International Journal of Pharmaceutics: X最新文献

{"title":"HPMA polymers as functional excipients in dermal nanoformulations of imiquimod","authors":"Eliška Kurfiřtová ,&nbsp;Stanislav Chvíla ,&nbsp;Nikola Strnádková ,&nbsp;Vendula Janoušková ,&nbsp;Petr Chytil ,&nbsp;Tomáš Etrych ,&nbsp;Jarmila Zbytovská","doi":"10.1016/j.ijpx.2026.100486","DOIUrl":"10.1016/j.ijpx.2026.100486","url":null,"abstract":"<div><div>A key challenge in topical drug delivery is the inherently low bioavailability of many active compounds within skin tissue. Here, we present the first comprehensive study investigating the impact of biocompatible hydrophilic polymers based on <em>N</em>-(2-hydroxypropyl)methacrylamide (p(HPMA)) on skin barrier properties and its potential to enhance drug permeation. Using imiquimod (IMQ), a model compound known for its poor dermal delivery, we demonstrate that p(HPMA) can significantly influence transport across the skin. To enhance the dermal delivery of IMQ, we investigated three p(HPMA) polymers of varying molecular sizes (5, 20, 80 kg/mol) with very low dispersity. Our initial focus was on the p(HPMA) interaction with the skin barrier, specifically within the <em>stratum corneum</em> (SC), which was studied by confocal microscopy. Results revealed that p(HPMA) can penetrate into deeper skin layers, with this ability inversely correlated with their molecular weight. FTIR analysis confirmed that the polymers increase SC hydration without disrupting lipid organization. As demonstrated by the <em>ex vivo</em> skin permeation study, the smallest p(HPMA) polymer (5 kg/mol) produced the strongest enhancement effect on IMQ delivery into skin tissue. Relative to p(HPMA)-free controls, IMQ accumulation increased by 90% from the conventional suspension and by 10% and 50% from the nanoemulsion and nanocrystal formulations, respectively. These findings substantiate the role of p(HPMA) as an effective skin-penetration enhancer and support its further investigation for optimizing topical drug-delivery systems.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"11 ","pages":"Article 100486"},"PeriodicalIF":6.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liposomal antimicrobials in the fight against bacterial and fungal pathogens: Clinical successes and development challenges","authors":"Hussein T. Kenaan ,&nbsp;Ross M. Duncan ,&nbsp;Wafa T. Al-Jamal ,&nbsp;David S. Jones ,&nbsp;Gavin P. Andrews ,&nbsp;Brendan Gilmore ,&nbsp;Vanessa Yardley ,&nbsp;Nicola Farrington ,&nbsp;Katharine E. Stott ,&nbsp;David Lawrence ,&nbsp;Joseph N. Jarvis ,&nbsp;Thomas S. Harrison ,&nbsp;Stephen Robinson ,&nbsp;Isabela Ribeiro ,&nbsp;William Hope ,&nbsp;Yiwei Tian","doi":"10.1016/j.ijpx.2025.100478","DOIUrl":"10.1016/j.ijpx.2025.100478","url":null,"abstract":"<div><div>Bacterial, fungal, and protozoan infections pose a rapidly escalating threat to global health, exacerbated by the rise in antimicrobial resistance. Current therapies against microbial pathogens are limited by high systemic toxicity and poor drug solubility. Liposomal formulations (spherical vesicles composed of lipid bilayers) have demonstrated remarkable clinical potential in addressing these concerns, as evidenced by the marketed products AmBisome® and Arikayce®. These products, which deliver amphotericin B via parenteral injection and amikacin via inhalation, exemplify how liposomes effectively mitigate drug-associated toxicity, enhance therapeutic efficacy, and overcome the biological barriers inherent to infection sites, including complex microbial biofilms, mucosal interfaces, or the blood–brain barrier. Complementary insights from anticancer research indicate that strategic manipulation of liposomal composition and structure can enhance their therapeutic potential. Adjustments in lipid charge, fluidity, and PEGylation, in particular, highlight their versatility and broad applicability for antimicrobial drug delivery. Liposomal antimicrobials can modulate pharmacokinetic profiles, achieve targeted release at sites of infection, and increase local drug concentrations, which are key advantages over conventional treatments. Despite these therapeutic advances, successful clinical translation and widespread adoption of liposomal antimicrobials remain highly dependent on overcoming existing technological and manufacturing challenges. This review emphasises the need for a paradigm shift within liposomal antimicrobial development, encouraging progression from initial research and development toward scalable, reproducible, and economically viable commercial manufacturing platforms. This transition is essential not only for ensuring the global accessibility and affordability of existing therapies but also for expanding the development of clinically relevant liposomal antimicrobial nanomedicines.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"11 ","pages":"Article 100478"},"PeriodicalIF":6.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogel-encapsulated antioxidant nanotherapeutics against age-related macular degeneration (AMD) oxidative damage","authors":"Jiemeng Xu ,&nbsp;Taoyang Cai ,&nbsp;Jing Li ,&nbsp;Shangjie Ge-Zhang ,&nbsp;Zhouzhou Jiang ,&nbsp;Mingfang Cao","doi":"10.1016/j.ijpx.2025.100477","DOIUrl":"10.1016/j.ijpx.2025.100477","url":null,"abstract":"<div><div>Age-related macular degeneration (AMD) is still the main cause of irreversible vision loss, and the current intravitreal injections is limited by frequent administration and short retinal residence time. This review summarizes the latest progress of hydrogel-nanocarrier hybrid systems, aiming at prolonging ophthalmic drug delivery and supporting retinal tissue. We summarized the pathogenesis of AMD, focusing on oxidative stress and degeneration of retinal pigment epithelium (RPE), and investigated inorganic and organic nano-platforms endowed with antioxidant, anti-inflammatory and anti-angiogenesis functions. The design strategy of embedding nanoparticles into injectable or stimulus-responsive hydrogels is discussed. However, challenges remain, including long-term biocompatibility, inflammatory response to degradation products and potential tissue accumulation. Finally, it is emphasized to accelerate clinical translation through comprehensive long-term in vivo safety evaluation, quantitative optimization of release kinetics, standardized evaluation scheme and development of extensible manufacturing process. It is worth noting that this review mainly emphasizes inorganic nanoparticles and extracellular vesicles, but does not discuss other mature organic nanocarriers in detail. These carriers have been widely studied and emphasized by many other reviews.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"11 ","pages":"Article 100477"},"PeriodicalIF":6.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gold-incorporated hyaluronic acid nanoparticles enhance ablative radiotherapy efficacy in lung cancer","authors":"Jenny Ling-Yu Chen ,&nbsp;Shu-Jyuan Yang ,&nbsp;Li-Cheng Lin ,&nbsp;Chun-Kai Pan ,&nbsp;Ching-Yi Tsai ,&nbsp;Yu-Sen Huang ,&nbsp;Ke-Cheng Chen ,&nbsp;Ming-Jium Shieh ,&nbsp;Yu-Li Lin","doi":"10.1016/j.ijpx.2025.100480","DOIUrl":"10.1016/j.ijpx.2025.100480","url":null,"abstract":"<div><div>We aimed to investigate the utility of Au-incorporated hyaluronic acid nanoparticles (Au/HA NPs) for improving the therapeutic efficacy of ablative radiotherapy (RT) for tumor control and microenvironment remodeling. HA-functionalized NPs exhibited uniform size, stability, and efficient SN38 encapsulation. Au incorporation increased NP diameter and reduced surface charge while remaining stable. HA and Au/HA NPs were efficiently internalized by lung cancer cells, with free HA pretreatment suppressing internalization. Moreover, Au/HA NP internalization strongly downregulated CD44 expression in lung cancer cells, confirming CD44-mediated internalization. <em>In vitro</em>, Au/HA NPs enhanced radiation-induced G2/M phase arrest and γH2AX foci formation with increased DNA double-strand breaks. Au/HA NPs and RT induced immunogenic cell death (ICD) in lung cancer cells, characterized by elevated reactive oxygen species, increased calreticulin surface expression, and extracellular adenosine triphosphate release. Tumor control, survival, immune infiltration, and systemic effects were investigated <em>in vivo</em> using A549 xenografts and Lewis lung carcinoma synchronous flank-lung tumor models. Au/HA NPs and ablative RT decreased tumor growth, reduced lung tumor burden in non-irradiated areas, and prolonged survival. This therapeutic combination led to increased infiltration of natural killer (NK), NK T, CD8⁺ T, and dendritic cells and decreased regulatory T cells, suggesting robust immunological activation. Biodistribution studies confirmed CD44-targeted tumor-specific NP accumulation. No substantial toxicity was observed. In conclusion, Au/HA NPs and ablative RT induced ICD <em>in vivo</em>. Au/HA NPs enhanced local and systemic immunity <em>via</em> radiosensitization and ICD. This NP-assisted approach may improve RT efficacy in lung cancer.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"11 ","pages":"Article 100480"},"PeriodicalIF":6.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-targeted delivery strategies for age-related diseases","authors":"Zefan Liu ,&nbsp;Pei Yang ,&nbsp;Guilin Cheng ,&nbsp;Xin Kang ,&nbsp;Lian Li ,&nbsp;Yucheng Xiang","doi":"10.1016/j.ijpx.2026.100494","DOIUrl":"10.1016/j.ijpx.2026.100494","url":null,"abstract":"<div><div>Aging is a complex progress accompanied with the progressive deterioration of physiological functions and a marked elevation in mortality risk. Among prominent aging theories, the free radical theory and the mitochondrial dysfunction hypothesis have gained significant attention. Thus, targeted delivery of therapeutic drug to mitochondria might be able to alleviate the mitochondrial dysfunction induced by reactive oxygen species. This review summarizes the possible molecular mechanisms between mitochondrial dysfunction and aging progression. Especially, the recent breakthroughs of mitochondrial-targeted delivery platforms for therapeutics against aging progress. Innovative strategies, including small molecular modification, mitochondrial targeting functional peptide guided delivery and some other strategies are discussed. Their translational potential in anti-aging interventions is evaluated. We anticipate that mitochondria-targeted anti-aging therapeutics will soon enter clinical translation, offering potential solutions to address current age-related challenges.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"11 ","pages":"Article 100494"},"PeriodicalIF":6.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Self-assembling rose-derived nanovesicles: A multifunctional tool for tissue regeneration.","authors":"Antonella Barone, Luigi Ciriolo, Salvatore Panza, Nicola d'Avanzo, Giuliana Faggio, Giacomo Messina, Tanzeel U Rehman, Caterina M Tone, Maria P De Santo, Rosario Mare, Anna M Tolomeo, Massimo Fresta, Donatella Paolino","doi":"10.1016/j.ijpx.2025.100465","DOIUrl":"10.1016/j.ijpx.2025.100465","url":null,"abstract":"<p><p>The development of biocompatible nanotherapeutics for skin regeneration remains a major goal in regenerative medicine. Here, we report the isolation and characterization of rose petal-derived extracellular vesicle-like nanovesicles (RPDNVs) obtained by differential ultracentrifugation and size exclusion chromatography. Comprehensive physicochemical analyses confirmed their vesicular morphology, nanoscale size distribution, and antioxidant-enriched molecular cargo, including lipids, phenols, and proteins. RPDNVs demonstrated mechanical stability compatible with tissue interfacing. Functionally, they enhanced fibroblast migration and modulated extracellular matrix gene expression without inducing fibrotic responses. Their biocompatibility was confirmed by in vitro and in vivo studies on human volunteers, thus supporting their translational relevance. Notably, RPDNVs retained structural and functional stability following freeze-drying in the absence of cryoprotectants, enabling long-term storage. These results establish RPDNVs as a promising class of plant-derived nanocarriers for therapeutic skin repair.</p>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"100465"},"PeriodicalIF":6.4,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12741408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145849989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multifunctional fungal defensin bladesin loaded-hydrogel for accelerated infectious wound healing.","authors":"Yating Chen, Yan Yu, Bingzheng Shen","doi":"10.1016/j.ijpx.2025.100463","DOIUrl":"10.1016/j.ijpx.2025.100463","url":null,"abstract":"<p><p>Wound management is significantly challenged by drug-resistant bacterial infections. In this study, a novel fungal defensin peptide derived from <i>Blastomyces dermatitis</i> was identified. The full-length peptide named bladesin was composed of 116 amino acids containing three regions: signal peptide, pro-peptide, and mature peptide. Sequence and structural analysis revealed that the linear mature peptide (reduced type) was consisted of 38 amino acids. The mature bladesin contains three intramolecular disulfide bonds (Cys4-Cys29, Cys14-Cys35 and Cys18-Cys37) and can form a characteristic cysteine-stabilized alpha-beta motif in the native state. <i>In vitro</i> studies demonstrated it exhibited potent antibacterial activity against Gram-positive pathogens with minimum inhibitory concentrations (MICs) ranging from 4 to 32 μM. Furthermore, bladesin was found to promote the proliferation of NIH/3 T3 fibroblasts cells. Using the Poloxamer 407 as the thermosensitive matrix, a bladesin-loaded sustained-release hydrogel was successfully prepared. <i>In vivo</i> experiments showed bladesin hydrogels can accelerate cutaneous wound healing. The mechanism exploration revealed that it can promote pathogen clearance, enhance collagen deposition and regulate inflammatory responses. These findings suggested that this bladesin-based dressings represented a promising therapeutic strategy for the treatment of infected wounds.</p>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"100463"},"PeriodicalIF":6.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12723373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dextran-modified dissolving microneedle patches for effective amelioration of psoriasis through transdermal delivery of hesperidin.","authors":"Nooshin Etemadi, Jaleh Varshosaz, Nahal Shamaeizadeh, Amir Mohamadsharifi Renani, Mohsen Minaiyan","doi":"10.1016/j.ijpx.2025.100462","DOIUrl":"10.1016/j.ijpx.2025.100462","url":null,"abstract":"<p><p>Psoriasis is a chronic, multifactorial, proliferative inflammatory skin disease characterized by immune-mediated relapsing and remitting phases. Topical treatments for mild to moderate psoriasis, as well as systemic treatments for severe cases, can be insufficiently effective and are often associated with significant side effects. The primary objective of this study was to develop a dissolvable microneedle patch containing the flavonoid hesperidin within a polymeric matrix composed of dextran modified polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) aiming to achieve effective control of psoriasis symptoms. The innovative laser ablation technique used in master mold fabrication resulted in well-structured pyramidal arrays, as evidenced by SEM images of the microneedle patches (MNPs). Various formulations were developed in which almost complete dissolving of the needle occured only 30 s. MNP containing PVP 150 mg, PVA 75 mg and Dextran 50 mg, with the highest compressive failure force, was able to sink into the skin well. Over 70 % of hesperidin was released within approximately 15 h from the dissolved MNs into skin. Animal studies were conducted using an imiquimod-induced psoriasis mouse model. PASI score or cumulative amount of three parameters; desquamation or scaling, erythema, and induration or thickness for each group on experimental days 1 to 7 were studied. Significant clinical improvement on PASI scores, was observed in the group treated with hesperidin-loaded optimal MNP (1.67 ± 0.47) compared to the positive control (11.67 ± 0.47) and the oral hesperidin groups (6.00 ± 0.82). The results of this study indicate that dextran modified MNPs of hesperidin can reduce epidermal hyperplasia and inflammatory cell infiltration, demonstrating an effective method for transdermal drug delivery.</p>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"100462"},"PeriodicalIF":6.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12720357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145819226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of the conjugation manner of targeting agent and tandem cell-penetrating peptide on the efficacy of mitomycin C liposomes in treating triple-negative breast tumors.","authors":"Mehrnaz Salahi, Jaleh Varshosaz, Mahboubeh Rostami, Salar Nasr Esfahani, Arsham Hekmat, Ali Jahanian-Najafaabadi, Mohsen Minayian","doi":"10.1016/j.ijpx.2025.100457","DOIUrl":"10.1016/j.ijpx.2025.100457","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) remains one of the most aggressive subtypes with limited therapeutic options. To address this unmet need, this study aimed to enhance the cellular uptake and cytotoxicity of mitomycin C (MMC) using surface-modified nanoliposomes functionalized with poly-L-arginine (PLA), a cell-penetrating peptide, and chondroitin sulfate (CS), a CD44-targeting ligand. Another object was to investigate how the conjugation manner of the targeting agent-chondroitin sulfate (CS), a CD44-targeting ligand, and a tandem cell-penetrating peptide (CPP) made of poly-L-arginine (PLA)-affects the enhancement of cellular uptake and anti-tumor effects of Mitomycin C (MMC) nanoliposomes in triple-negative breast cancer (TNBC). We synthesized and characterized four liposomal formulations; CS-liposomes, PLA-liposomes, PLA-CS-liposomes, and CS-PLA-liposomes and their particle size, polydispersity index, zeta potential, encapsulation efficiency, and drug release were evaluated. In vitro studies on 4 T1 TNBC cells included cytotoxicity (MTT), cellular uptake, apoptosis, cell cycle arrest, and caspase-3/8 expression (qRT-PCR). In vivo efficacy was tested in BALB/c mice bearing orthotopic 4 T1 tumors by monitoring tumor growth, body weight, and histopathology (H&E and Ki-67). Optimized PLA-CS liposomes had a mean particle size of 144.0 ± 2.4 nm, a PDI of 0.31 ± 0.02, and 73 % encapsulation efficiency, with sustained MMC release over 24 h. PLA-functionalized liposomes showed significantly greater cytotoxicity and uptake than free MMC and non-targeted controls. They induced G1 cell cycle arrest and strongly upregulated caspase-3 (+64-fold in CS-PLA, +13-fold in PLA-CS), consistent with activation of the intrinsic apoptosis pathway. Animal studies revealed PLA-CS liposomes produced the strongest tumor suppression (Ki-67 index 6 %), reduced tumor grade to 1, and showed no liver or kidney metastasis. All liposomal formulations performed better than free MMC in tumor control and safety. PLA-CS-liposomes provide a potent and well-tolerated delivery platform for MMC in TNBC, combining improved tumor targeting, enhanced apoptotic response, and favorable organ safety.</p>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"100457"},"PeriodicalIF":6.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12753249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal pharmacokinetic and safety studies of an antibody-erythropoietin fusion protein for Alzheimer's disease.","authors":"Rudy Chang, Devaraj V Chandrashekar, G Chuli Roules, Nataraj Jagadeesan, Emi Iwasaki, Adenike Oyegbesan, Hayk Davtyan, Rachita K Sumbria","doi":"10.1016/j.ijpx.2025.100459","DOIUrl":"10.1016/j.ijpx.2025.100459","url":null,"abstract":"<p><p>Erythropoietin (EPO) shows promise for Alzheimer's disease (AD) but has poor brain penetration, necessitating high doses that cause hematopoietic side effects. To improve brain delivery, EPO was fused to a transferrin receptor monoclonal antibody (TfRMAb), and this study evaluated the pharmacokinetics (PK), safety, and efficacy of repeated TfRMAb-EPO dosing in mice to further its preclinical development. C57BL/6J male mice (10 weeks old, <i>n</i> = 4-5/dose) received subcutaneous (SQ) low (1 mg/kg), mid (3 and 6 mg/kg), or high (20 mg/kg) TfRMAb-EPO doses for 4 weeks. The 1 mg/kg dose showed no adverse effects and resulted in sustained brain and plasma exposure, making it suitable for longitudinal dosing. Paradoxically, higher doses reduced plasma and brain exposure, and altered hematocrit, TfR expression, and spleen weight; these changes were largely reversible. Anti-drug antibodies and TfR expression changes likely contributed to reduced plasma exposure at higher doses. Subsequently, 5.5-month-old APP_SAA knock-in (KI) mice (<i>n</i> = 6) received 1 mg/kg TfRMAb-EPO SQ for 14 weeks. Controls included vehicle-treated APP_SAA KI and APP wild-type mice (<i>n</i> = 4-5/group). Despite the low dose, TfRMAb-EPO showed profound brain Aβ-lowering effects measured by immunostaining (70-80 % reduction, <i>p</i> < 0.001) and improved spatial memory in the Y maze (<i>p</i> < 0.05). These findings offer important preclinical data to guide dose optimization in longitudinal studies using TfRMAb-based therapeutics, specifically TfRMAb-EPO, given the movement of TfRMAb-based therapeutics into clinical trials for AD, and show the robust therapeutic potential of low-dose TfRMAb-EPO in APP_SAA KI AD mice.</p>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"10 ","pages":"100459"},"PeriodicalIF":6.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12765438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}