Anti-Fas Antibody Conjugated Nanoparticles Enhancing the Antitumor Effect of Camptothecin by Activating the Fas-FasL Apoptotic Pathway
Anti-Fas Antibody Conjugated Nanoparticles Enhancing the Antitumor Effect of Camptothecin by Activating the Fas-FasL Apoptotic Pathway
复制标题
抗 Fas 抗体缀合纳米粒子通过激活 Fas-FasL 凋亡途径增强喜树碱的抗肿瘤作用
DOI：
10.1021/acsami.6b09760
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发表时间：
2016
影响因子：
9.5
通讯作者：
Hu Y
中科院分区：
文献类型：
--
作者：
Yu;Hongliang;He;Jian;Lu;Qian;Huo;Da;Yuan;Shanmei;Zhou;Zhengyang;Xu;Peipei;Hu;Yong;Yu Hongliang;He Jian;Zhou Zhengyang;Xu Peipei;Lu Qian;Huo Da;Yuan Shanmei;Hu Yong;Zhou ZY;Xu PP;Hu Y
越来越多的证据表明，引入Fas配体（FasL）可以增强Fas依赖性细胞凋亡并诱导持久的肿瘤免疫应答。然而，在保留正常细胞的情况下选择性触发肿瘤细胞凋亡仍然是基于fasl的治疗策略应用的一大挑战。本文制备了具有三明治结构的智能纳米颗粒。这些NPs由基质金属蛋白酶（MMP）可切割的PEG外层、抗fas抗体中间层和喜树碱（CPT）装载的内核组成。它们可以通过增强的渗透性和滞留效应（EPR）在肿瘤部位积聚。可移动的PEG层保护细胞毒性抗fas抗体不过早与正常组织接触，从而避免在到达肿瘤部位之前发生意想不到的致命副作用。由于肿瘤细胞在肿瘤组织内高水平表达MMP，这些NPs会脱落其PEG层，导致抗Fas抗体暴露，结合Fas受体，引发肿瘤细胞凋亡。Western blot结果证实，这些NPs可以模拟活化的细胞毒性淋巴细胞（CTL）的功能，激活肿瘤细胞Fas-FasL凋亡通路。在CPT有效载荷的帮助下，这些抗fas抗体偶联的NPs在B16同种异体肿瘤动物模型中获得了很高的肿瘤抑制作用。这些NPs的设计提供了一种将细胞毒性配体递送到靶向组织的方法，这可能在癌症治疗中有价值。
Emerging evidence suggest that the introduction of Fas ligand (FasL) can enhance the Fas-dependent apoptosis and induce durable immune responses against tumor. However, selective triggering of apoptosis in tumor cells while sparing normal cells remains a great challenge for the application of FasL-based therapeutic strategies. Herein, smart nanoparticles (NPs) with a sandwich structure were fabricated. These NPs consist of a matrix metalloproteinase (MMP) cleavable PEG outer layer, an anti-Fas antibody middle layer, and a camptothecin (CPT)-loaded inner core. They could accumulate at a tumor site by the enhanced permeability and retention (EPR) effect. The removable PEG layer protects the cytotoxic anti-Fas antibody from premature contact with normal tissues, thus avoiding the unexpected lethal side effect before they reach the tumor site. Due to the high level of MMP expressed by tumor cells inside the tumor tissue, these NPs would shed their PEG layers, resulting in the exposure of anti-Fas antibody to bind the Fas receptor and triggering the apoptosis of tumor cells. Results of Western blot confirmed that these NPs could mimic the function of activated cytotoxic lymphocyte (CTL) to activate the Fas–FasL apoptosis pathway of tumor cells. With the aid of CPT payload, these anti-Fas antibody conjugated NPs achieved a high tumor inhibition in the B16 allograft tumor animal model. The design of these NPs provides a method for delivering cytotoxic ligand to targeting tissue, which may be valuable in cancer therapy.