Comprehensively priming the tumor microenvironment by cancer-associated fibroblast-targeted liposomes for combined therapy with cancer cell-targeted chemotherapeutic drug delivery system
Comprehensively priming the tumor microenvironment by cancer-associated fibroblast-targeted liposomes for combined therapy with cancer cell-targeted chemotherapeutic drug delivery system
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癌症相关成纤维细胞靶向脂质体全面启动肿瘤微环境，与癌细胞靶向化疗药物递送系统联合治疗
DOI：
10.1016/j.jconrel.2016.09.014
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发表时间：
2016-11-10
影响因子：
10.8
通讯作者：
Zhang, Qiang
中科院分区：
文献类型：
--
作者：
Chen, Binlong;Dai, Wenbing;Zhang, Qiang
癌相关成纤维细胞（CAFs）不仅通过与癌细胞的相互作用支持肿瘤的发生和转移，而且还重塑细胞外基质（ECM）和肿瘤微环境的结构。这导致传统化疗纳米药物的肿瘤渗透性差，并导致耐药性。在这项研究中，我们使用一种新型的肿瘤基质靶向纳米载体（FH-SSL-Nav）来特异性地根除CAF，促进纳米药物的肿瘤渗透并切断基质对癌细胞的支持。FH-SSL-Nav表现出优异和全面的肿瘤微环境调节，包括下调ECM沉积，降低间质液压力（IFP）和促进血液灌注。因此，更多的化疗药物递送系统在体外和体内穿透到肿瘤球体和肿瘤组织中。FH-SSL-Nav可部分逆转微环境诱导的化疗耐药。在人Hep G2异种移植裸鼠模型中，FH-SSL-Nav以低剂量和低毒性大大提高了癌细胞靶向脂质体阿霉素（7 pep-SSL-DOX）的肿瘤抑制。由于Nav和DOX对Hep G2细胞没有协同作用，因此很明显，提高的抗肿瘤功效基本上是由于FH-SSL-Nav的全面肿瘤微环境引发。(C)© 2016 Elsevier B. V.版权所有。
Cancer-associated fibroblasts (CAFs) not only support tumorigenesis and tumor metastasis by reciprocal cellular cross-talk with cancer cells, but also remodel the extracellular matrix (ECM) and architecture of tumormicroen-vironment. This leads to poor tumor penetration of traditional chemotherapeutic nanomedicines and resulting drug resistance. In this study, we use a novel tumor stroma-targeted nanovehicle (FH-SSL-Nav) to specifically eradicate CAFs, promote tumor penetration of nanomedicines and cut off the stroma's support to cancer cells. FH-SSL-Nav exhibited excellent and comprehensive tumor microenvironment modulation including downregulation ECM deposition, decreasing interstitial fluid pressure (IFP) and facilitating blood perfusion. As a result, more chemotherapeutic drug delivery systems penetrated deep into tumor spheroids in vitro and tumor tissues in vivo. Furthermore, chemotherapeutic drug resistance induced by microenvironment was partly reversed by FH-SSL-Nav. In a human Hep G2 xenograft nude mouse model, FH-SSL-Nav greatly improved the tumor suppression of cancer cell-targeted liposomal doxorubicin (7pep-SSL-DOX) with low dose and low toxicity. Since Nav and DOX exhibited no synergy against Hep G2 cells, it was clear that the improved antitumor efficacy was basically due to the comprehensive tumor microenvironment priming by FH-SSL-Nav. (C) 2016 Elsevier B.V. All rights reserved.