Pu Yinying, Zhou Bangguo, Xiang Huijing, Wu Wencheng, Yin Haohao, Yue Wenwen, Yin Yifei, Li Hongyan, Chen Yu, Xu Huixiong
Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai, 200072, PR China.
State Key Lab of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, PR China.
Biomaterials. 2020 Nov;259:120329. doi: 10.1016/j.biomaterials.2020.120329. Epub 2020 Aug 15.
Malignant melanoma is one of the most aggressive skin cancers, posing severe threat to human health. Tyrosinase, overexpressed in melanoma cells, is a specific in-situ weapon to augment the therapeutic efficacy of melanoma-specific treatment by in-situ accelerating the activation of anti-melanoma prodrugs. Herein, we developed a tyrosinase-triggered oxidative stress amplifier, denoted as APAP@PEG/HMnO, to achieve synergistic chemotherapy and amplified oxidative stress for melanoma-specific treatment. The APAP@PEG/HMnO nanosystem was constructed by encapsulating non-toxic prodrug acetaminophen (APAP) into hollow PEG/HMnO nanostructures. After tumor accumulation of APAP@PEG/HMnO amplifier, substantial amounts of oxygen (O) was generated through reaction between HMnO and excessive HO present in tumor environment. Meanwhile, APAP was released at acidic tumor environment and subsequently activated by overexpressed tyrosinase in the presence of O to produce cytotoxic benzoquinone metabolites (AOBQ). On the basis of the combinational effect of AOBQ-triggered reactive oxygen species (ROS) generation and synergistic glutathione (GSH) depletion as promoted by HMnO and AOBQ, the APAP@PEG/HMnO administration augmented the therapeutic efficacy of chemotherapy by amplifying the intratumoral oxidative stress, thus inducing remarkable cell apoptosis in vitro and tumor suppression in vivo. Therefore, the constructed prodrug nanomedicine represents a prospective tumor-specific therapeutic nanoagent for melanoma treatment.
恶性黑色素瘤是最具侵袭性的皮肤癌之一，对人类健康构成严重威胁。酪氨酸酶在黑色素瘤细胞中过表达，是一种特异性原位武器，可通过原位加速抗黑色素瘤前药的活化来增强黑色素瘤特异性治疗的疗效。在此，我们开发了一种酪氨酸酶触发的氧化应激放大器，称为APAP@PEG/HMnO，以实现协同化疗和放大氧化应激用于黑色素瘤特异性治疗。APAP@PEG/HMnO纳米系统是通过将无毒前药对乙酰氨基酚（APAP）封装到中空PEG/HMnO纳米结构中构建而成。APAP@PEG/HMnO放大器在肿瘤中蓄积后，通过HMnO与肿瘤环境中过量存在的H₂O₂之间的反应产生大量氧气（O₂）。同时，APAP在酸性肿瘤环境中释放，随后在O₂存在的情况下被过表达的酪氨酸酶激活，生成细胞毒性苯醌代谢产物（AOBQ）。基于AOBQ触发的活性氧（ROS）生成以及HMnO和AOBQ促进的协同谷胱甘肽（GSH）消耗的联合作用，APAP@PEG/HMnO给药通过放大肿瘤内氧化应激增强了化疗疗效，从而在体外诱导显著的细胞凋亡并在体内抑制肿瘤。因此，构建的前药纳米药物代表了一种用于黑色素瘤治疗的前瞻性肿瘤特异性治疗纳米制剂。
