Zhong Ping, Gu Xiaolei, Cheng Ru, Deng Chao, Meng Fenghua, Zhong Zhiyuan
Biomedical Polymers Laboratory.
Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, China.
Int J Nanomedicine. 2017 Oct 27;12:7913-7921. doi: 10.2147/IJN.S146505. eCollection 2017.
Antibody-mertansine (DM1) conjugates (AMCs) are among the very few active targeting therapeutics that are approved or clinically investigated for treating various cancers including metastatic breast cancer. However, none of the AMCs are effective for the treatment of triple-negative breast cancers (TNBCs). Here, we show that cRGD-decorated, redox-activatable micellar mertansine prodrug (cRGD-MMP) can effectively target and deliver DM1 to αβ integrin overexpressing MDA-MB-231 TNBC xenografts in nude mice, resulting in potent tumor growth inhibition. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that cRGD-MMP had obvious targetability to MDA-MB-231 cells with a low half-maximal inhibitory concentration (IC) of 0.18 μM, which was close to that of free DM1 and 2.2-fold lower than that of micellar mertansine prodrug (MMP; nontargeting control). The confocal microscopy studies demonstrated that cRGD-MMP mediated a clearly more efficient cellular uptake and intracellular release of doxorubicin (used as a fluorescent anticancer drug model) in MDA-MB-231 cells. Notably, cRGD-MMP loaded with 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide (DiR; a hydrophobic near-infrared dye) was shown to quickly accumulate in the MDA-MB-231 tumor with strong DiR fluorescence from 2 to 24 h post injection. MMP loaded with DiR could also accumulate in the tumor, although significantly less than cRGD-MMP. The biodistribution studies revealed a high DM1 accumulation of 8.1%ID/g in the tumor for cRGD-MMP at 12 h post injection. The therapeutic results demonstrated that cRGD-MMP effectively suppressed MDA-MB-231 tumor growth at 1.6 mg DM1 equiv./kg without causing noticeable side effects, as shown by little body weight loss and histological analysis. This MMP has appeared as a promising platform for potent treatment of TNBCs.
抗体-美登素（DM1）偶联物（AMCs）是少数已获批准或正在进行临床研究用于治疗包括转移性乳腺癌在内的多种癌症的活性靶向治疗药物。然而，没有一种AMC对三阴性乳腺癌（TNBCs）有效。在此，我们表明，用cRGD修饰的、可氧化还原激活的胶束型美登素前药（cRGD-MMP）能够有效地将DM1靶向递送至在裸鼠中过表达αβ整合素的MDA-MB-231 TNBC异种移植瘤，从而有效抑制肿瘤生长。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）试验表明，cRGD-MMP对MDA-MB-231细胞具有明显的靶向性，其半数最大抑制浓度（IC）低至0.18 μM，接近游离DM1，比胶束型美登素前药（MMP；非靶向对照）低2.2倍。共聚焦显微镜研究表明，cRGD-MMP介导多柔比星（用作荧光抗癌药物模型）在MDA-MB-231细胞中更高效的细胞摄取和细胞内释放。值得注意的是，负载1,1'-二辛基四甲基吲哚三碳菁碘化物（DiR；一种疏水性近红外染料）的cRGD-MMP在注射后2至24小时显示出能迅速在MDA-MB-231肿瘤中积聚，并伴有强烈的DiR荧光。负载DiR的MMP也能在肿瘤中积聚，尽管明显少于cRGD-MMP。生物分布研究显示，注射后12小时，cRGD-MMP在肿瘤中的DM1高积聚量为8.1%ID/g。治疗结果表明，cRGD-MMP以1.6 mg DM1当量/千克有效抑制MDA-MB-231肿瘤生长，且未引起明显副作用，体重减轻和组织学分析均显示如此。这种MMP已成为一种有前景的强效治疗TNBCs的平台。
