Thermoresponsive Hyaluronate-Based Nanogels for Enhanced Phenanthriplatin Delivery in Cisplatin-Resistant Ovarian Cancer.

IF 5.5 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomacromolecules Pub Date : 2025-07-22 DOI:10.1021/acs.biomac.5c00692

Filip Latečka, Tamara Juriňáková, Lukáš Münster, Monika Muchová, Michal Masařík, Anton Kuchynski, Petr Humpolíček, Michaela Fojtů, Jan Vícha

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引用次数: 0

Abstract

Stimuli-responsive hyaluronic acid carriers face limitations due to limited carboxyl groups, which are divided between drug conjugation and functional modifications. Thermoresponsive nanogels based on selectively oxidized hyaluronan (2,3-dicarboxy hyaluronate, DCH) grafted with poly(N-isopropyl acrylamide) (pNIPAM) were developed for phenanthriplatin (PhPt) delivery. Sequential oxidation after pNIPAM grafting introduced additional carboxylic groups, enabling a more efficient drug loading and controlled release. Compared to nonoxidized pNIPAM-modified HA, this approach achieved 3 times higher loading efficacy and significantly slower drug release. Upon PhPt loading, DCH-pNIPAM conjugates self-assembled into nanogels, with the drug binding mode (ionic vs covalent) influencing particle rearrangement and drug release behavior. Covalently bound PhPt showed reduced release compared to nonthermoresponsive controls. In vitro studies on ovarian cancer cell lines, including cisplatin-resistant variants, demonstrated up to an 18-fold increase in cytotoxicity versus free PhPt. These nanogels offer a promising strategy for enhancing drug efficacy, reducing off-target effects, and overcoming resistance in cancer therapy.

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基于热反应性透明质酸的纳米凝胶增强顺铂耐药卵巢癌非那西铂的递送。

刺激反应性透明质酸载体由于羧基有限而面临限制，羧基分为药物偶联和功能修饰。以选择性氧化透明质酸（2,3-二羧基透明质酸，DCH）接枝聚n -异丙基丙烯酰胺（pNIPAM）为基础，研制了用于非那西铂（PhPt）递送的热响应纳米凝胶。pNIPAM接枝后的顺序氧化引入了额外的羧基，使药物负载和控制释放更有效。与未氧化的pnipam修饰的HA相比，该方法的负载效率提高了3倍，药物释放速度明显减慢。负载PhPt后，DCH-pNIPAM自组装成纳米凝胶，其药物结合模式（离子与共价）影响颗粒重排和药物释放行为。与非热响应对照相比，共价结合的PhPt释放量减少。在卵巢癌细胞系（包括顺铂耐药变体）的体外研究中，表明与游离PhPt相比，PhPt的细胞毒性增加了18倍。这些纳米凝胶为提高药物疗效、减少脱靶效应和克服癌症治疗中的耐药性提供了一种有前途的策略。

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

Biomacromolecules 化学-高分子科学

CiteScore

10.60

自引率

4.80%

发文量

417

审稿时长

1.6 months

期刊介绍： Biomacromolecules is a leading forum for the dissemination of cutting-edge research at the interface of polymer science and biology. Submissions to Biomacromolecules should contain strong elements of innovation in terms of macromolecular design, synthesis and characterization, or in the application of polymer materials to biology and medicine. Topics covered by Biomacromolecules include, but are not exclusively limited to: sustainable polymers, polymers based on natural and renewable resources, degradable polymers, polymer conjugates, polymeric drugs, polymers in biocatalysis, biomacromolecular assembly, biomimetic polymers, polymer-biomineral hybrids, biomimetic-polymer processing, polymer recycling, bioactive polymer surfaces, original polymer design for biomedical applications such as immunotherapy, drug delivery, gene delivery, antimicrobial applications, diagnostic imaging and biosensing, polymers in tissue engineering and regenerative medicine, polymeric scaffolds and hydrogels for cell culture and delivery.