Drug Delivery最新文献

{"title":"Immunomodulator loaded microneedle arrays for targeted intradermal drug delivery to skin tumors.","authors":"Akmal H Sabri, Fiona Smith, Zachary Cater, Pratik Gurnani, Ami Nash, Victoria Brentville, Lindy Durrant, John McKenna, Joel Segal, David J Scurr, Maria Marlow","doi":"10.1080/10717544.2025.2527824","DOIUrl":"10.1080/10717544.2025.2527824","url":null,"abstract":"<p><p>Topical therapy with imiquimod in a cream [5% w/w imiquimod cream (Aldara™)] for the treatment of nodular basal cell carcinoma (BCC) currently results in low cure rates, attributed to low imiquimod permeation. Herein we have developed novel microneedle array patches (MAPs), to maximize imiquimod intradermal delivery and retention in the skin, with potential as an efficacious treatment for BCC. Enhanced delivery of imiquimod in pig skin and <i>ex vivo</i> BCC tissue was found with the obelisk poly N-acryloylmorpholine (pNAM) MAPs as compared to the 5% w/w imiquimod cream and MAPS manufactured from a commercially available polymer (PVPVA). Additionally, the increased retention in <i>ex vivo</i> BCC tissue was found with the obelisk pNAM MAPs as compared to the 5% w/w imiquimod cream. In addition, detailed characterization of single needles and mechanistic studies of MAPs in tissue using mass spectrometry imaging confirmed the imiquimod homogeneity in the needles. Most importantly, the <i>in vivo</i> tumor efficacy study showed that pNAM obelisk MAPs could deliver imiquimod into the tumor, retarding tumor growth. This study suggests that the drug loaded obelisk pNAM MAPs manufactured here may be of clinical utility for localized intradermal delivery of imiquimod.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2527824"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12247101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599744","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":"Targeted nanoliposomes for precision rheumatoid arthritis therapy: a review on mechanisms and <i>in vivo</i> potential.","authors":"Rushikesh Girase, Nayan A Gujarathi, Amey Sukhia, Sri Sai Nikitha Kota, Tulshidas S Patil, Abhijeet A Aher, Yogeeta O Agrawal, Shreesh Ojha, Charu Sharma, Sameer N Goyal","doi":"10.1080/10717544.2025.2459772","DOIUrl":"10.1080/10717544.2025.2459772","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is an inflammatory immune-triggered disease that causes synovitis, cartilage degradation, and joint injury. In nanotechnology, conventional liposomes were extensively investigated for RA. However, they frequently undergo rapid clearance, reducing circulation time and therapeutic efficacy. Additionally, their stability in the bloodstream is often compromised, resulting in premature drug release. The current review explores the potential of targeted liposomal-based nanosystems in the treatment of RA. It highlights the pathophysiology of RA, explores selective targeting sites, and elucidates diverse mechanisms of novel liposomal types and their applications. Furthermore, the targeting strategies of pH-sensitive, flexible, surface-modified, PEGylated, acoustic, ROS-mediated, and biofunctionalized liposomes are addressed. Targeted nanoliposomes showed potential in precisely delivering drugs to CD44, SR-A, FR-β, FLS, and toll-like receptors through the high affinity of ligands. <i>In vitro</i> studies interpreted stable release profiles and improved stability. <i>Ex vivo</i> studies on skin demonstrated that ultradeformable and glycerol-conjugated liposomes enhanced drug penetrability. <i>In vivo</i> experiments for liposomal types in the arthritis rat model depicted remarkable efficacy in reducing joint swelling, pro-inflammatory cytokines, and synovial hyperplasia. In conclusion, these targeted liposomes represented a significant leap forward in drug delivery, offering effective therapeutic options for RA. In the future, integrating these advanced liposomes with artificial intelligence, immunotherapy, and precision medicine holds great promise.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2459772"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074272","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":"Pharmacokinetic profile and <i>in vivo</i> anticancer efficacy of anagrelide administered subcutaneously in rodents.","authors":"Kirsi Toivanen, Luna De Sutter, Agnieszka Wozniak, Karo Wyns, Nanna Merikoski, Sami Salmikangas, Jianmin Duan, Mikael Maksimow, Maria Lahtinen, Tom Böhling, Patrick Schöffski, Harri Sihto","doi":"10.1080/10717544.2025.2463433","DOIUrl":"10.1080/10717544.2025.2463433","url":null,"abstract":"<p><p>Anagrelide (ANA) is a phosphodiesterase 3A (PDE3A) inhibitor, commonly prescribed for essential thrombocythemia. It also functions as a molecular glue, inducing complex formation between PDE3A and Schlafen 12. This association either triggers apoptosis or inhibits proliferation in tumor cells, supporting its use in cancer therapy. Conventionally administered orally, ANA undergoes rapid metabolism and elimination, resulting in a short drug exposure time at the site of action. Here, we explored the pharmacokinetic profile of a subcutaneously (SC) injected ANA formulation in Sprague-Dawley rats by quantifying plasma ANA and metabolite concentrations using liquid-chromatography-tandem mass spectrometry. We further evaluated the <i>in vivo</i> tumor regression efficacy of orally and SC administered ANA in a patient-derived gastrointestinal stromal xenograft mouse model - UZLX-GIST2B - characterized by a <i>KIT</i> exon 9 driver mutation. The SC ANA exhibited extended-release plasma concentration-time profiles compared to intravenous and oral administrations. After a single administration in rats, plasma concentrations of ANA were detected up to 56 days later, and ANA metabolites up to 30 days later. The SC formulation also significantly reduced tumor volumes and demonstrated dose-dependent histological responses, nearly eradicating tumor tissue in 11 days with the highest dose. These findings suggest that the SC slow-release formulation maintains stable drug concentrations during treatment, potentially improving therapeutic efficacy at the target site.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2463433"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11816618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390246","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":"Development, <i>in vitro</i> and <i>ex vivo</i> characterization of lamotrigine-loaded bovine serum albumin nanoparticles using QbD approach.","authors":"Maryana Salamah, Bence Sipos, Zsuzsanna Schelz, István Zupkó, Ágnes Kiricsi, Ágnes Szalenkó-Tőkés, László Rovó, Gábor Katona, György Tibor Balogh, Ildikó Csóka","doi":"10.1080/10717544.2025.2460693","DOIUrl":"10.1080/10717544.2025.2460693","url":null,"abstract":"<p><p>The present study aimed to prepare and optimize lamotrigine-loaded bovine serum albumin nanoparticles (LAM-NP) using the Quality by Design (QbD) approach and to investigate both the <i>in vitro</i> and <i>ex vivo</i> effects of different cross-linking agents glutaraldehyde (GLUT), glucose (GLUC) and 1-(3-dimethylaminutesopropyl)-3-ethylcarbodiimide hydrochloride (EDC) on intranasal applicability. Cross-linked LAM-NP from EDC (NP-EDC-1) showed the lowest Z-average value (163.7 ± 1.9 nm) and drug encapsulation efficacy (EE%) of 97.31 ± 0.17%. The drug release of GLUC cross-linked LAM-NP (NP-GLUC-9), glutaraldehyde cross-linked LAM-NP (NP-GLUT-2), and NP-EDC-1 at blood circulation conditions was higher than the initial LAM. The results of the blood-brain barrier parallel artificial membrane permeability assay (BBB-PAMPA) showed an increase in the permeability of LAM through the BBB with NP-GLUC-9 and an increase in flux with all selected formulations. The <i>ex vivo</i> study showed that LAM diffusion from the selected formulations through the human nasal mucosa was higher than in case of initial LAM. The cytotoxicity study indicated that BSA-NP reduced LAM toxicity, and GLUC 9 mM and EDC 1 mg could be alternative cross-linking agents to avoid GLUT 2% v/v toxicity. Furthermore, permeability through Caco-2 cells showed that nasal epithelial transport/absorption of LAM was improved by using BSA-NPs. The use of BSA-NP may be a promising approach to enhance the solubility, permeability through BBB and decrease the frequency of dosing and adverse effects of LAM.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2460693"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11795762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122491","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":"Numerical simulation of magnetic drug targeting for lung cancer therapy using a bulk superconducting magnet.","authors":"Zhenyang Xu, Tayebeh Mousavi, Mark Ainslie","doi":"10.1080/10717544.2025.2490836","DOIUrl":"https://doi.org/10.1080/10717544.2025.2490836","url":null,"abstract":"<p><p>Primary bronchus cancer is one kind of lung cancer with a very high mortality rate. Magnetic drug targeting (MDT) technology could concentrate drugs in a specific area, which could have useful application in lung cancer therapy. Due to a bulk superconducting magnet's ability to generate a superior magnetic field strength and gradient in comparison to conventional permanent magnets, there is great potential for achieving MDT external to the body. However, current research in this area is still in its infancy, and numerical simulations exploring the guidance ability of this technology have been limited to only two-dimensional geometries, which limits further exploration toward clinical transformation. In this work, a three-dimensional lung and bulk superconducting magnet model have been built in the finite-element software package COMSOL Multiphysics. The model is used to simulate the drug delivery process in the lung via the superconducting magnet. The influence of various parameters on the capture efficiency is investigated, including lung-magnet distance, bulk superconductor properties, particle properties, and physiological or tumor structural parameters. The results demonstrate that the bulk superconducting magnet can effectively improve the capture efficiency of magnetic drugs or drug carriers within a suitable distance outside of the body, which could potentially guide the design of a practical, external superconducting MDT system in the near future.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2490836"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973072","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":"Novel ethosomal gel formulation for enhanced transdermal delivery of curcumin and cyclosporine: a preclinical approach to rheumatoid arthritis management.","authors":"Sankalp Gharat, Munira Momin, Urvashi Panchal, Abdelwahab Omri","doi":"10.1080/10717544.2025.2512620","DOIUrl":"10.1080/10717544.2025.2512620","url":null,"abstract":"<p><p>Vesicular systems have demonstrated efficacy in the management of Rheumatoid Arthritis (RA). This study explores the synergistic effect of edge-activated ethosomal gel to enhance the transdermal delivery of Curcumin (CUR) and Cyclosporine (CYC). Ethosomal vesicles prepared via the ethanol injection method were incorporated into a gel, with the optimized formulation exhibiting an average particle size of 93.3 ± 1.17 nm and a zeta potential of -29.2 ± 0.17 mV. <i>Ex vivo</i> diffusion studies on porcine ear skin demonstrated 97.115 ± 0.40% CUR and 98.331 ± 1.08% CYC release over 18 hours, exhibiting Hixson-Crowell diffusion mechanisms. The steady-state flux and permeability coefficients were 0.095 µg/cm²/hr and 0.0095 cm/hr for CUR, and 0.0804 µg/cm²/hr and 0.01608 cm/hr for CYC respectively. In anti-inflammatory tests on lipopolysaccharide (LPS)-induced RAW 264.7 cells, the gel significantly increased IL-10 levels (p < 0.001), inhibited prostaglandin-E2, and reduced IL-6 and TNF-α levels (p < 0.001). Moreover, the ethosomal gel demonstrated nonirritating properties and exhibited significant reduction in arthritic symptoms in the Complete Freund's Adjuvant induced 28-day rat model, surpassing the effects of marketed and conventional gel. These findings highlight the synergistic benefits of combining CUR and CYC in an ethosomal gel, offering a promising alternative for RA management. Future clinical investigations are warranted to validate its safety and efficacy in humans and facilitate potential therapeutic integration.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2512620"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208015","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":"Biomimetic cancer cell membrane-enriched vitamin E-stapled gemcitabine-loaded TPGS micelles for pancreatic cancer therapy.","authors":"Miguel Pereira-Silva, Luis Diaz-Gomez, Bárbara Blanco-Fernandez, Ana Cláudia Paiva-Santos, Francisco Veiga, Angel Concheiro, Carmen Alvarez-Lorenzo","doi":"10.1080/10717544.2025.2527759","DOIUrl":"10.1080/10717544.2025.2527759","url":null,"abstract":"<p><p>Pancreatic cancer (PC) is currently a leading cause of death worldwide and its incidence is expected to increase in the following years. Chemotherapy with gemcitabine (GEM) is precluded by extensive enzymatic inactivation and clearance, and the nonspecific tissue distribution contributes to unwanted systemic toxicity and tumor resistance. In this work, GEM was encapsulated in d-ɑ-tocopheryl polyethylene glycol succinate (TPGS) micelles by 'stapling' GEM at 4-NH₂ position with vitamin E succinate (VES) through a highly stable amide bond, achieving successful GEM hydrophobization by means of a prodrug system (VES-GEM). Recurring to solvent evaporation methodology, TPGS/VES-GEM (6/1 molar ratio) micelles were prepared, optimized regarding TPGS-to-VES-GEM ratio, and characterized regarding size, surface charge, polydispersity index, morphology, drug loading, and encapsulation efficiency (EE). Furthermore, purification methods were explored together with VES-GEM release profile and stability. Lastly, cell viability and cellular uptake of the formulation were analyzed in 2D and 3D BxPC3 cell line models. TPGS/VES-GEM micelles (6/1) showed ultra-small size (∼30 nm), and remarkable EE (>95%) together with ability to retain VES-GEM for long period of time (>7 days) with high stability. The micelles demonstrated exceptional cell cytotoxic activity for concentrations of 10 and 100 µM VES-GEM (∼0% cell viability) which may be explained by concerted action of GEM, VES, and TPGS. The nanocarrier was further enriched with PC cell membrane nanovesicles, displaying size ∼150 nm, ZP ∼ -30 mV and PDI ∼0.2 to improve biointerfacing properties and targeting properties. BxPC3 cell membrane-modified TPGS/VES-GEM micelles may be attractive biomimetic nanosystem for next-generation PC therapeutics.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2527759"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590722","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":"Valency-affinity mapping of multivalent liposomes for tunable target cell discrimination.","authors":"Victor A Garcia, Paulina M Eberts, Brenda M Ogle, Casim A Sarkar","doi":"10.1080/10717544.2025.2512950","DOIUrl":"10.1080/10717544.2025.2512950","url":null,"abstract":"<p><p>Multivalency can drive high-avidity binding of ligand-functionalized nanoparticles to cells with high target receptor expression, but it can also contribute to off-target binding to low-expression non-target cells. We explored how ligand affinity and liposome valency shape the resulting binding performance index (BPI), defined as the product of the proportion of liposome-bound target cells and that of non-bound non-target cells. Designed ankyrin repeat proteins (DARPins) spanning a wide range of HER2-binding affinities were tethered onto PEGylated liposomes at varying concentrations. BPI was initially evaluated in mixed-cell suspensions of HER2^high SKBR3 (target) cells and HER2^low T47D (non-target) cells, with the highest BPI (> 0.8) observed for high-valency liposomes displaying high-affinity DARPins. To further map the BPI landscape, we measured particle binding to HEK293T cells transiently transfected with HER2-EGFP, leveraging the inherent transfection heterogeneity to generate continuous binding response curves as a function of HER2 expression. HER2^high (target) and HER2^low (non-target) populations were defined by a HER2 threshold, which was varied across the range of HER2 expression to determine maximum BPI values (> 0.85) and corresponding HER2 threshold optima (HER2_OPT). BPI generally tracks with traditional binding selectivity, but BPI is more sensitive to off-target effects or poor on-target binding and thus may better assess particle performance. We further demonstrate that HER2_OPT can be rationally increased or decreased by adjusting DARPin valency and affinity (separately or synergistically) to lower or higher values, respectively. The approach outlined here enables rapid testing and optimization of ligand parameters for nanoparticle binding toward a given therapeutic target.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2512950"},"PeriodicalIF":8.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474285","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":"Harnessing nanofibers for targeted delivery of phytoconstituents in age-related macular degeneration.","authors":"Ulia Andrades, Sahil Gaikar, Khushali Nathani, Sujata Sawarkar, Abdelwahab Omri","doi":"10.1080/10717544.2025.2489491","DOIUrl":"10.1080/10717544.2025.2489491","url":null,"abstract":"<p><p>Age-related macular degeneration is a degenerative eye condition that affects the macula and results in central vision loss. Phytoconstituents show great promise in the treatment of AMD. AMD therapy can benefit from the advantages of phytoconstituents loaded nanofibers. There are opportunities to improve the effectiveness of phytoconstituents in the treatment of age-related macular degeneration (AMD) through the use of nanofiber-based delivery methods. These novel platforms encapsulate and distribute plant-derived bioactives by making use of the special qualities of nanofibers. These qualities include their high surface area-to-volume ratio, variable porosity, and biocompatibility. Exploring the use of nanofiber-based delivery methods to provide phytoconstituents in AMD treatment is a great choice for enhancing patient adherence, safety, and efficacy in managing this condition. This article explores the potential of nanofiber-based delivery methods to revolutionize AMD treatment, providing an innovative and effective approach to treat this condition.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2489491"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794964","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":"Enhancing targeted delivery and efficacy of PEGylated liposomal doxorubicin with liposomal minoxidil: comprehensive in silico, in vitro, and in vivo tumor model studies.","authors":"Vahideh Mohammadzadeh, Leila Arabi, Seyedeh Maryam Hosseinikhah, Mohammad Mashreghi, Fatemeh Kalalinia, Neda Mostajeran, Mohammad Reza Zirak, Farzin Hadizadeh, Mojgan Nejabat, Hossein Kamali, Niloufar Rahiman, Mahmoud Reza Jaafari","doi":"10.1080/10717544.2025.2536802","DOIUrl":"10.1080/10717544.2025.2536802","url":null,"abstract":"<p><p>The therapeutic efficacy of nanoparticle (NP)-encapsulated cytotoxic drugs has remained limited by poor penetration into solid tumors. To address this challenge, we developed a novel strategy using minoxidil-loaded nanoliposomes (Lip-MXD) to induce tumor vasodilation and enhance the delivery of PEGylated liposomal doxorubicin (PLD). We developed a remote loading method utilizing a calcium acetate gradient to encapsulate MXD into liposomes, achieving a high MXD encapsulation efficiency (87%). The resulting Lip-MXD formulation displayed an average particle size of 111 nm, a polydispersity index of 0.05, and a zeta potential of -15.7 mV. Pretreatment with Lip-MXD demonstrated multifunctional effects. It significantly downregulated CLDN-1 expression, improving NP penetration into advanced, fibrotic tumors. The stability of interaction between CLDN-1 and MXD was confirmed by molecular dynamics (MD) simulation. Immunohistochemistry and gene expression analyses in mouse models of colorectal (CRC) and pancreatic (PCa) cancers revealed that Lip-MXD administration significantly reduced the number of tumor-associated stromal cells. Furthermore, Lip-MXD mitigated tumor hypoxia and substantially enhanced PLD permeability within the dense microenvironment of desmoplastic tumors through its vasodilatory effects. A single dose of PLD following Lip-MXD pretreatment exhibited significant antitumor activity, resulting in a prolonged survival rate of 60% in the Lip-MXD+PLD-treated group in CRC models. In nude mice bearing PCa, the Lip-MXD+PLD-treated group achieved a significant reduction in tumor volume compared to the PLD group over a 14-day evaluation period. This MXD liposomal formulation offers a promising method to overcome tumor penetration, enhance NP delivery and improve therapeutic outcomes in CRC and PCa cancers, meriting further investigation.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2536802"},"PeriodicalIF":8.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774887","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}