Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug (molecular weight, MW: 93.5 kDa) was produced by reversible addition–fragmentation chain transfer (RAFT) polymerization. The amphiphilic block polymer-doxorubicin (DOX) prodrug was employed to deliver a hydrophobic photosensitizer (PS), chlorin e6 (Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione (GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 kDa in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition (TGI, 58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.

精确递送联合治疗剂已成为抗肿瘤治疗的关键挑战。在本研究中，通过可逆加成-断裂链转移（RAFT）聚合制备了一种新型的氧化还原响应性聚合物前药（分子量，MW：93.5 kDa）。两亲性嵌段聚合物-多柔比星 (DOX) 前药用于递送疏水性光敏剂 (PS)、二氢卟酚 e6 (Ce6)，并将所制备的纳米级系统 [NPs(Ce6)] 作为化学光动力抗癌剂进行研究代理人。将谷胱甘肽 (GSH) 可切割的二硫键插入聚合物骨架中，在肿瘤细胞内进行生物降解，通过二硫键缀合到聚合物上的 DOX 成功释放到细胞内。NPs(Ce6) 释放具有原始分子结构的 DOX 和 Ce6，并在 GSH 存在下降解为 41.2 kDa 的低分子量片段。NPs(Ce6) 显示出杀死 4T1 鼠乳腺癌细胞的化学光动力治疗效果，这从细胞形态崩溃、细胞内活性氧水平升高、活力降低和诱导细胞凋亡得到证实。而且，离体荧光图像表明，NPs(Ce6) 保留在肿瘤中，并表现出显着的体内抗癌功效。联合治疗显示出显着增加的肿瘤生长抑制（TGI，58.53%）。因此，氧化还原响应性、两亲性嵌段聚合前药可能具有作为化学光动力抗癌剂的巨大潜力。