Jiang Meijuan, Mu Jing, Jacobson Orit, Wang Zhantong, He Liangcan, Zhang Fuwu, Yang Weijing, Lin Qiaoya, Zhou Zijian, Ma Ying, Lin Jing, Qu Junle, Huang Peng, Chen Xiaoyuan
Marshall Laboratory of Biomedical Engineering, International Cancer Center, Laboratory of Evolutionary Theranostics (LET), School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen 518060, China.
Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China.
ACS Nano. 2020 Dec 22;14(12):16875-16886. doi: 10.1021/acsnano.0c05722. Epub 2020 Nov 18.
Nanotheranostics based on tumor-selective small molecular prodrugs could be more advantageous in clinical translation for cancer treatment, given its defined chemical structure, high drug loading efficiency, controlled drug release, and reduced side effects. To this end, we have designed and synthesized a reactive oxygen species (ROS)-activatable heterodimeric prodrug, namely, HRC, and nanoformulated it for tumor-selective imaging and synergistic chemo- and photodynamic therapy. The prodrug consists of the chemodrug camptothecin (CPT), the photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH), and a thioketal linker. Compared to CPT- or HPPH-loaded polymeric nanoparticles (NPs), HRC-loaded NPs possess higher drug loading capacity, better colloidal stability, and less premature drug leakage. Interestingly, HRC NPs were almost nonfluorescent due to the strong π-π stacking and could be effectively activated by endogenous ROS once entering cells. Thanks to the higher ROS levels in cancer cells than normal cells, HRC NPs could selectively light up the cancer cells and exhibit much more potent cytotoxicity to cancer cells. Moreover, HRC NPs demonstrated highly effective tumor accumulation and synergistic tumor inhibition with reduced side effects on mice.
基于肿瘤选择性小分子前药的纳米诊疗剂在癌症治疗的临床转化中可能更具优势，因为其具有明确的化学结构、高载药效率、可控的药物释放以及减少的副作用。为此，我们设计并合成了一种活性氧（ROS）可激活的异二聚体前药，即HRC，并将其制成纳米制剂用于肿瘤选择性成像以及协同化疗和光动力治疗。该前药由化学药物喜树碱（CPT）、光敏剂2-(1-己氧基乙基)-2-去乙烯基焦脱镁叶绿酸-a（HPPH）和一个硫代缩酮连接子组成。与负载CPT或HPPH的聚合物纳米颗粒（NPs）相比，负载HRC的NPs具有更高的载药能力、更好的胶体稳定性以及更少的药物过早泄漏。有趣的是，由于强烈的π-π堆积作用，HRC NPs几乎没有荧光，一旦进入细胞就能被内源性ROS有效激活。由于癌细胞中的ROS水平高于正常细胞，HRC NPs能够选择性地照亮癌细胞，并对癌细胞表现出更强的细胞毒性。此外，HRC NPs在小鼠体内表现出高效的肿瘤蓄积和协同的肿瘤抑制作用，且副作用减少。
