Wang Guanchun, Su Yue, Chen Xinliang, Zhou Yongfeng, Huang Ping, Huang Wei, Yan Deyue
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China.
The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Bioact Mater. 2023 Feb 4;25:189-200. doi: 10.1016/j.bioactmat.2023.01.026. eCollection 2023 Jul.
The combination of chemotherapy and photodynamic therapy (PDT) based on nanoparticles (NPs) has been extensively developed to improve the therapeutic effect and decrease the systemic toxicity of current treatments. However, overexpressed glutathione (GSH) in tumor cells efficiently scavenges singlet oxygens (O) generated from photosensitizers and results in the unsatisfactory efficacy of PDT. To address this obstacle, here we design HO-responsive polymer prodrug NPs with GSH-scavenger (Ce6@P(EG--CPBE) NPs) for chemo-photodynamic synergistic cancer therapy. They are constructed by the co-self-assembly of photosensitizer chlorin e6 (Ce6) and amphiphilic polymer prodrug P(EG--CPBE), which is synthesized from a hydrophilic alternating copolymer P(EG--PD) by conjugating hydrophobic anticancer drug chlorambucil (CB) via an HO-cleavable linker 4-(hydroxymethyl)phenylboronic acid (PBA). Ce6@P(EG--CPBE) NPs can efficiently prevent premature drug leakage in blood circulation because of the high stability of the PBA linker under the physiological environment and facilitate the delivery of Ce6 and CB to the tumor site after intravenous injection. Upon internalization of Ce6@P(EG--CPBE) NPs by tumor cells, PBA is cleaved rapidly triggered by endogenous HO to release CB and Ce6. Ce6 can effectively generate abundant O under 660 nm light irradiation to synergistically kill cancer cells with CB. Concurrently, PBA can be transformed into a GSH-scavenger (quinine methide, QM) under intracellular HO and prevent the depletion of O, which induces the cooperatively strong oxidative stress and enhanced cancer cell apoptosis. Collectively, such HO-responsive polymer prodrug NPs loaded with photosensitizer provide a feasible approach to enhance chemo-photodynamic synergistic cancer treatment.
基于纳米颗粒（NPs）的化疗与光动力疗法（PDT）相结合已得到广泛发展，以提高治疗效果并降低当前治疗的全身毒性。然而，肿瘤细胞中过表达的谷胱甘肽（GSH）能有效清除光敏剂产生的单线态氧（O），导致PDT疗效不尽人意。为克服这一障碍，我们在此设计了具有GSH清除剂的HO响应型聚合物前药纳米颗粒（Ce6@P(EG--CPBE) NPs）用于化疗-光动力协同癌症治疗。它们由光敏剂二氢卟吩e6（Ce6）与两亲性聚合物前药P(EG--CPBE)共同自组装而成，P(EG--CPBE)是由亲水性交替共聚物P(EG--PD)通过可被HO裂解的连接子4-(羟甲基)苯硼酸（PBA）连接疏水性抗癌药物苯丁酸氮芥（CB）合成的。由于PBA连接子在生理环境下具有高稳定性，Ce6@P(EG--CPBE) NPs能有效防止血液循环中药物过早泄漏，并在静脉注射后促进Ce6和CB向肿瘤部位递送。肿瘤细胞摄取Ce6@P(EG--CPBE) NPs后，内源性HO迅速触发PBA裂解，释放出CB和Ce6。Ce6在660 nm光照射下能有效产生大量O，与CB协同杀死癌细胞。同时，PBA在细胞内HO作用下可转化为GSH清除剂（喹宁鎓盐，QM），防止O消耗，诱导协同强烈的氧化应激并增强癌细胞凋亡。总体而言，这种负载光敏剂的HO响应型聚合物前药纳米颗粒为增强化疗-光动力协同癌症治疗提供了一种可行的方法。
