文献：磷脂修饰的PEI基纳米载体用于体内siRNA*多药耐药*

链接：https://www.nature.com/articles/gt201497

作者：埃塞克斯郡南部G纳瓦罗P·萨巴钱达尼，脉络膜M Trivedi，S Movassaghian＆副总裁托尔奇林

节选：

实体瘤中P-糖蛋白过表达介导的多药耐药性(MDR)是多种化疗失败的主要因素。本研究评估了磷脂修饰的低分子量聚乙烯亚胺(DOPE-PEI)纳米载体用于静脉输送*P-糖蛋白siRNA至*的效果，最终目标是调控乳腺癌的MDR。首先，我们研究了DOPE-PEI纳米载体的生物分布以及PEG涂层在皮下乳腺*模型中的作用。注射后四小时，PEG化载体通过增强的渗透性和滞留效应，在实体瘤中积累了8%的注射剂量(ID)，由于PEG介导的循环时间延长，在血清中积累了22%的ID。其次，我们确定了DOPE-PEI/siRNA介导的P-gp下调联合阿霉素(Dox)化疗在MCF-7/MDR异种移植瘤中的疗效和安全性。每周注射siRNA纳米制剂和Dox，持续长达5周，使*对原本无效剂量的Dox产生敏感性，并使*体积与对照组相比缩小了三倍。这种对Dox疗效的改善归因于DOPE-PEI制剂介导的切除*中显著的序列特异性P-gp下调。

Multidrug resistance (MDR) mediated by P-glycoprotein overexpression in solid tumors is a major factor in the failure of many forms of chemotherapy. Here we evaluated phospholipid-modified, low-molecular-weight polyethylenimine (DOPE-PEI) nanocarriers for intravenous delivery of anti-P-pg siRNA to tumors with the final goal of modulating MDR in breast cancer. First, we studied the biodistribution of DOPE-PEI nanocarriers and the effect of PEG coating in a subcutaneous breast tumor model. Four hours postinjection, PEGylated carriers showed an 8% injected dose (ID) accumulation in solid tumor via the enhanced permeability and retention effect and 22% ID in serum due to a prolonged, PEG-mediated circulation. Second, we established the therapeutic efficacy and safety of DOPE-PEI/siRNA-mediated P-gp downregulation in combination with doxorubicin (Dox) chemotherapy in MCF-7/MDR xenografts. Weekly injection of siRNA nanopreparations and Dox for up to 5 weeks sensitized the tumors to otherwise non-effective doses of Dox and decreased the tumor volume by threefold vs controls. This therapeutic improvement in response to Dox was attributed to the significant, sequence-specific P-gp downregulation in excised tumors mediated by the DOPE-PEI formulations.

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DSPE-Pyrene

DSPE-Thiol

DSPE-PEG-GE11(二硬脂酰基磷脂酰乙醇胺-聚乙二醇-*细胞表皮生长因子EGFR靶向肽)

DSPE-PEG-His

DSPE-PEG-cRGD(二硬脂酰基磷脂酰乙醇胺-聚乙二醇-整合素靶向环肽)

ALC-0315

DOPE-PEG-Mal

DSPE-PEG-M2pep

DSPE-PEG-cisplatin

DSPE

GPC3靶向肽-PEG-DSPE

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