Department of Orthopedics, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, 610041, China.
Department of Orthopedics, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400014, China.
J Nanobiotechnology. 2021 Mar 19;19(1):79. doi: 10.1186/s12951-021-00831-6.
Osteosarcoma (OS) is the most common primary malignant bone tumor occurring in children and young adults. Drug-resistant osteosarcoma often results in chemotherapy failure. Therefore, new treatments aimed at novel therapeutic targets are urgently needed for the treatment of drug-resistant osteosarcoma. Mitochondria-targeted phototherapy, i.e., synergistic photodynamic/photothermal therapy, has emerged as a highly promising strategy for treating drug-resistant tumors. This study proposed a new nano-drug delivery system based on near-infrared imaging and multifunctional graphene, which can target mitochondria and show synergistic phototherapy, with preferential accumulation in tumors.
Based on our previous study, (4-carboxybutyl) triphenyl phosphonium bromide (TPP), a mitochondria-targeting ligand, was conjugated to indocyanine green (ICG)-loaded, polyethylenimine-modified PEGylated nanographene oxide sheets (TPP-PPG@ICG) to promote mitochondrial accumulation after cellular internalization. Thereafter, exposure to a single dose of near-infrared irradiation enabled synergistic photodynamic and photothermal therapy, which simultaneously inhibited adenosine triphosphate synthesis and mitochondrial function. Induction of intrinsic apoptosis assisted in surmounting drug resistance and caused tumor cell death. After fluorescence imaging-guided synergistic phototherapy, the mitochondria-targeting, multifunctional graphene-based, drug-delivery system showed highly selective anticancer efficiency in vitro and in vivo, resulting in marked inhibition of tumor progression without noticeable toxicity in mice bearing doxorubicin-resistant MG63 tumor cells.
The mitochondria-targeting TPP-PPG@ICG nanocomposite constitutes a new class of nanomedicine for fluorescence imaging-guided synergistic phototherapy and shows promise for treating drug-resistant osteosarcoma.
骨肉瘤（OS）是儿童和青少年中最常见的原发性恶性骨肿瘤。耐药骨肉瘤常导致化疗失败。因此，迫切需要针对新的治疗靶点的新治疗方法来治疗耐药骨肉瘤。线粒体靶向光疗，即协同光动力/光热疗法，已成为治疗耐药肿瘤的一种很有前途的策略。本研究提出了一种基于近红外成像和多功能石墨烯的新型纳米药物传递系统，该系统可以靶向线粒体并表现出协同光疗作用，在肿瘤中有优先积累。
基于我们之前的研究，（4-羧丁基）三苯基溴化磷（TPP），一种线粒体靶向配体，被共轭到吲哚菁绿（ICG）负载的聚乙二胺修饰的聚乙二醇化纳米氧化石墨烯片（TPP-PPG@ICG）上，以促进细胞内化后线粒体的积累。此后，单次近红外辐射暴露可实现协同光动力和光热治疗，同时抑制三磷酸腺苷合成和线粒体功能。诱导内在凋亡有助于克服耐药性并导致肿瘤细胞死亡。在荧光成像引导的协同光疗后，线粒体靶向、多功能石墨烯基药物传递系统在体外和体内表现出高度选择性的抗癌效率，导致荷有多柔比星耐药 MG63 肿瘤细胞的小鼠肿瘤进展明显抑制，而无明显毒性。
线粒体靶向 TPP-PPG@ICG 纳米复合材料构成了一种新型的荧光成像引导协同光疗纳米医学，有望用于治疗耐药骨肉瘤。
