School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Key Laboratory of Electrical Insulation and Thermal Ageing, Shanghai Jiao Tong University, Shanghai 200240, PR China.
Department of Oral and Maxillofacial-Head Neck Oncology, Department of Laser and Aesthetic Medicine, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China.
Biomaterials. 2019 Aug;211:68-80. doi: 10.1016/j.biomaterials.2019.04.029. Epub 2019 May 3.
Up to now, limited tumor penetration and poor therapeutic efficiency of drug-loaded nanoparticles are still the major challenges in nanomedicines for cancer chemotherapy. In photodynamic therapy, photosensitizers are often used to generate cytotoxic reactive oxygen species to kill cancer cells. Here, we report a kind of ROS-responsive nanoparticles with light-triggered size-reducing for enhanced tumor penetration and in vivo drug delivery to improve therapeutic efficiency. The nanoparticles were constructed by the self-assembly of an amphiphilic hyperbranched polyphosphoester containing thioketal units and photosensitizers, which is synthesized through the self-condensing ring-opening polymerization of a novel cyclic phosphate monomer and then end-capped with photosensitizer Chlorin e6. These nanoparticles have an initial averaged diameter of ∼210 nm, which can be used as drug carriers to load camptothecin with relatively stable in blood circulation. The CPT-loaded nanoparticles can be concentrated in tumor tissues through the long blood circulation and enhanced permeability and retention effect. Upon 660 nm laser irradiation on tumor tissues, the Ce6s in nanoparticles can effectively generate ROS to kill cancer cells meanwhile cleave the thioketal units to sequentially reduce the size of nanoparticles, which facilitate them more efficient tumor penetration with a programmable release of CPT. Both in vitro and in vivo studies confirmed the above results. Such ROS-responsive nanoparticles with light-triggered size-reducing provided a feasible approach to improve drug tumor penetration and achieve satisfied therapeutic efficacy.
迄今为止，载药纳米颗粒在肿瘤组织中的穿透能力有限和治疗效率低下仍然是癌症化疗纳米医学的主要挑战。在光动力疗法中，常使用光敏剂来产生细胞毒性的活性氧物质来杀死癌细胞。在这里，我们报道了一种具有 ROS 响应性的纳米颗粒，其具有光触发的尺寸减小特性，可增强肿瘤穿透和体内药物递送，从而提高治疗效率。该纳米颗粒由含有硫缩酮单元的两亲性超支化聚膦酸酯和亲脂性光敏剂通过自缩合开环聚合新型环状磷酸酯单体合成，并进一步用光敏剂 Chlorin e6 封端。这些纳米颗粒的初始平均直径约为 210nm，可用作药物载体来装载喜树碱，其在血液循环中相对稳定。载有 CPT 的纳米颗粒可以通过长循环和增强的渗透性和保留效应在肿瘤组织中聚集。在肿瘤组织上用 660nm 激光照射时，纳米颗粒中的 Ce6s 可以有效地产生 ROS 来杀死癌细胞，同时切断硫缩酮单元以顺序减小纳米颗粒的尺寸，从而更有效地促进它们穿透肿瘤，并实现 CPT 的可编程释放。体外和体内研究均证实了上述结果。这种具有 ROS 响应性的、光触发的尺寸减小的纳米颗粒为提高药物肿瘤穿透能力和实现令人满意的治疗效果提供了一种可行的方法。
