磷酸钙固化聚(L-谷氨酸)-顺铂/三氧化二砷纳米团簇协同治疗腹腔转移卵巢癌  

Calcium Phosphate-cured Nanocluster of Poly(L-glutamic acid)-Cisplatin and Arsenic Trioxide for Synergistic Chemotherapy of Peritoneal Metastasis of Ovarian Cancer

作　　者：姜中雨 冯祥汝[1,2] 许维国 庄秀丽[1,2] 丁建勋 陈学思[1,2] Zhong-yu Jiang;Xiang-ru Feng;Wei-guo Xu;Xiu-li Zhuang;Jian-xun Ding;Xue-si Chen(Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022;School of Applied Chemistry and Engineering,University of Science and Technology of China,Hefei 230026)

机构地区：[1]中国科学院长春应用化学研究所中国科学院生态环境高分子材料重点实验室,长春130022 [2]中国科学技术大学应用化学与工程学院,合肥230026

出　　处：《高分子学报》2020年第8期901-910,共10页Acta Polymerica Sinica

基　　金：国家自然科学基金(基金号51973216,51873207,51833010)资助项目。

摘　　要：在临床上,顺铂(CDDP)作为一线化疗药物被广泛应用于治疗各种实体肿瘤.然而,肿瘤细胞内的还原微环境会降低CDDP的疗效.在本研究中,通过磷酸钙固化技术将聚(L-谷氨酸)-CDDP纳米粒子(PGN-Pt)与三氧化二砷(ATO)结合,构建细胞内酸敏感的纳米团簇NCPGN-Pt+ATO,以提高肿瘤治疗效果. NCPGN-Pt+ATO为粒径在129.8 nm的纳米球,能够在血液中长循环并通过增强渗透与滞留效应在肿瘤组织富集. NCPGN-Pt+ATO被细胞摄取后在细胞内酸性环境中释放PGN-Pt和ATO. PGN-Pt在细胞内持续释放CDDP以保持其有效杀伤浓度. CDDP和ATO共同提高细胞内活性氧的水平杀死肿瘤细胞,同时提升CDDP的疗效协同抑制肿瘤进展.鉴于良好的有效性和安全性,NCPGN-Pt+ATO为CDDP纳米药物的设计提供了新的有效策略.Cisplatin(CDDP), as a traditional first-line chemotherapeutic drug, has been broadly used for the treatment of numerous solid cancers in the clinic. However, the treatment efficacy of CDDP is limited by a variety of issues, including enhanced efflux, increased detoxification capability, and improved ability of DNA damage repair of cancer cells. For example, the high level of intracellular glutathione(GSH) significantly decreases the cytotoxicity of CDDP through the formation of stable GS-Pt complex, which can be rapidly extracted from the tumor cells through an adenosine triphosphate-dependent glutathione S-conjugate export pump(GS-X pump).Therefore, the antitumor efficacy of CDDP can be upregulated by inhibiting the synthesis of GSH with drugs,directly depleting GSH with organic or inorganic nanoparticles, or neutralizing GSH through upregulating the level of reactive oxygens species(ROS) in the cells. Herein, the intracellular acidity-sensitive nanocluster(NCPGN-Pt+As) was developed to improve the antitumor efficacy, which was fabricated by the calcium phosphate(Ca3(PO4)2)-curing of CDDP-loaded poly(L-glutamic acid) nanoparticle(PGN-Pt) and arsenic trioxide(ATO).The optimal mass ratio of CDDP and ATO in NCPGN-Pt+As was determined to be 2:1 by the coefficient of drug interaction(CDI) between CDDP and ATO. NCPGN-Pt+As exhibited a nanosphere structure with a diameter of129.8 nm. NCPGN-Pt+As showed prolonged blood circulation, evidenced by the increased half-life(t1/2β) and the area under the drug concentration-time curve(AUC0-t). Moreover, NCPGN-Pt+As demonstrated the reduced accumulation in the normal tissues and improved accumulation in the tumor. The intratumoral accumulations of CDDP and ATO were 5.7 and 3.9 times higher than those of the free CDDP+ATO group, respectively, which should be attributed to the enhanced permeability and retention effect. Upon entering the endosome, NCPGN-Pt+As decomposed and released PGN-Pt and ATO under the acidic conditions. CDDP was sustainedly released from PGN-Pt in the cells

关 键 词：高分子纳米药物 三氧化二砷 磷酸钙纳米团簇 细胞内药物递送 癌症协同化疗 

分 类 号：R737.31[医药卫生—肿瘤]