Kim Byeong Kook, Kumar Parveen, Yadav Sonyabapu, Jo Sung-Han, Kim Seon-Hwa, Cho Hongsik, Park Sang-Hyug, Lim Kwon Taek
Department of Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan 48513, Republic of Korea.
Institute of Display Semiconductor Technology, Pukyong National University, Busan 48513, Republic of Korea.
Carbohydr Polym. 2025 Oct 15;366:123808. doi: 10.1016/j.carbpol.2025.123808. Epub 2025 May 27.
The instability of nanocarriers and premature leakage of drugs during circulation in the body remain major challenges that frequently lead to undesirable side effects in the development of nanomedicines. Achieving effective drug release within the tumor microenvironment is a key goal for desirable chemotherapy. In this study, we designed a novel type of core-cross-linked micelles (CCL) formed from biocompatible oligosaccharide-based AB miktoarm block copolymers of (maltoheptaose)-b-poly(furfuryl methacrylate) ((MH)-b-PFMA). The synthesis of the copolymer involved the chemical coupling of alkyne-functionalized MH with diazide-functionalized PFMA through click-chemistry. The (MH)-b-PFMA copolymers were self-assembled in water into micelles (Non-CCL) with a hydrodynamic radius of ca. 72 nm. To prevent undesired drug leakage and burst release, the PFMA core of the doxorubicin (DOX)-loaded micelles was cross-linked using disulfide and diselenide-containing cross-linkers via Diels-Alder reaction. The core-cross-linked micelles (S-S/CCL and Se-Se/CCL) demonstrated enhanced stability under physiological conditions. In a reduction environment, they de-cross-linked, ensuring effective drug release. The micelles exhibited no significant cytotoxicity in HEK-293 cells, while DOX-loaded micelles showed potent antitumor efficacy against HeLa cells. Interestingly, Se-Se/CCL/DOX demonstrated preferential accumulation at the tumor site and exhibited superior efficacy compared to free DOX, Non-CCL/DOX, and S-S/CCL/DOX in inhibiting tumor growth in HT-29 tumor-bearing nude mice.
纳米载体的不稳定性以及药物在体内循环过程中的过早泄漏仍然是主要挑战，这在纳米药物的开发中经常导致不良副作用。在肿瘤微环境中实现有效的药物释放是理想化疗的关键目标。在本研究中，我们设计了一种新型的核交联胶束（CCL），它由生物相容性的基于寡糖的（麦芽七糖）-b-聚（甲基丙烯酸糠酯）（（MH）-b-PFMA）AB型 miktoarm 嵌段共聚物形成。共聚物的合成涉及炔基功能化的 MH 与叠氮功能化的 PFMA 通过点击化学进行化学偶联。（MH）-b-PFMA 共聚物在水中自组装成流体动力学半径约为 72 nm 的胶束（非 CCL）。为了防止不期望的药物泄漏和突发释放，使用含二硫键和二硒键的交联剂通过狄尔斯-阿尔德反应对负载阿霉素（DOX）的胶束的 PFMA 核进行交联。核交联胶束（S-S/CCL 和 Se-Se/CCL）在生理条件下表现出增强的稳定性。在还原环境中，它们发生去交联，确保有效的药物释放。这些胶束在 HEK-293 细胞中没有显著的细胞毒性，而负载 DOX 的胶束对 HeLa 细胞显示出强大的抗肿瘤功效。有趣的是，Se-Se/CCL/DOX 在 HT-29 荷瘤裸鼠中显示出在肿瘤部位的优先积累，并且在抑制肿瘤生长方面比游离 DOX、非 CCL/DOX 和 S-S/CCL/DOX 表现出更高的功效。
