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首页> 美国卫生研究院文献>International Journal of Nanomedicine >Folate-mediated and pH-responsive chidamide-bound micelles encapsulating photosensitizers for tumor-targeting photodynamic therapy
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Folate-mediated and pH-responsive chidamide-bound micelles encapsulating photosensitizers for tumor-targeting photodynamic therapy

机译：叶酸介导的与pH响应的与酰胺反应的与胶体结合的胶束封装了用于肿瘤靶向光动力疗法的光敏剂

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>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) (~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.
机译：>背景：非特异性肿瘤靶向，治疗后肿瘤的潜在复发和转移是临床光动力疗法（PDT）治疗癌症的主要障碍，因此，抑制肿瘤的复发和转移是临床上的重要问题。 strong>目的：在这项工作中，作为组蛋白脱乙酰基酶抑制剂（HADCi）的Chidamide结合在pH响应嵌段聚合物叶酸上聚乙二醇b-聚天冬氨酸（PEG-b-PAsp）接枝叶酸（FA-PEG-b-PAsp）制得的嵌段聚合物叶酸聚乙二醇-b-聚（天冬酰胺基-酰胺）（FA-PEG-b-PAsp-chidamide，FPPC）作为抑制肿瘤的多峰靶向药物传递载体小鼠肿瘤细胞增殖和转移-chidamide）胶束包裹Pha]。通过透射电镜和动态光散射对Pha @ FPPC进行了表征。此外，还通过测定细胞内ROS水平，检测细胞凋亡和细胞周期阻滞，PDT体内抗肿瘤活性和组织学分析来研究体内和体外抗肿瘤活性。>结果：具有良好且稳定的球体在透射电子显微镜（TEM）（〜93.0 nm）的形态下，Pha @ FPPC由于叶酸介导的小鼠黑素瘤B16-F10细胞的有效内吞作用以及PDT诱导的肿瘤细胞中ROS的产生，大大提高了细胞的摄取，并且PDT后不仅在G2期而且在G1 / G0期引起坏死并阻断细胞生长周期。由于Pha @ FPPC具有较高的暗细胞毒性/光细胞毒性比，因此其在体外的暗细胞毒性较低，并且治疗指数更高。此外，由于Pha @ FPPC具有叶酸介导的肿瘤靶向作用以及通过EPR（增强的通透性和滞留性）效应选择性地聚集在肿瘤部位，因此不仅显着抑制了荷瘤的小鼠的生长并延长了黑色素瘤小鼠的存活时间。与游离Pha相比，PDT后的胶束纳米颗粒还显着防止了小鼠黑素瘤的肺转移，证明了其具有PDT和HDACi的双重抗肿瘤特性。>结论：是叶酸介导的酸活化的千酰胺移植药物。传递载体，FPPC由于其作为光敏剂的有效和多模式肿瘤靶向性能，在临床光动力治疗中可能具有抑制肿瘤转移的巨大潜力。

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