全反式维甲酸包裹、CD20抗体偶联的聚乳酸-乙醇酸纳米颗粒在体外能有效靶向并消除黑色素瘤起始细胞。
All-trans retinoic acid-encapsulated, CD20 antibody-conjugated poly(lactic--glycolic acid) nanoparticles effectively target and eliminate melanoma-initiating cells in vitro.
作者信息
Chen Xingyu, Zhang Zhiyuan, Yang Shengfeng, Chen Hairong, Wang Dan, Li Jun
机构信息
Department of Dermatology and Venerology, Shandong University School of Medicine, Jinan, Shandong, 250000, China,
Department of Dermatology, Qingdao Municipal Hospital, Qingdao, Shandong 266011, China,
出版信息
Onco Targets Ther. 2018 Sep 25;11:6177-6187. doi: 10.2147/OTT.S169957. eCollection 2018.
PURPOSE
Melanoma, which is initiated from melanocytes, is the most fatal type of skin cancer. Melanoma-initiating cells significantly contribute to the initiation, metastasis, and recurrence of melanoma, and CD20 is a marker of melanoma-initiating cells. All-trans retinoic acid (ATRA) has been demonstrated to induce differentiation, inhibit proliferation, and promote the apoptosis of cancer cells and cancer-initiating cells (CICs). However, there has been no report on ATRA activity against melanoma-initiating cells. In this study, we examined the activity of ATRA against melanoma-initiating cells and developed ATRA-encapsulated poly(lactic--glycolic acid) (PLGA) nanoparticles, which were conjugated with a CD20 antibody (ATRA-PNP-CD20) for targeted delivery of ATRA to CD20 melanoma-initiating cells.
MATERIALS AND METHODS
The effects of ATRA and ATRA-PNP-CD20 against melanoma-initiating cells were investigated using a cytotoxicity assay, tumorsphere formation assay, and flow cytometry.
RESULTS
ATRA-PNP-CD20 had a size of 126.9 nm and a negative zeta potential. The drug-loading capacity of ATRA-PNP-CD20 was 8.7%, and ATRA-PNP-CD20 displayed a sustained release of ATRA for 144 hours. The results showed that ATRA-PNP-CD20 could effectively and specifically deliver ATRA to CD20 melanoma-initiating cells, achieving superior inhibitory effects against CD20 melanoma-initiating cells compared with those of free ATRA and nontargeted nanoparticles. To the best of our knowledge, we report for the first time a potent activity of ATRA against CD20 melanoma-initiating cells, targeted drug delivery of ATRA via nanoparticles to melanoma-initiating cells, and the achievement of a superior inhibitory effect against melanoma-initiating cells by using a CD20 antibody.
CONCLUSION
ATRA-PNP-CD20 represents a promising tool for eliminating melanoma-initiating cells and shows a potential for the therapy of melanoma.
目的
黑色素瘤起源于黑素细胞，是最致命的皮肤癌类型。黑色素瘤起始细胞对黑色素瘤的起始、转移和复发有显著贡献，而CD20是黑色素瘤起始细胞的标志物。全反式维甲酸（ATRA）已被证明可诱导癌细胞和癌症起始细胞（CICs）分化、抑制增殖并促进其凋亡。然而，尚无关于ATRA对黑色素瘤起始细胞活性的报道。在本研究中，我们检测了ATRA对黑色素瘤起始细胞的活性，并制备了包裹ATRA的聚乳酸-乙醇酸共聚物（PLGA）纳米颗粒，其与CD20抗体偶联（ATRA-PNP-CD20），用于将ATRA靶向递送至CD20黑色素瘤起始细胞。
材料与方法
采用细胞毒性试验、肿瘤球形成试验和流式细胞术研究ATRA和ATRA-PNP-CD20对黑色素瘤起始细胞的作用。
结果
ATRA-PNP-CD20粒径为126.9 nm，zeta电位为负。ATRA-PNP-CD20的载药率为8.7%，且ATRA-PNP-CD20可使ATRA持续释放144小时。结果表明，ATRA-PNP-CD20能有效且特异性地将ATRA递送至CD20黑色素瘤起始细胞，与游离ATRA和非靶向纳米颗粒相比，对CD20黑色素瘤起始细胞具有更强的抑制作用。据我们所知，我们首次报道了ATRA对CD20黑色素瘤起始细胞具有强效活性、通过纳米颗粒将ATRA靶向递送至黑色素瘤起始细胞以及利用CD20抗体对黑色素瘤起始细胞实现更强抑制作用。
结论
ATRA-PNP-CD20是消除黑色素瘤起始细胞的一种有前景的工具，显示出治疗黑色素瘤的潜力。
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