摘要
Developing intrinsically mitochondria-targetable nanosystems for subcellular structure-oriented precise cancer therapy is highly desirable.Here,we conjugate the cluster determinant 44(CD44)-targetable hyaluronic acid(HA)with cholesterol-poly(ethylene glycol)2 k-NH2 and mitochondria-acting IR825-NH2(a cyanine dye)to construct a self-assembled nanostructure(abbreviated as HA-IR825-Chol)for photothermal therapy.The HA-IR825-Chol exhibits improved photostability and desirable photothermal properties,and can rapidly and substantially enter CD44-overexpressed cancer cells and selectively accumulate in the mitochondria of the cells.Upon near-infrared laser irradiation,it can induce severe mitochondrial damage,which causes cytochrome c release and triggers cell apoptosis.Furthermore,we demonstrate the feasibility of loading the chemotherapeutics 10-hydroxycamptothecin(HCPT)into the hydrophobic cores of HA-IR825-Chol NPs for combined chemophotothermal therapy.HCPT encapsulated within HA-IR825-Chol achieves significantly increased cellular uptake and simultaneous mitochondrial and nuclear localization,leading to the release of cytochrome c from mitochondria and upregulation of cleaved caspase-3,both of which contribute to the cell apoptosis/death.In vivo experiments reveal the excellent tumor-targeting ability of HA-IR825-Chol/HCPT,ensuring the efficient tumor eradication by the chemo-photothermal therapy.This work exemplifies the development of an intrinsically mitochondria-targetable nanocarrier for precise subcellular structure-localized drug delivery,and the Chol-mediated rapid and massive endocytosis of the nanoagents may represent a robust strategy for enhancing the efficacies of nanomedicines.
开发本身即具有线粒体靶向能力的亚细胞精准纳米诊疗试剂对于改善癌症治疗效果具有重要意义.本文使用可靶向癌细胞表面过度表达的CD44抗原的透明质酸、胆固醇-聚乙二醇-氨基和可作用于线粒体的花菁类染料IR825-NH2,构建了一种可实现光热治疗的自组装纳米材料(HA-IR825-Chol).相较于游离的IR825-NH2,该结构具有更好的光稳定性、更高的光热转换效率和对癌细胞的识别能力.HA-IR825-Chol可以有效靶向细胞线粒体,并可以在近红外激光照射下诱导线粒体损伤.此外,我们通过疏水作用包裹了化疗试剂10-羟基喜树碱(HCPT)(所形成的药物命名为HAIR825-Chol/HCPT).相关实验结果显示,包裹于纳米材料后HCPT被细胞摄取的效率显著提高,并能够同时分布于线粒体和细胞核中,从而诱导线粒体中细胞色素c的释放和细胞中cleaved caspase-3的上调,最终促进细胞凋亡与死亡.另外,HA-IR825-Chol/HCPT优异的体内肿瘤靶向能力为光化疗联合治疗消除肿瘤提供了必要保证.该工作实现了定位于线粒体的精准亚细胞药物递送,并发展了利用胆固醇提高药物摄取速率和效率的策略,预期将为提高纳米药物抗癌效果提供借鉴.
基金
supported by the National Natural Science Foundation of China(21673037).
