Essex Sean, Navarro Gemma, Sabhachandani Pooja, Chordia Aabha, Trivedi Malav, Movassaghian Sara, Torchilin Vladimir P
Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
Gene Ther. 2015 Mar;22(3):257-266. doi: 10.1038/gt.2014.97. Epub 2014 Oct 30.
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.
实体瘤中由P-糖蛋白过表达介导的多药耐药（MDR）是多种化疗失败的主要因素。在此，我们评估了磷脂修饰的低分子量聚乙烯亚胺（DOPE-PEI）纳米载体用于将抗P-pg siRNA静脉注射到肿瘤中，最终目标是调节乳腺癌中的MDR。首先，我们在皮下乳腺肿瘤模型中研究了DOPE-PEI纳米载体的生物分布以及聚乙二醇（PEG）包被的作用。注射后4小时，聚乙二醇化载体通过增强的渗透和滞留效应在实体瘤中显示出8%的注射剂量（ID）积累，由于PEG介导的循环延长，在血清中的积累为22% ID。其次，我们在MCF-7/MDR异种移植物中建立了DOPE-PEI/siRNA介导的P-糖蛋白下调联合阿霉素（Dox）化疗的治疗效果和安全性。每周注射siRNA纳米制剂和Dox，持续5周，使肿瘤对原本无效剂量的Dox敏感，并使肿瘤体积比对照组减小了三倍。对Dox反应的这种治疗改善归因于DOPE-PEI制剂介导的切除肿瘤中显著的、序列特异性的P-糖蛋白下调。
