Latečka Filip, Juriňáková Tamara, Münster Lukáš, Muchová Monika, Masařík Michal, Kuchynski Anton, Humpolíček Petr, Fojtů Michaela, Vícha Jan
Centre of Polymer Systems, Tomas Bata University in Zlín, tř. Tomáše Bati 5678, 760 01 Zlín, Czech Republic.
Department of Pathophysiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic.
Biomacromolecules. 2025 Aug 11;26(8):5232-5244. doi: 10.1021/acs.biomac.5c00692. Epub 2025 Jul 22.
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(-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. 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.
由于羧基数量有限,刺激响应性透明质酸载体面临局限性,这些羧基需分配用于药物偶联和功能修饰。基于接枝聚(N-异丙基丙烯酰胺)(pNIPAM)的选择性氧化透明质酸(2,3-二羧基透明质酸,DCH)开发了热响应纳米凝胶用于菲啶铂(PhPt)递送。pNIPAM接枝后进行顺序氧化引入了额外的羧基,从而实现更高效的药物负载和控释。与未氧化的pNIPAM修饰的HA相比,这种方法实现了3倍更高的负载效率和显著更慢的药物释放。负载PhPt后,DCH-pNIPAM共轭物自组装成纳米凝胶,药物结合模式(离子键与共价键)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显示出释放减少。对卵巢癌细胞系(包括顺铂耐药变体)的研究表明,与游离PhPt相比,细胞毒性增加了18倍。这些纳米凝胶为提高癌症治疗中的药物疗效、减少脱靶效应和克服耐药性提供了一种有前景的策略。
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