Shabana Ahmed M, Xu Beibei, Schneiderman Zachary, Ma Jun, Chen Clark C, Kokkoli Efrosini
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Pharmaceutics. 2021 Jul 21;13(8):1115. doi: 10.3390/pharmaceutics13081115.
Despite potential for clinical efficacy, therapeutic delivery of microRNAs (miRNA) remains a major translational barrier. Here, we explore a strategy for miRNA delivery in the treatment of glioblastoma, the most common form of adult brain cancer, that involves complexation of miRNA with polyethylenimine (PEI) and encapsulation in targeted liposomes. miRNA 603 (miR-603) is a master regulatory miRNA that suppresses glioblastoma radiation resistance through down-regulation of insulin-like growth factor 1 (IGF1) signaling. miR-603 was complexed with PEI, a cationic polymer, and encapsulated into liposomes decorated with polyethylene glycol (PEG) and PR_b, a fibronectin-mimetic peptide that specifically targets the αβ integrin that is overexpressed in glioblastomas. Cultured patient-derived glioblastoma cells internalized PR_b-functionalized liposomes but not the non-targeted liposomes. The integrin targeting and complexation of the miRNA with PEI were associated with a 22-fold increase in intracellular miR-603 levels, and corresponding decreases in IGF1 and IGF1 receptor (IGF1R) mRNA expression. Moreover, treatment of glioblastoma cells with the PR_b liposomes encapsulating miR-603/PEI sensitized the cells to ionizing radiation (IR), a standard of care treatment for glioblastomas. These results suggest that PR_b-functionalized PEGylated liposomes encapsulating miR-603/PEI complexes hold promise as a therapeutic platform for glioblastomas.
尽管具有临床疗效的潜力，但微小RNA（miRNA）的治疗性递送仍然是一个主要的转化障碍。在这里，我们探索了一种在胶质母细胞瘤（成人大脑癌症最常见的形式）治疗中递送miRNA的策略，该策略涉及将miRNA与聚乙烯亚胺（PEI）复合并封装在靶向脂质体中。miRNA 603（miR-603）是一种主要的调节性miRNA，它通过下调胰岛素样生长因子1（IGF1）信号传导来抑制胶质母细胞瘤的辐射抗性。miR-603与阳离子聚合物PEI复合，并封装到用聚乙二醇（PEG）和PR_b修饰的脂质体中，PR_b是一种模拟纤连蛋白的肽，可特异性靶向在胶质母细胞瘤中过表达的αβ整合素。培养的患者来源的胶质母细胞瘤细胞内化了PR_b功能化的脂质体，但没有内化非靶向脂质体。整合素靶向以及miRNA与PEI的复合与细胞内miR-603水平增加22倍以及IGF1和IGF1受体（IGF1R）mRNA表达相应降低有关。此外，用封装有miR-603/PEI的PR_b脂质体处理胶质母细胞瘤细胞可使细胞对电离辐射（IR）敏感，电离辐射是胶质母细胞瘤的一种标准治疗方法。这些结果表明，封装有miR-603/PEI复合物并经PR_b功能化的聚乙二醇化脂质体有望成为胶质母细胞瘤的治疗平台。
