Targeting CD44 expressing cancer cells with anti-CD44 monoclonal antibody improves cellular uptake and antitumor efficacy of liposomal doxorubicin
Targeting CD44 expressing cancer cells with anti-CD44 monoclonal antibody improves cellular uptake and antitumor efficacy of liposomal doxorubicin
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DOI：
10.1016/j.jconrel.2015.10.044
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发表时间：
2015-12-28
影响因子：
10.8
通讯作者：
Jaafari, Mahmoud Reza
中科院分区：
文献类型：
--
作者：
Arabi, Leila;Badiee, Ali;Jaafari, Mahmoud Reza
虽然脂质体改善了游离药物的安全性和药代动力学性质，但与游离药物相比，它们没有充分增强治疗功效。为了解决这一问题，肿瘤细胞的靶向治疗与非靶向脂质体相比，有望进一步提高治疗指数并降低脱靶效应。在抗体介导的靶向癌症治疗的背景下，我们评估了Doxil的抗肿瘤活性和治疗效果，以及用抗CD 44的单克隆抗体（mAb）修饰的Doxil的抗肿瘤活性和治疗效果，CD 44是与癌症干细胞（CSC）相关的最知名的表面标志物之一。流式细胞术分析和共聚焦激光扫描显微镜结果显示，与Doxil相比，CD 44阳性C-26细胞中CD 44靶向Doxil（CD 44-Doxil）的细胞摄取显著增强。然而，CD 44阴性NIH-3 T3细胞显示出与CD 44-Doxil和非靶向Doxil相似的摄取和体外细胞毒性。在携带C-26小鼠癌的BALB/c小鼠中，CD 44-Doxil组在肿瘤细胞内表现出显著更高的多柔比星浓度（比Doxil），而它们的循环时间和分布特征保持相当。CD 44-Doxil在10或15 mg/kg剂量下导致上级肿瘤生长抑制和更高的肿瘤倾向，表明抗CD 44 mAb靶向治疗疗效改善的潜力。本研究为主动肿瘤靶向概念提供了原理性证明，值得进一步研究。(C)2015 Elsevier B. V.版权所有。
Although liposomes improve the safety and pharmacokinetic properties of free drugs, they have not sufficiently enhanced the therapeutic efficacy compared to them. To address this problem, targeted therapy of tumor cells holds great promise to further enhance therapeutic index and decreases off-target effects compared with nontargeted liposomes. In the context of antibody-mediated targeted cancer therapy, we evaluated the anti-tumor activity and therapeutic efficacy of Doxil, and that of Doxil modified with a monoclonal antibody (mAb) against CD44, which is one of the most well-known surface markers associated with Cancer Stem Cells (CSCs). Flow cytometry analyses and confocal laser scanning microscopy results showed significant enhanced cellular uptake of CD44-targeted Doxil (CD44-Doxil) in CD44-positive C-26 cells compared to Doxil. However, CD44-negative NIH-3T3 cells showed a similar uptake and in vitro cytotoxicity with both CD44-Doxil and non-targeted Doxil. In BALB/c mice bearing C-26 murine carcinoma, CD44-Doxil groups exhibited significantly higher doxorubicin concentration (than Doxil) inside the tumor cells, while their circulation time and distribution profile remained comparable. CD44-Doxil at doses of either 10 or 15 mg/kg resulted in superior tumor growth inhibition and higher inclination to tumor, indicating the potential of anti-CD44 mAb targeting in therapeutic efficacy improvement. This study provides proof-of-principle for actively tumor-targeting concept and merits further investigations. (C) 2015 Elsevier B.V. All rights reserved.