Cai Hao, Tan Ping, Chen Xiaoting, Kopytynski Michal, Pan Dayi, Zheng Xiuli, Gu Lei, Gong Qiyong, Tian Xiaohe, Gu Zhongwei, Zhang Hu, Chen Rongjun, Luo Kui
Huaxi MR Research Center (HMRRC), Department of Radiology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Animal Experimental Center of West China Hospital, Sichuan University, Chengdu, 610041, China.
Adv Mater. 2022 Feb;34(8):e2108049. doi: 10.1002/adma.202108049. Epub 2022 Jan 13.
Linear-dendritic block copolymer (LDBCs) are highly attractive candidates for smart drug-delivery vehicles. Herein, an amphiphilic poly[(ethylene glycol) methyl ether methacrylate] (POEGMA) linear-peptide dendritic prodrug of doxorubicin (DOX) prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization is reported. The hydrophobic-dye-based photosensitizer chlorin e6 (Ce6) is employed for encapsulation in the prodrug nanoparticles (NPs) to obtain an LDBCs-based drug-delivery system (LD-DOX/Ce6) that offers a combination cancer therapy. Due to the presence of Gly-Phe-Leu-Gly peptides and hydrazone bonds in the prodrug structure, LD-DOX/Ce6 is degraded into small fragments, thus specifically triggering the intracellular release of DOX and Ce6 in the tumor microenvironment. Bioinformatics analysis suggests that LD-DOX/Ce6 with laser irradiation treatment significantly induces apoptosis, DNA damage, and cell cycle arrest. The combination treatment can not only suppress tumor growth, but also significantly reduce tumor metastasis compared with treatments with DOX or Ce6 through regulating EMT pathway, TGFβ pathway, angiogenesis, and the hypoxia pathway. LD-DOX/Ce6 displays a synergistic chemo-photodynamic antitumor efficacy, resulting in a high inhibition in tumor growth and metastasis, while maintaining an excellent biosafety. Therefore, this study demonstrates the potential of the biodegradable and tumor-microenvironment-responsive LDBCs as an intelligent multifunctional drug-delivery vehicle for high-efficiency cancer combination therapy.
线性-树枝状嵌段共聚物（LDBCs）是智能药物递送载体极具吸引力的候选材料。在此，报道了一种通过可逆加成-断裂链转移（RAFT）聚合制备的阿霉素（DOX）两亲性聚[（乙二醇）甲基醚甲基丙烯酸酯]（POEGMA）线性-肽树枝状前药。基于疏水染料的光敏剂叶绿素e6（Ce6）被用于封装在前药纳米颗粒（NPs）中，以获得一种基于LDBCs的药物递送系统（LD-DOX/Ce6），该系统提供联合癌症治疗。由于前药结构中存在甘氨酸-苯丙氨酸-亮氨酸-甘氨酸肽和腙键，LD-DOX/Ce6降解为小片段，从而在肿瘤微环境中特异性触发DOX和Ce6的细胞内释放。生物信息学分析表明，经激光照射处理的LD-DOX/Ce6显著诱导细胞凋亡、DNA损伤和细胞周期停滞。与单独使用DOX或Ce6治疗相比，联合治疗不仅可以抑制肿瘤生长，还能通过调节上皮-间质转化（EMT）途径、转化生长因子β（TGFβ）途径、血管生成和缺氧途径显著减少肿瘤转移。LD-DOX/Ce6显示出协同的化学-光动力抗肿瘤功效，在抑制肿瘤生长和转移方面具有高效性，同时保持优异的生物安全性。因此，本研究证明了可生物降解且对肿瘤微环境有响应的LDBCs作为一种智能多功能药物递送载体用于高效癌症联合治疗的潜力。
