University of Coimbra, Center for Neuroscience and Cell Biology, Coimbra, Portugal; University of Coimbra, Institute for Interdisciplinary Research, Coimbra, Portugal; University of Coimbra, Centre for Mechanical Engineering, Materials and Processes, Department of Chemical Engineering, Coimbra, Portugal.
University of Coimbra, Centre for Mechanical Engineering, Materials and Processes, Department of Chemical Engineering, Coimbra, Portugal.
Int J Pharm. 2023 Apr 25;637:122865. doi: 10.1016/j.ijpharm.2023.122865. Epub 2023 Mar 20.
The chemosensitization of tumor cells by gene therapy represents a promising strategy for hepatocellular carcinoma (HCC) treatment. In this regard, HCC-specific and highly efficient gene delivery nanocarriers are urgently needed. For this purpose, novel lactobionic acid-based gene delivery nanosystems were developed to downregulate c-MYC expression and sensitize tumor cells to low concentration of sorafenib (SF). A library of tailor-made cationic glycopolymers, based on poly(2-aminoethyl methacrylate hydrochloride) (PAMA) and poly(2-lactobionamidoethyl methacrylate) (PLAMA) were synthesized by a straightforward activators regenerated by electron transfer atom transfer radical polymerization. The nanocarriers prepared with PAMA-co-PLAMA glycopolymer were the most efficient for gene delivery. These glycoplexes specifically bound to the asialoglycoprotein receptor and were internalized through the clathrin-coated pit endocytic pathway. c-MYC expression was significantly downregulated by MYC short-hairpin RNA (MYC shRNA), resulting in efficient inhibition of tumor cells proliferation and a high levels apoptosis in 2D and 3D HCC-tumor models. Moreover, c-MYC silencing increased the sensitivity of HCC cells to SF (IC for MYC shRNA + SF 1.9 μM compared to 6.9 μM for control shRNA + SF). Overall, the data obtained demonstrated the great potential of PAMA-co-PLAMA/MYC shRNA nanosystems combined with low doses of SF for the treatment of HCC.
通过基因治疗使肿瘤细胞对化疗增敏代表了一种治疗肝细胞癌（HCC）的很有前途的策略。在这方面，迫切需要 HCC 特异性和高效的基因传递纳米载体。为此，开发了新型的基于乳糖酸的基因传递纳米系统，以下调 c-MYC 表达并使肿瘤细胞对低浓度索拉非尼（SF）敏感。通过电子转移原子转移自由基聚合，合成了基于聚（2-氨基乙基甲基丙烯酸盐酸盐）（PAMA）和聚（2-乳糖酰基乙酰胺基甲基丙烯酸酯）（PLAMA）的定制阳离子糖聚合物库。用 PAMA-co-PLAMA 糖聚合物制备的纳米载体对基因传递最有效。这些糖复合物特异性地与去唾液酸糖蛋白受体结合，并通过网格蛋白包被的陷窝内吞途径被内化。通过 MYC 短发夹 RNA（MYC shRNA）显著下调 c-MYC 表达，导致 2D 和 3D HCC 肿瘤模型中肿瘤细胞增殖的有效抑制和高水平凋亡。此外，c-MYC 沉默增加了 HCC 细胞对 SF 的敏感性（IC 对于 MYC shRNA+SF 为 1.9 μM，而对照 shRNA+SF 为 6.9 μM）。总的来说，获得的数据表明，PAMA-co-PLAMA/MYC shRNA 纳米系统联合低剂量 SF 治疗 HCC 的潜力巨大。
