Folate-mediated and pH-responsive chidamide-bound micelles encapsulating photosensitizers for tumor-targeting photodynamic therapy
Folate-mediated and pH-responsive chidamide-bound micelles encapsulating photosensitizers for tumor-targeting photodynamic therapy
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叶酸介导且 pH 响应的西达酰胺结合胶束封装光敏剂用于肿瘤靶向光动力治疗
DOI：
10.2147/ijn.s208649
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发表时间：
2019-01-01
影响因子：
8
通讯作者：
Yang, Feng
中科院分区：
文献类型：
--
作者：
Ma, Zhiqiang;Hu, Pengwei;Yang, Feng
背景资料：肿瘤的非特异性靶向性以及治疗后肿瘤的潜在复发和转移是光动力治疗（PDT）临床应用的主要障碍，因此抑制肿瘤的复发和转移是临床上的重要课题。目的：在这项工作中，将作为组蛋白去乙酰化酶抑制剂的西达米特（HADCi）结合到pH响应性嵌段聚合物叶酸聚乙二醇-b-聚（天冬氨酸）（PEG-b-PAsp）接枝叶酸（FA-PEG-b-PAsp），得到嵌段聚合物叶酸聚乙二醇-b-聚（天冬酰胺基）（FA-PEG-b-PAsp-chidamide，FPPC）作为多模式肿瘤靶向给药载体，抑制小鼠肿瘤细胞增殖和肿瘤转移。方法：将模型光敏剂焦脱镁叶绿酸-a（Pha）用FPPC包埋在PBS中形成聚合物胶束Pha@FPPC [包埋Pha的叶酸聚乙二醇-b-聚（天冬酰胺基-chidamide）胶束]。采用透射电镜和动态光散射技术对Pha@FPPC进行了表征，并通过测定细胞内活性氧水平、细胞凋亡和细胞周期阻滞检测、体内PDT抗肿瘤活性和组织学分析等方法研究了Pha@FPPC的体内外抗肿瘤活性。透射电子显微镜（TEM）下具有良好稳定的球形形貌（类似于93.0 nm），Pha@FPPC由于其叶酸介导的小鼠黑色素瘤B16-F10细胞的有效内吞作用而极大地增强了细胞摄取，PDT后主要引起细胞坏死，细胞生长周期阻滞于G2期和G1/G 0期。Pha@FPPC具有较低的体外暗细胞毒性和较好的治疗指数，这是由于其较高的暗细胞毒性/光细胞毒性比。此外，Pha@FPPC具有叶酸靶向性和EPR选择性蓄积于肿瘤部位的作用，不仅显著抑制移植瘤的生长，而且延长荷瘤小鼠的生存时间（增强的渗透性和保留）作用，而且与游离Pha相比，证明其具有PDT和HDACi的双重抗肿瘤特性。作为叶酸介导和酸活化的西达明接枝的药物递送载体，FPPC具有高效、多模式的肿瘤转移抑制作用，在临床光动力治疗肿瘤中有很大的应用潜力。作为光敏剂载体的靶向性能。
Background: Nonspecific tumor targeting, potential relapse and metastasis of tumor after treatment are the main barriers in clinical photodynamic therapy (PDT) for cancer, hence, inhibiting relapse and metastasis of tumor is significant issues in clinic.Purpose: In this work, chidamide as a histone deacetylases inhibitor (HADCi) was bound onto a pH-responsive block polymer folate polyethylene glycol-b-poly(aspartic acid) (PEG-b-PAsp) grafted folate (FA-PEG-b-PAsp) to obtain the block polymer folate polyethylene glycol-b-poly(asparaginyl-chidamide) (FA-PEG-b-PAsp-chidamide, FPPC) as multimodal tumor-targeting drug-delivery carrier to inhibiting tumor cell proliferation and tumor metastasis in mice.Methods: Model photosensitizer pyropheophorbide-a (Pha) was encapsulated by FPPC in PBS to form the polymer micelles Pha@FPPC [folate polyethylene glycol-b-poly (asparaginyl-chidamide) micelles encapsulating Pha]. Pha@FPPC was characterized by transmission electron microscope and dynamic light scattering; also, antitumor activity in vivo and in vitro were investigated by determination of cellular ROS level, detection of cell apoptosis and cell cycle arrest, PDT antitumor activity in vivo and histological analysis.Results: With favorable and stable sphere morphology under transmission electron microscope (TEM) (similar to 93.0 nm), Pha@FPPC greatly enhanced the cellular uptake due to its folate-mediated effective endocytosis by mouse melanoma B16-F10 cells and the yield of ROS in tumor cells induced by PDT, and mainly caused necrocytosis and blocked cell growth cycle not only in G2 phase but also in G1/G0 phase after PDT. Pha@FPPC exhibited lower dark cytotoxicity in vitro and a better therapeutic index because of its higher dark cytotoxicity/photocytotoxicity ratio. Moreover, Pha@FPPC not only significantly inhibited the growth of implanted tumor and prolonged the survival time of melanoma-bearing mice due to both its folate-mediated tumor-targeting and selectively accumulation at tumor site by EPR (enhanced permeability and retention) effect as micelle nanoparticles but also remarkably prevented pulmonary metastasis of mice melanoma after PDT compared to free Pha, demonstrating its dual antitumor characteristics of PDT and HDACi.Conclusion: As a folate-mediated and acid-activated chidamide-grafted drug-delivery carrier, FPPC may have great potential to inhibit tumor metastasis in clinical photodynamic treatment for cancer because of its effective and multimodal tumor-targeting performance as photosensitizer vehicle.