current literature on the diverse cellular internalization pathways of PAMAM dendrimers and their cargo molecules, emphasizing the mechanisms of entry, intracellular trafficking, and factors influencing these processes. Full article
(This article belongs to the Special Issue Biomedical Applications: Advances in Bioengineering and Drug Delivery)
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24 pages, 2213 KB  
Article
Triple-Loaded Nanoemulsions Incorporating Coffee Extract for the Photoprotection of Curcumin and Capsaicin: Experimental and Computational Evaluation
by Nuttapol Boonrueang, Siripat Chaichit, Wipawadee Yooin, Siriporn Okonogi, Kanokwan Kiattisin and Chadarat Ampasavate
Pharmaceutics 2025, 17(7), 926; https://doi.org/10.3390/pharmaceutics17070926 - 17 Jul 2025
Viewed by 572
Abstract
Background/Objectives: This study aims to present a strategic approach to enhancing the photostability and antioxidative resilience of curcumin and capsaicin by integrating selected natural stabilizers within a nanoemulsion-based delivery system. Methods: Coffee extract (Coffea arabica Linn.), along with its active [...] Read more.
Background/Objectives: This study aims to present a strategic approach to enhancing the photostability and antioxidative resilience of curcumin and capsaicin by integrating selected natural stabilizers within a nanoemulsion-based delivery system. Methods: Coffee extract (Coffea arabica Linn.), along with its active components and vitamin E-containing natural oils, was assessed in terms of improving the photostabilizing and antioxidative retention abilities of curcumin and capsaicin. An optimized ratio of the active mixture was then loaded into a nanoformulation. Results: The analysis of active contents with validated high-performance liquid chromatography (HPLC), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays confirmed the stabilization enhancement after irradiation with UV and white light for 72,000–84,000 lux hours. The optimized combination of coffee extract with turmeric and chili mixtures loaded into the optimized nanoemulsion enhanced the half-lives (T1/2) of curcumin and capsaicin by 416% and 390%, respectively. The interactions of curcumin and capsaicin with caffeine and chlorogenic acid were elucidated using computational calculations. Interaction energies (Eint), HOMO-LUMO energy gap (HLG) analysis, and global reactivity descriptors revealed hydrogen bonding interactions be-tween capsaicin and chlorogenic acid, as well as between curcumin and caffeine. Conclusions: By leveraging the synergistic antioxidative properties of coffee extract and vitamin E within a nanoemulsion matrix, this study overcomes the intrinsic stability limitations of curcumin and capsaicin, offering a robust platform for future pharmaceutical and nutraceutical applications. Full article
(This article belongs to the Special Issue Regenerative Biomaterials with Plant Derivatives for Skin Wound Therapy)
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23 pages, 6606 KB  
Article
Clove Oil-Based Nanoemulsion Containing Amphotericin B as a Therapeutic Approach to Combat Fungal Infections
by Marcel Lucas de Almeida, Ana Paula dos Santos Matos, Veronica da Silva Cardoso, Tatielle do Nascimento, Ralph Santos-Oliveira, Leandro Machado Rocha, Francisco Paiva Machado, Franklin Chimaobi Kenechukwu, Alane Beatriz Vermelho and Eduardo Ricci-Júnior
Pharmaceutics 2025, 17(7), 925; https://doi.org/10.3390/pharmaceutics17070925 - 17 Jul 2025
Viewed by 642
Abstract
Background/Objectives: Candidiasis, primarily caused by Candida albicans, and sporotrichosis, mainly caused by Sporothrix schenckii, are skin fungal infections that pose serious threats to global health. The Candida auris is a great concern in immunocompromised individuals, and while Sporothrix brasiliensis cause sporotrichosis, [...] Read more.
Background/Objectives: Candidiasis, primarily caused by Candida albicans, and sporotrichosis, mainly caused by Sporothrix schenckii, are skin fungal infections that pose serious threats to global health. The Candida auris is a great concern in immunocompromised individuals, and while Sporothrix brasiliensis cause sporotrichosis, an infection commonly found in cats, this disease can be transmitted to humans through scratches or bites. Existing treatments for these fungal infections often cause problems related to resistance and significant side effects. Consequently, development of alternative therapeutic approaches such as nanotechnology-based topical lipid-based formulations is interesting. Thus, the objectives of this study were to prepare clove oil (CO)-in-water nanoemulsions (NEs) containing amphotericin B (AmB) and characterize them with respect to stability, release profile, and in vitro cytotoxic activity against Candida and Sporothrix strains. As a future alternative for the treatment of fungal skin diseases. Methods: Chemical analysis of clove oil was obtained by GC-MS. The NEs were produced using an ultrasound (sonicator) method with varying proportions of CO, Pluronic® F-127, and AmB. The NEs were characterized by droplet size, morphology, stability and in vitro release profile. The antifungal and cytotoxic activity against C. albicans, C. auris, S. schenckii, and S. brasiliensis were ascertained employing agar diffusion and colorimetric MTT assay methods. A checkerboard assay was carried out using clove oil and amphotericin B against C. auris. Results: Eugenol was the major compound identified in CO at a concentration of 80.09%. AmB-loaded NEs exhibited particle sizes smaller than 50 nm and a polydispersity index below 0.25. The optimal Ne (NEMLB-05) remained stable after 150 days of storage at 4 °C. It exhibited rapid release within the first 24 h, followed by a slow and controlled release up to 96 h. NEMLB-05 more effectively inhibited C. auris compared to free AmB and also demonstrated greater activity against C. albicans, S. schenckii, and S. brasiliensis. Clove oil and amphotericin B presented synergism inhibiting the growth of C. auris. Conclusions: The selected CO-in-water NEs containing AmB demonstrated promising potential as a topical therapeutic alternative for treating fungal infections. Full article
(This article belongs to the Special Issue Nanotechnology in the Treatment of Neglected Parasitic Diseases)
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15 pages, 1034 KB  
Article
In Vitro Oral Cavity Permeability Assessment to Enable Simulation of Drug Absorption
by Pankaj Dwivedi, Priyata Kalra, Haiying Zhou, Khondoker Alam, Eleftheria Tsakalozou, Manar Al-Ghabeish, Megan Kelchen and Giovanni M. Pauletti
Pharmaceutics 2025, 17(7), 924; https://doi.org/10.3390/pharmaceutics17070924 - 17 Jul 2025
Viewed by 675
Abstract
Background/Objectives: The oral cavity represents a convenient route of administration for drugs that exhibit significant hepatic first-pass extraction. In this study, the mucosal permeation properties of selected active pharmaceutical ingredients (APIs) incorporated into oral cavity drug products that are approved by the U.S. [...] Read more.
Background/Objectives: The oral cavity represents a convenient route of administration for drugs that exhibit significant hepatic first-pass extraction. In this study, the mucosal permeation properties of selected active pharmaceutical ingredients (APIs) incorporated into oral cavity drug products that are approved by the U.S. Food and Drug Administration were quantified using the human-derived sublingual HO-1-u-1 and buccal EpiOral™ in vitro tissue models. Methods: Epithelial barrier properties were monitored using propranolol and Lucifer Yellow as prototypic transcellular and paracellular markers. APIs were dissolved in artificial saliva, pH 6.7, and transepithelial flux from the apical to the basolateral compartment was quantified using HPLC. Results: Apparent permeability coefficients (Papp) calculated for these APIs in the sublingual HO-1-u-1 tissue model varied from Papp = 2.72 ± 0.06 × 10−5 cm/s for asenapine to Papp = 6.21 ± 2.60 × 10−5 cm/s for naloxone. In contrast, the buccal EpiOral™ tissue model demonstrated greater discrimination power in terms of permeation properties for the same APIs, with values ranging from Papp = 3.31 ± 0.83 × 10−7 cm/s for acyclovir to Papp = 2.56 ± 0.68 × 10−5 cm/s for sufentanil. The tissue-associated dose fraction recovered at the end of the transport experiment was significantly increased in the buccal EpiOral™ tissue model, reaching up to 8.5% for sufentanil. Conclusions: Experimental permeation data collected for selected APIs in FDA-approved oral cavity products will serve as a training set to aid the development of predictive computational models for improving algorithms that describe drug absorption from the oral cavity. Following a robust in vitro–in vivo correlation analysis, it is expected that such innovative in silico modeling strategies will the accelerate development of generic oral cavity products by facilitating the utility of model-integrated evidence to support decision making in generic drug development and regulatory approval. Full article
(This article belongs to the Special Issue Next-Generation Biomaterials for Oral Healthcare: Focus on Regenerative and Delivery Functions)
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29 pages, 1610 KB  
Review
Tyrosine Kinase Inhibitors for Gastrointestinal Stromal Tumor After Imatinib Resistance
by Xian-Hao Xiao, Qian-Shi Zhang, Ji-Yuan Hu, Yin-Xu Zhang and He Song
Pharmaceutics 2025, 17(7), 923; https://doi.org/10.3390/pharmaceutics17070923 - 17 Jul 2025
Viewed by 773
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, primarily driven by activating mutations in KIT (CD117) and platelet-derived growth factor receptor alpha (PDGFRA). The introduction of tyrosine kinase inhibitors (TKIs), especially imatinib, has significantly transformed GIST treatment. [...] Read more.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, primarily driven by activating mutations in KIT (CD117) and platelet-derived growth factor receptor alpha (PDGFRA). The introduction of tyrosine kinase inhibitors (TKIs), especially imatinib, has significantly transformed GIST treatment. However, the emergence of both primary and secondary resistance to imatinib presents ongoing therapeutic challenges. This review comprehensively explores the mechanisms underlying imatinib resistance and evaluates subsequent TKI therapies. Sunitinib, regorafenib, and ripretinib are currently approved as standard second-, third-, and fourth-line therapies, each demonstrating efficacy against distinct mutational profiles. Avapritinib, notably effective against PDGFRA D842V mutations, represents a milestone for previously untreatable subgroups. Several alternative agents—such as nilotinib, masitinib, sorafenib, dovitinib, pazopanib, and ponatinib—have shown varying degrees of success in refractory cases or specific genotypes. Investigational compounds, including crenolanib, bezuclastinib, famitinib, motesanib, midostaurin, IDRX-42, and olverembatinib, are under development to address resistant or wild-type GISTs. Despite progress, long-term efficacy remains limited due to evolving resistance. Future strategies include precision medicine approaches such as ctDNA-guided therapy, rational drug combinations, and novel drug delivery systems to optimize bioavailability and reduce toxicity. Ongoing research will be crucial for refining treatment sequencing and expanding therapeutic options, especially for rare GIST subtypes. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy, 2nd Edition)
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18 pages, 1790 KB  
Article
Development of Co-Amorphous Systems for Inhalation Therapy—Part 1: From Model Prediction to Clinical Success
by Eleonore Fröhlich, Aurora Bordoni, Nila Mohsenzada, Stefan Mitsche, Hartmuth Schröttner and Sarah Zellnitz-Neugebauer
Pharmaceutics 2025, 17(7), 922; https://doi.org/10.3390/pharmaceutics17070922 - 16 Jul 2025
Viewed by 523
Abstract
Background/Objectives: The integration of machine learning (ML) and artificial intelligence (AI) has revolutionized the pharmaceutical industry by improving drug discovery, development and manufacturing processes. Based on literature data, an ML model was developed by our group to predict the formation of binary [...] Read more.
Background/Objectives: The integration of machine learning (ML) and artificial intelligence (AI) has revolutionized the pharmaceutical industry by improving drug discovery, development and manufacturing processes. Based on literature data, an ML model was developed by our group to predict the formation of binary co-amorphous systems (COAMSs) for inhalation therapy. The model’s ability to develop a dry powder formulation with the necessary properties for a predicted co-amorphous combination was evaluated. Methods: An extended experimental validation of the ML model by co-milling and X-ray diffraction analysis for 18 API-API (active pharmaceutical ingredient) combinations is presented. Additionally, one COAMS of rifampicin (RIF) and ethambutol (ETH), two first-line tuberculosis (TB) drugs are developed further for inhalation therapy. Results: The ML model has shown an accuracy of 79% in predicting suitable combinations for 35 APIs used in inhalation therapy; experimental accuracy was demonstrated to be 72%. The study confirmed the successful development of stable COAMSs of RIF-ETH either via spray-drying or co-milling. In particular, the milled COAMSs showed better aerosolization properties (higher ED and FPF with lower standard deviation). Further, RIF-ETH COAMSs show much more reproducible results in terms of drug quantity dissolved over time. Conclusions: ML has been shown to be a suitable tool to predict COAMSs that can be developed for TB treatment by inhalation to save time and cost during the experimental screening phase. Full article
(This article belongs to the Special Issue New Platform for Tuberculosis Treatment)
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14 pages, 2997 KB  
Article
The Development of a Multilayer Transdermal Patch Platform Based on Electrospun Nanofibers for the Delivery of Caffeine
by Jorge Teno, Zoran Evtoski, Cristina Prieto and Jose M. Lagaron
Pharmaceutics 2025, 17(7), 921; https://doi.org/10.3390/pharmaceutics17070921 - 16 Jul 2025
Viewed by 552
Abstract
Background/Objectives: The work presented herein focused on the development and characterization of a transdermal caffeine platform fabricated from ultrathin micro- and submicron fibers produced via electrospinning. Methods: The formulations incorporated caffeine encapsulated in a polyethylene oxide (PEO) matrix, combined with various [...] Read more.
Background/Objectives: The work presented herein focused on the development and characterization of a transdermal caffeine platform fabricated from ultrathin micro- and submicron fibers produced via electrospinning. Methods: The formulations incorporated caffeine encapsulated in a polyethylene oxide (PEO) matrix, combined with various permeation enhancers. A backing layer made of annealed electrospun polycaprolactone (PCL) facilitated the lamination of the two layers to form the final multilayer patch. Comprehensive characterization was conducted, utilizing scanning electron microscopy (SEM) to assess the fiber morphology, attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) for chemical detection and to assess the stability of the caffeine, and differential scanning calorimetry (DSC) along with wide-angle X-ray scattering (WAXS) to analyze the physical state of the caffeine within the fibers of the active layer. Additionally, Franz cell permeation studies were performed using both synthetic membranes (Strat-M) and ex vivo human stratum corneum (SC) to evaluate and model the permeation kinetics. Results: These experiments demonstrated the significant role of enhancers in modulating the caffeine permeation rates provided by the patch, achieving permeation rates of up to 0.73 mg/cm2 within 24 h. Conclusions: This work highlights the potential of using electro-hydrodynamic processing technology to develop innovative transdermal delivery systems for drugs, offering a promising strategy for enhancing efficacy and innovative therapeutic direct plasma administration. Full article
(This article belongs to the Special Issue Dermal and Transdermal Drug Delivery Systems)
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19 pages, 3398 KB  
Article
Synthesis and Evaluation of [18F]AlF-NOTA-iPD-L1 as a Potential Theranostic Pair for [177Lu]Lu-DOTA-iPD-L1
by Guillermina Ferro-Flores, Myrna Luna-Gutiérrez, Blanca Ocampo-García, Nallely Jiménez-Mancilla, Nancy Lara-Almazán, Rigoberto Oros-Pantoja, Clara Santos-Cuevas, Erika Azorín-Vega and Laura Meléndez-Alafort
Pharmaceutics 2025, 17(7), 920; https://doi.org/10.3390/pharmaceutics17070920 - 16 Jul 2025
Viewed by 535
Abstract
Background/Objective: Programmed cell death ligand-1 (PD-L1), which is overexpressed in certain tumors, inhibits the body’s natural immune response by providing an “off” signal that enables cancer cells to evade the immune system. It has been demonstrated that [177Lu]Lu-DOTA-iPD-L1 (PD-L1 inhibitor [...] Read more.
Background/Objective: Programmed cell death ligand-1 (PD-L1), which is overexpressed in certain tumors, inhibits the body’s natural immune response by providing an “off” signal that enables cancer cells to evade the immune system. It has been demonstrated that [177Lu]Lu-DOTA-iPD-L1 (PD-L1 inhibitor cyclic peptide) promotes immune responses. This study aimed to synthesize and evaluate [18F]AlF-NOTA-iPD-L1 as a novel radiotracer for PD-L1 positron emission tomography (PET) imaging and as a potential theranostic pair for [177Lu]Lu-DOTA-iPD-L1. Methods: The NOTA-iPD-L1 peptide conjugate was synthesized and characterized by U.V.-vis, I.R.-FT, and UPLC-mass spectroscopies. Radiolabeling was performed using [18F]AlF as the precursor, and the radiochemical purity (HPLC), partition coefficient, and serum stability were assessed. Cellular uptake and internalization (in 4T1 triple-negative breast cancer cells), binding competition, immunofluorescence, and Western blot assays were applied for the radiotracer in vitro characterization. Biodistribution in mice bearing 4T1 tumors was performed, and molecular imaging (Cerenkov images) of [18F]AlF-NOTA-iPD-L1 and [177Lu]Lu-DOTA-iPD-L1 in the same mouse was obtained. Results: [18F]AlF-NOTA-iPD-L1 was prepared with a radiochemical purity greater than 97%, and it demonstrated high in vitro and in vivo stability, as well as specific recognition by the PD-L1 protein (IC50 = 9.27 ± 2.69 nM). Biodistribution studies indicated a tumor uptake of 6.4% ± 0.9% ID/g at 1-hour post-administration, and Cerenkov images showed a high tumor uptake of both [18F]AlF-NOTA-iPD-L1 and 177Lu-iPD-L1 in the same mouse. Conclusions: These results warrant further studies to evaluate the clinical usefulness of [18F]AlF-NOTA-iPD-L1/[177Lu]Lu-DOTA-iPD-L1 as a radiotheranostic pair in combination with anti-PD-L1/PD1 immunotherapy. Full article
(This article belongs to the Special Issue Advances in Radiopharmaceuticals: Enhancing Targeted Delivery, Disease Diagnosis, and Therapeutic Applications)
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16 pages, 689 KB  
Article
Quantification of Total and Unbound Selinexor Concentrations in Human Plasma by a Fully Validated Liquid Chromatography-Tandem Mass Spectrometry Method
by Suhyun Lee, Seungwon Yang, Hyeonji Kim, Wang-Seob Shim, Eunseo Song, Seunghoon Han, Sung-Soo Park, Suein Choi, Sungpil Han, Sung Hwan Joo, Seok Jun Park, Beomjin Shin, Donghyun Kim, Hyeon Su Kim, Kyung-Tae Lee and Eun Kyoung Chung
Pharmaceutics 2025, 17(7), 919; https://doi.org/10.3390/pharmaceutics17070919 - 16 Jul 2025
Viewed by 465
Abstract
Background/Objectives: Selinexor is a selective nuclear-export inhibitor approved for hematologic malignancies, characterized by extensive plasma protein binding (>95%). However, a validated analytical method to accurately measure the clinically relevant unbound fraction of selinexor in human plasma has not yet been established. This study [...] Read more.
Background/Objectives: Selinexor is a selective nuclear-export inhibitor approved for hematologic malignancies, characterized by extensive plasma protein binding (>95%). However, a validated analytical method to accurately measure the clinically relevant unbound fraction of selinexor in human plasma has not yet been established. This study aimed to develop a fully validated bioanalytical assay for simultaneous quantification of total and unbound selinexor concentrations in human plasma. Methods: We established and fully validated an analytical method based on liquid chromatography–tandem mass spectrometry (LC-MS/MS) capable of quantifying total and unbound selinexor concentrations in human plasma. Unbound selinexor was separated using ultrafiltration, and selinexor was efficiently extracted from 50 μL of plasma by liquid–liquid extraction. Chromatographic separation was achieved on a C18 column using an isocratic mobile phase (0.1% formic acid:methanol, 12:88 v/v) with a relatively short runtime of 2.5 min. Results: Calibration curves showed excellent linearity over a range of 5–2000 ng/mL for total selinexor (r2 ≥ 0.998) and 0.05–20 ng/mL for unbound selinexor (r2 ≥ 0.995). The precision (%CV ≤ 10.35%) and accuracy (92.5–104.3%) for both analytes met the regulatory criteria. This method successfully quantified selinexor in plasma samples from renally impaired patients with multiple myeloma, demonstrating potential inter-individual differences in unbound drug concentrations. Conclusions: This validated bioanalytical assay enables precise clinical pharmacokinetic assessments in a short runtime using a small plasma volume and, thus, assists in individualized dosing of selinexor, particularly for renally impaired patients with altered protein binding. Full article
(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)
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21 pages, 1132 KB  
Article
Ferroptosis Among the Antiproliferative Pathways Activated by a Lipophilic Ruthenium(III) Complex as a Candidate Drug for Triple-Negative Breast Cancer
by Maria Grazia Ferraro, Federica Iazzetti, Marco Bocchetti, Claudia Riccardi, Daniela Montesarchio, Rita Santamaria, Gabriella Misso, Marialuisa Piccolo and Carlo Irace
Pharmaceutics 2025, 17(7), 918; https://doi.org/10.3390/pharmaceutics17070918 - 16 Jul 2025
Viewed by 601
Abstract
Background/Objectives: In the context of preclinical studies, we have hitherto showcased that a low-molecular-weight ruthenium(III) complex we named AziRu holds significant potential for further developments as an anticancer candidate drug. When appropriately converted into stable nanomaterials and delivered into tumor cells, AziRu [...] Read more.
Background/Objectives: In the context of preclinical studies, we have hitherto showcased that a low-molecular-weight ruthenium(III) complex we named AziRu holds significant potential for further developments as an anticancer candidate drug. When appropriately converted into stable nanomaterials and delivered into tumor cells, AziRu exhibits superior antiproliferative activity, benefiting from a multimodal mechanism of action. The activation of regulated cell death (RCD) pathways (i.e., apoptosis and autophagy) has been proved in metastatic phenotypes, including triple-negative breast cancer (TNBC) cells. This study focuses on a bioengineered lipophilic derivative of AziRu, named PalmiPyRu, that we are currently developing as a potential anticancer drug in preclinical studies. When delivered in this way, AziRu confirms a multimodal mechanism of action in effectively blocking the growth and proliferation of TNBC phenotypes. Special focus is reserved for the activation of the ferroptotic pathway as a consequence of redox imbalance and interference with iron homeostasis, as well as the glutathione biosynthetic pathway. Methods: Human preclinical models of specific TNBC phenotypes and healthy cell cultures of different histological origin were selected. After in vitro treatments, cellular responses were carefully analyzed, and targeted biochemical and molecular biology experiments coupled to confocal microscopy allowed us to explore the antiproliferative effects of PalmiPyRu. Results: In this study, we unveil that PalmiPyRu can enter TNBC cells and interfere with both the iron homeostasis and the cystine-glutamate antiporter system Xc-, causing significant oxidative stress and the accumulation of lipid oxidation products. The increase in intracellular reactive free iron and depletion of glutathione engender a lethal condition, driving cancer cells toward the activation of ferroptosis. Conclusions: Overall, these outcomes allow us, for the first time, to couple the antiproliferative effect of a ruthenium-based candidate drug with the inhibition of the Xc- antiporter system and Fenton chemistry, thereby branding PalmiPyRu as an effective multimodal inducer of ferroptosis. Molecular mechanisms of action deserve further investigations, and new studies are underway to uncover how interference with Xc- controls cell fate, allowing us to explore the connection between iron metabolism regulation, oxidative stress and RCD pathways activation. Full article
(This article belongs to the Section Drug Targeting and Design)
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31 pages, 4404 KB  
Review
Recent Advances in the Use of Ganoderma lucidum and Coriolus versicolor Mushrooms to Enhance the Anticancer Efficacy of EGFR-Targeted Drugs in Lung Cancer
by Hang Zhang, Longling Wang, Yuet Wa Chan, William C. Cho, Zhong Zuo and Kenneth K. W. To
Pharmaceutics 2025, 17(7), 917; https://doi.org/10.3390/pharmaceutics17070917 - 15 Jul 2025
Viewed by 1378
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the major subtype, accounting for more than 85% of all lung cancer cases. Recent advances in precision oncology have allowed NSCLC patients bearing specific oncogenic epidermal growth [...] Read more.
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the major subtype, accounting for more than 85% of all lung cancer cases. Recent advances in precision oncology have allowed NSCLC patients bearing specific oncogenic epidermal growth factor receptor (EGFR) mutations to respond well to EGFR tyrosine kinase inhibitors (TKIs). Due to the high EGFR mutation frequency (up to more than 50%) observed particularly in Asian NSCLC patients, EGFR-TKIs have produced unprecedented clinical responses. Depending on their binding interactions with EGFRs, EGFR-TKIs are classified as reversible (first-generation: gefitinib and erlotinib) or irreversible inhibitors (second-generation: afatinib and dacomitinib; third-generation: osimertinib). While the discovery of osimertinib represents a breakthrough in the treatment of NSCLC, most patients eventually relapse and develop drug resistance. Novel strategies to overcome osimertinib resistance are urgently needed. In Asian countries, the concomitant use of Western medicine and traditional Chinese medicine (TCM) is very common. Ganoderma lucidum (Lingzhi) and Coriolus versicolor (Yunzhi) are popular TCMs that are widely consumed by cancer patients to enhance anticancer efficacy and alleviate the side effects associated with cancer therapy. The bioactive polysaccharides and triterpenes in these medicinal mushrooms are believed to contribute to their anticancer and immunomodulating effects. This review presents the latest update on the beneficial combination of Lingzhi/Yunzhi and EGFR-TKIs to overcome drug resistance. The effects of Lingzhi/Yunzhi on various oncogenic signaling pathways and anticancer immunity, as well as their potential to overcome EGFR-TKI resistance, are highlighted. The potential risk of herb–drug interactions could become critical when cancer patients take Lingzhi/Yunzhi as adjuvants during cancer therapy. The involvement of drug transporters and cytochrome P450 enzymes in these herb–drug interactions is summarized. Finally, we also discuss the opportunities and future prospects regarding the combined use of Lingzhi/Yunzhi and EGFR-TKIs in cancer patients. Full article
(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)
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