Sustained and localized delivery of gemcitabine using chitosan-PVA-TPP polymeric implant enhances antitumor efficacy and delays surgical relapse in pancreatic cancer

IF 6 2区医学 Q2 MATERIALS SCIENCE, BIOMATERIALS

Materials Science & Engineering C-Materials for Biological Applications Pub Date : 2025-09-04 DOI:10.1016/j.bioadv.2025.214489

Archana Kumari , Arijit Mal , Rahul Thorat , Panchali Saha , Parikshit Patel , Snehal K. Valvi , Murali Krishna Chilakapati , Abhijit De , Rajdip Bandyopadhyaya

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Abstract

Gemcitabine (GEM), one of the first lines of therapy in pancreatic cancer (PC) patients, has certain limitations, such as, low plasma half-life, limited bioavailability and treatment index. To address these issues, a localized and sustained delivery approach is undertaken, where we have developed a biodegradable polymeric film implant, by solvent casting method, using chitosan, polyvinyl alcohol (PVA), and sodium tripolyphosphate (TPP). Incorporating PVA and crosslinker TPP with chitosan enhances the mechanical strength of the chitosan film, evident from reduction of elastic modulus from 18.51 to 0.19 MPa. Under in vitro conditions, the film gradually releases GEM, exhibiting increased cell-killing capabilities in both 2D and 3D cell models and enhanced efficacy against GEM-resistant PC cells. Delivery through implant induces alteration of the lipid content of cells and significantly (p < 0.0001) enhances DNA double-strand break and antiproliferative properties. Furthermore, antitumor efficacy of GEM-loaded film (GEM-film) in pre-clinical settings significantly (p < 0.05) impairs tumor growth in advanced subcutaneous models and mitigates therapy resistance. GEM-film implants have proven ~7 times more effective in orthotopic models and have also delayed surgical relapse in PC mice models. Our study demonstrates that the delivery of GEM using the polymeric composite film is advantageous over that of free GEM in a pre-clinical context.

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壳聚糖- pva - tpp聚合物植入物持续和局部给药吉西他滨可提高胰腺癌的抗肿瘤疗效并延缓手术复发

吉西他滨（GEM）作为胰腺癌（PC）患者的一线治疗药物之一，存在血浆半衰期低、生物利用度和治疗指数有限等局限性。为了解决这些问题，我们采取了一种局部和持续的递送方法，我们开发了一种可生物降解的聚合物膜植入物，通过溶剂铸造法，使用壳聚糖、聚乙烯醇（PVA）和三聚磷酸钠（TPP）。壳聚糖与PVA和交联剂TPP的掺入提高了壳聚糖膜的机械强度，弹性模量从18.51降低到0.19 MPa。在体外条件下，薄膜逐渐释放GEM，在2D和3D细胞模型中均表现出更高的细胞杀伤能力，并增强了对GEM抗性PC细胞的功效。通过植入给药可诱导细胞脂质含量的改变，并显著（p < 0.0001）增强DNA双链断裂和抗增殖特性。此外，GEM-film在临床前的抗肿瘤效果显著（p < 0.05）损害了晚期皮下模型的肿瘤生长并减轻了治疗抵抗。GEM-film植入物在原位模型中的有效性提高了约7倍，并且在PC小鼠模型中也延迟了手术复发。我们的研究表明，在临床前环境中，使用聚合物复合膜递送GEM比自由递送GEM更有利。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Materials Science & Engineering C-Materials for Biological Applications 工程技术-材料科学：生物材料

CiteScore

17.80

自引率

0.00%

发文量

501

审稿时长

27 days

期刊介绍： Biomaterials Advances, previously known as Materials Science and Engineering: C-Materials for Biological Applications (P-ISSN: 0928-4931, E-ISSN: 1873-0191). Includes topics at the interface of the biomedical sciences and materials engineering. These topics include: • Bioinspired and biomimetic materials for medical applications • Materials of biological origin for medical applications • Materials for "active" medical applications • Self-assembling and self-healing materials for medical applications • "Smart" (i.e., stimulus-response) materials for medical applications • Ceramic, metallic, polymeric, and composite materials for medical applications • Materials for in vivo sensing • Materials for in vivo imaging • Materials for delivery of pharmacologic agents and vaccines • Novel approaches for characterizing and modeling materials for medical applications Manuscripts on biological topics without a materials science component, or manuscripts on materials science without biological applications, will not be considered for publication in Materials Science and Engineering C. New submissions are first assessed for language, scope and originality (plagiarism check) and can be desk rejected before review if they need English language improvements, are out of scope or present excessive duplication with published sources. Biomaterials Advances sits within Elsevier''s biomaterials science portfolio alongside Biomaterials, Materials Today Bio and Biomaterials and Biosystems. As part of the broader Materials Today family, Biomaterials Advances offers authors rigorous peer review, rapid decisions, and high visibility. We look forward to receiving your submissions!