Enhanced Antitumor Effects of Epidermal Growth Factor Receptor Targetable Cetuximab-Conjugated Polymeric Micelles for Photodynamic Therapy.
Enhanced Antitumor Effects of Epidermal Growth Factor Receptor Targetable Cetuximab-Conjugated Polymeric Micelles for Photodynamic Therapy.
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DOI：
10.3390/nano8020121
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发表时间：
2018-02-22
期刊：
影响因子：
--
通讯作者：
Lai PS
中科院分区：
文献类型：
--
作者：
Chang MH;Pai CL;Chen YC;Yu HP;Hsu CY;Lai PS
基于纳米载体的给药系统是提高有毒药物疗效和安全性的有前途的策略。光动力疗法(PDT)是一种光引发的化学反应，在疾病治疗中会产生局部组织损伤，通常会有副作用，因此接受光敏剂治疗的患者应该远离直射光，以避免皮肤光毒性。在这项研究中，临床治疗性抗体西妥昔单抗(C225)通过硫醇-马来酰亚胺偶联的方式连接到甲氧基聚乙二醇聚b-丙交酯(mpeg-b-plc)胶束表面，从而实现了肿瘤靶向的氯化e6(Ce6)的传递。激光共聚焦扫描显微镜观察到，在表皮生长因子受体高表达的A431细胞中，C225-Ce6负载的聚合物胶束(C225-Ce6/PM)比Ce6/PM或CE6/PM被选择性地摄取了更多的C225-Ce6/PM，从而使Ce6介导的PDT的IC50值从0.42降低到0.173μM。在低EGFR表达的HT-29细胞中，C225-Ce6/PM和Ce6/PM组之间的IC50值没有显著差异。在抗肿瘤研究中，C225-Ce6/PM-PDT组在第21天的肿瘤体积(肿瘤生长抑制率，TGI%=84.8)明显小于CE6-PDT组(TGI%=38.4)和Ce6/PM-PDT组(TGI%=53.3)(p<；0.05)，这是因为C225-Ce6/PM-PDT组在第21天时抑制了A431移植瘤的细胞增殖。这些结果表明，主动的EGFR靶向光敏剂胶束为解决传统光敏剂的剂量限制毒性提供了一种可能的途径，并为临床提供了一种潜在的PDT给药系统。
Nanocarrier-based delivery systems are promising strategies for enhanced therapeutic efficacy and safety of toxic drugs. Photodynamic therapy (PDT)—a light-triggered chemical reaction that generates localized tissue damage for disease treatments—usually has side effects, and thus patients receiving photosensitizers should be kept away from direct light to avoid skin phototoxicity. In this study, a clinically therapeutic antibody cetuximab (C225) was conjugated to the surface of methoxy poly(ethylene glycol)-b-poly(lactide) (mPEG-b-PLA) micelles via thiol-maleimide coupling to allow tumor-targetable chlorin e6 (Ce6) delivery. Our results demonstrate that more C225-conjugated Ce6-loaded polymeric micelles (C225-Ce6/PM) were selectively taken up than Ce6/PM or IgG conjugated Ce6/PM by epidermal growth factor receptor (EGFR)-overexpressing A431 cells observed by confocal laser scanning microscopy (CLSM), thereby decreasing the IC50 value of Ce6-mediated PDT from 0.42 to 0.173 μM. No significant differences were observed in cellular uptake study or IC50 value between C225-Ce6/PM and Ce6/PM groups in lower EGFR expression HT-29 cells. For antitumor study, the tumor volumes in the C225-Ce6/PM-PDT group (percentage of tumor growth inhibition, TGI% = 84.8) were significantly smaller than those in the Ce6-PDT (TGI% = 38.4) and Ce6/PM-PDT groups (TGI% = 53.3) (p < 0.05) at day 21 through reduced cell proliferation in A431 xenografted mice. These results indicated that active EGFR targeting of photosensitizer-loaded micelles provides a possible way to resolve the dose-limiting toxicity of conventional photosensitizers and represents a potential delivery system for PDT in a clinical setting.
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