Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, China.
Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
Adv Healthc Mater. 2024 Jun;13(15):e2304130. doi: 10.1002/adhm.202304130. Epub 2024 Mar 10.
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) often leads to the failure of antitumor chemotherapy, and codelivery of chemodrug with P-gp siRNA (siP-gp) represents a promising approach for treating chemoresistant tumors. To maximize the antitumor efficacy, it is desired that the chemodrug be latently released upon completion of siP-gp-mediated gene silencing, which however, largely remains an unmet demand. Herein, core-shell nanocomplexes (NCs) are developed to overcome MDR via staged liberation of siP-gp and chemodrug (doxorubicin, Dox) in hierarchical response to reactive oxygen species (ROS) concentration gradients. The NCs are constructed from mesoporous silica nanoparticles (MSNs) surface-decorated with cRGD-modified, PEGylated, ditellurium-crosslinked polyethylenimine (RPPT), wherein thioketal-linked dimeric doxorubicin (TK-Dox) and photosensitizer are coencapsulated inside MSNs while siP-gp is embedded in the RPPT polymeric layer. RPPT with ultrahigh ROS-sensitivity can be efficiently degraded by the low-concentration ROS inside cancer cells to trigger siP-gp release. Upon siP-gp-mediated gene silencing and MDR reversal, light irradiation is performed to generate high-concentration, lethal amount of ROS, which cleaves thioketal with low ROS-sensitivity to liberate the monomeric Dox. Such a latent release profile greatly enhances Dox accumulation in Dox-resistant cancer cells (MCF-7/ADR) in vitro and in vivo, which cooperates with the generated ROS to efficiently eradicate MCF-7/ADR xenograft tumors.
P-糖蛋白（P-gp）介导的多药耐药（MDR）常常导致抗肿瘤化疗失败，而将化疗药物与 P-gp siRNA（siP-gp）共递送至肿瘤是一种很有前途的治疗耐药肿瘤的方法。为了最大限度地提高抗肿瘤疗效，希望在 siP-gp 介导的基因沉默完成后，化疗药物能够潜伏释放，但这在很大程度上仍是一个未满足的需求。在此，通过级联响应活性氧（ROS）浓度梯度，开发了核壳纳米复合物（NCs）来克服 MDR，实现 siP-gp 和化疗药物（阿霉素，Dox）的阶段性释放。NCs 由介孔硅纳米粒子（MSNs）构建，表面修饰有 cRGD 修饰的、聚乙二醇化的、双碲交联的聚乙烯亚胺（RPPT），其中硫缩酮连接的二聚体阿霉素（TK-Dox）和光敏剂共包封在 MSNs 内部，而 siP-gp 则嵌入在 RPPT 聚合物层中。具有超高 ROS 敏感性的 RPPT 可以被癌细胞内的低浓度 ROS 有效降解，从而触发 siP-gp 释放。在 siP-gp 介导的基因沉默和 MDR 逆转后，进行光照以产生高浓度、致死量的 ROS，ROS 可以低 ROS 敏感性切割硫缩酮，释放出单体 Dox。这种潜伏释放谱极大地增强了 Dox 在多柔比星耐药的 MCF-7/ADR 细胞（MCF-7/ADR）中的积累，在体外和体内都显著增强了 Dox 的积累，与生成的 ROS 一起有效地消除了 MCF-7/ADR 异种移植肿瘤。
