Tang Zhiyuan, Sun Yuening, Yi Quanhua, Ding Qian, Ding Yang, Huang Jianfei
Department of Pharmacy, Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
Pharmacy School of Nantong University, Nantong 226001, China.
Asian J Pharm Sci. 2025 Jun;20(3):101023. doi: 10.1016/j.ajps.2025.101023. Epub 2025 Jan 31.
The effective intracellular accumulation of doxorubicin (DOX) is crucial for improving antitumor efficacy, which is severely impeded by limited drug penetration, uncontrollable drug release, and drug resistance. In this study, a thermal-deformative polymer embedding ultrasmall ceria (CeO) was rationally designed for deep tumor drug shuttling and hypoxia reversal to improve chemotherapy. Structurally, the CeO nanozyme was covalently grafted with a polymer of p(NIPAM-co-AM) that could sharply shrink for DOX loading, which was consolidated with polydopamine (PDA) film encapsulation. Thereafter, a tumor penetration guide of apolipoprotein A-I (apoA-I) conjugated iRGD peptide (apoA-I-iRGD) was further decorated onto the PDA shell via Michael addition for preparing CeOP/DOX@iAPDA. With the aid of apoA-I-iRGD, CeOP/DOX@iAPDA penetrated both the tumor spheroids (∼78 µm) and the tumors of the mouse model deeply. After internalization by tumor cells and triggering by low pH in lysosomes, rapid DOX release was achieved by peeling off the PDA shell and thermosensitive deformation of p(NIPAM-co-AM). CeOP/DOX@iAPDA provided 66.4 % tumor suppression in 4T1-derived tumor spheroids and 63.2 % in 4T1-tumor-bearing mice, respectively. Preliminary mechanistic research involving western blotting and immunohistochemistry revealed that CeOP/DOX@iAPDA reversed resistance through the through HIF-1α-P-gp/lipid axis. Collectively, this study intelligently integrated CeO nanozymes, temperature-sensitive polymers, and imitated biochemical modifications to improve chemotherapy for breast cancer.
阿霉素（DOX）在细胞内的有效蓄积对于提高抗肿瘤疗效至关重要，然而，有限的药物渗透、不可控的药物释放和耐药性严重阻碍了这一过程。在本研究中，我们合理设计了一种嵌入超小二氧化铈（CeO）的热变形聚合物，用于深部肿瘤药物穿梭和缺氧逆转，以改善化疗效果。在结构上，CeO纳米酶与聚（N-异丙基丙烯酰胺-共-丙烯酰胺）（p(NIPAM-co-AM)）聚合物共价接枝，该聚合物在装载DOX时会急剧收缩，并通过聚多巴胺（PDA）膜包封进行加固。此后，通过迈克尔加成反应将载脂蛋白A-I（apoA-I）偶联的iRGD肽（apoA-I-iRGD）这一肿瘤穿透导向剂进一步修饰在PDA外壳上，制备出CeOP/DOX@iAPDA。借助apoA-I-iRGD，CeOP/DOX@iAPDA能够深入穿透肿瘤球体（约78 µm）和小鼠模型中的肿瘤。被肿瘤细胞内化并在溶酶体中低pH触发后，通过剥离PDA外壳和p(NIPAM-co-AM)的热敏变形实现了DOX的快速释放。CeOP/DOX@iAPDA在4T1来源的肿瘤球体中提供了66.4%的肿瘤抑制率，在4T1荷瘤小鼠中提供了63.2%的肿瘤抑制率。涉及蛋白质免疫印迹和免疫组织化学的初步机制研究表明，CeOP/DOX@iAPDA通过HIF-1α-P-gp/脂质轴逆转耐药性。总的来说，本研究巧妙地整合了CeO纳米酶、温度敏感聚合物和模拟生化修饰，以改善乳腺癌的化疗效果。
