Inhibition of MDR1 gene expression and enhancing cellular uptake for effective colon cancer treatment using dual-surface-functionalized nanoparticles.
Inhibition of MDR1 gene expression and enhancing cellular uptake for effective colon cancer treatment using dual-surface-functionalized nanoparticles.
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DOI：
10.1016/j.biomaterials.2015.01.014
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发表时间：
2015-04
期刊：
影响因子：
14
通讯作者：
Merlin, Didier
中科院分区：
文献类型：
--
作者：
Xiao, Bo;Zhang, Mingzhen;Viennois, Emilie;Zhang, Yuchen;Wei, Na;Baker, Mark T.;Jung, Yunjin;Merlin, Didier
关键词：
纳米药物治疗结肠癌的选择受到了限制，因为缺乏合适的载体能够将足够的药物输送到肿瘤中，从而产生致命的毒性。为了克服这一限制，我们制备了喜树碱(CPT)载药的聚乳酸-乙醇酸共聚纳米粒(NP)，具有双表面功能化-Pluronic F127和壳聚糖-用于抑制多药耐药基因1(MDR1)的表达和增强肿瘤的摄取。所制得的球形NPs-P/C具有理想的颗粒尺寸(~268 nm)、轻微的正Zeta电位以及有效下调MDR1表达的能力。体外细胞毒性实验表明，NPs-P/C1的24和48hIC50值分别为2.03和0.67µM，明显低于游离CPT和其他NPs。有趣的是，在不同的药物制剂中，NPs-P/C1显示出最高的细胞摄取效率(约85.5%)。最重要的是，用不同的药物制剂治疗结肠癌小鼠证实，将Pluronic F127和壳聚糖引入NP表面显著提高了CPT的治疗效果，诱导了肿瘤细胞凋亡，并降低了全身毒性。总而言之，这些发现表明，我们的一步制造、双表面功能化的NPs可能有望成为一种易于扩展和有效的药物载体，在结肠癌治疗中具有临床潜力。
Nanomedicine options for colon cancer therapy have been limited by the lack of suitable carriers capable of delivering sufficient drug into tumors to cause lethal toxicity. To circumvent this limitation, we fabricated a camptothecin (CPT)-loaded poly(lactic-co-glycolic acid) nanoparticle (NP) with dual-surface functionalization—Pluronic F127 and chitosan—for inhibiting multi-drug resistant gene 1 (MDR1) expression and enhancing tumor uptake. The resultant spherical NPs-P/C had a desirable particle size (~268 nm), slightly positive zeta-potential, and the ability to efficiently down-regulate the expression of MDR1. In vitro cytotoxicity tests revealed that the 24 and 48 h IC50 values of NPs-P/C1 were 2.03 and 0.67 µM, respectively, which were much lower than those for free CPT and other NPs. Interestingly, NPs-P/C1 showed the highest cellular uptake efficiency (approximately 85.5%) among the different drug formulations. Most importantly, treatment of colon tumor-bearing mice with various drug formulations confirmed that the introduction of Pluronic F127 and chitosan to the NP surface significantly enhanced the therapeutic efficacy of CPT, induced tumor cell apoptosis, and reduced systemic toxicity. Collectively, these findings suggest that our one-step–fabricated, dual-surface–functionalized NPs may hold promise as a readily scalable and effective drug carrier with clinical potential in colon cancer therapy.
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