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.
西安齐岳生物提供相关产品:
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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