Targeting CD44 expressing cancer cells with anti-CD44 monoclonal antibody improves cellular uptake and antitumor efficacy of liposomal doxorubicin

CD44细胞 单克隆抗体 阿霉素 癌症研究 流式细胞术 化学 靶向治疗 医学 药理学 治疗指标 脂质体 癌症 抗体 体外 免疫学 化疗 内科学 药品 生物化学
作者
Leila Arabi,Ali Badiee,Fatemeh Mosaffa,Mahmoud Reza Jaafari
出处
期刊:Journal of Controlled Release [Elsevier]
卷期号:220: 275-286 被引量:162
标识
DOI:10.1016/j.jconrel.2015.10.044
摘要

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 non-targeted 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.
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