Yalamarty Satya Siva Kishan, Filipczak Nina, Li Xiang, Pathrikar Tanvi Vinod, Cotter Colin, Torchilin Vladimir P
Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
Pharmaceutics. 2022 Jul 15;14(7):1470. doi: 10.3390/pharmaceutics14071470.
Multidrug resistance (MDR) observed in tumors significantly hinders the efficacy of chemotherapy. Downregulation of efflux proteins, such as P-glycoprotein (P-gp), using small interfering RNA (siRNA) can be an effective way to minimize the resistance in tumors. In this study, monoclonal antibody 2C5 (mAb 2C5)-PEG-DOPE conjugates were post-inserted into the mixed dendrimer micelles containing generation 4 (G4) polyamidoamine (PAMAM)-PEG-DOPE and PEG-DOPE. The inherent amphiphilic nature of DOPE conjugates causes the copolymers to self-assemble to form a micelle, which can encapsulate hydrophobic chemotherapeutic drugs in its core. The siRNA electrostatically binds to the cationic charges on the G4 PAMAM dendrimer. The tumor-specific mAb 2C5 on the surface of these nano-preparations resulted in improved tumor targeting. This active targeting to tumors can cause increase in the drug and siRNA accumulation at the tumor site, and thereby minimizing the off-target effects. The micelles were shown to have higher cellular association and effectiveness in vitro. The immunomicelle preparation was also tested for cytotoxicity in breast (MDA-MB-231) and ovarian (SKOV-3TR) MDR cancer cell lines.
肿瘤中观察到的多药耐药性（MDR）显著阻碍了化疗的疗效。使用小干扰RNA（siRNA）下调外排蛋白，如P-糖蛋白（P-gp），可能是一种有效降低肿瘤耐药性的方法。在本研究中，将单克隆抗体2C5（mAb 2C5）-聚乙二醇-二油酰磷脂酰乙醇胺（PEG-DOPE）偶联物后插入到含有第4代（G4）聚酰胺胺（PAMAM）-PEG-DOPE和PEG-DOPE的混合树枝状聚合物胶束中。DOPE偶联物固有的两亲性质导致共聚物自组装形成胶束，其可在核心中包封疏水性化疗药物。siRNA通过静电作用与G4 PAMAM树枝状聚合物上的阳离子电荷结合。这些纳米制剂表面的肿瘤特异性mAb 2C5导致肿瘤靶向性提高。这种对肿瘤的主动靶向可导致药物和siRNA在肿瘤部位的积累增加，从而将脱靶效应降至最低。结果表明，该胶束在体外具有更高的细胞亲和力和有效性。还对免疫胶束制剂在乳腺癌（MDA-MB-231）和卵巢癌（SKOV-3TR）多药耐药癌细胞系中的细胞毒性进行了测试。
