P-glycoprotein silencing with siRNA delivered by DOPE-modified PEI overcomes doxorubicin resistance in breast cancer cells.
P-glycoprotein silencing with siRNA delivered by DOPE-modified PEI overcomes doxorubicin resistance in breast cancer cells.
复制标题
DOPE 修饰的 PEI 传递的 siRNA 沉默 P-糖蛋白，克服了乳腺癌细胞中的阿霉素耐药性。
DOI：
10.2217/nnm.11.93
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Torchilin VP
中科院分区：
文献类型：
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作者：
Navarro G;Sawant RR;Biswas S;Essex S;Tros de Ilarduya C;Torchilin VP
由 P-糖蛋白 (P-gp) 等药物外排转运蛋白过度表达介导的多药耐药性 (MDR) 是一个主要问题，限制了乳腺癌化疗的成功。使用siRNA抑制MDR肿瘤中P-gp的表达是提高抗癌药物有效性的一种有吸引力的策略。我们合成了一种用于 siRNA 递送的磷脂（二油酰磷脂酰乙醇胺）和聚乙烯亚胺 (PEI) 之间的新型缀合物，其目的是沉默 P-gp 以克服 MCF-7 人乳腺癌细胞中的阿霉素耐药性。二油酰磷脂酰乙醇胺-PEI 缀合物增强了低分子量 PEI 的转染功效，否则完全无效。此外，新复合物的聚乙二醇/脂质涂层产生了具有改善的生物相容性的小胶束状纳米颗粒。包被和非包被制剂均将 P-gp 特异性 siRNA 递送至 MDR 细胞。阿霉素和P-gp沉默制剂的组合导致阿霉素摄取增加两倍，并且显着改善阿霉素在耐药细胞中的治疗效果。
Multidrug resistance (MDR) mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem, limiting successful chemotherapy of breast cancer. The use of siRNA to inhibit P-gp expression in MDR tumors is an attractive strategy to improve the effectiveness of anticancer drugs. We have synthesized a novel conjugate between a phospholipid (dioleoylphosphatidylethanolamine) and polyethylenimine (PEI) for siRNA delivery, for the purpose of silencing P-gp to overcome doxorubicin resistance in MCF-7 human breast cancer cells. The dioleoylphosphatidylethanolamine-PEI conjugate enhanced the transfection efficacy of low-molecular-weight PEI, which was otherwise totally ineffective. In addition, the polyethylene glycol/lipid coating of the new complexes gave rise to small micelle-like nanoparticles with improved biocompatibility properties. Both coated and noncoated formulations delivered P-gp-specific siRNA to MDR cells. The combination of doxorubicin and P-gp silencing formulations led to a twofold increase of doxorubicin uptake and a significant improvement of the therapeutic effect of doxorubicin in resistant cells.