Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal.
Institute for Interdisciplinary Research, University of Coimbra, Coimbra 3030-789, Portugal.
Biomacromolecules. 2023 Mar 13;24(3):1274-1286. doi: 10.1021/acs.biomac.2c01329. Epub 2023 Feb 13.
Cationic glycopolymers stand out as gene delivery nanosystems due to their inherent biocompatibility and high binding affinity to the asialoglycoprotein receptor (ASGPR), a target receptor overexpressed in hepatocellular carcinoma (HCC) cells. However, their synthesis procedure remains laborious and complex, with problems of solubilization and the need for protection/deprotection steps. Here, a mini-library of well-defined poly(2-aminoethyl methacrylate hydrochloride--poly(2-lactobionamidoethyl methacrylate) (PAMA--PLAMA) glycopolymers was synthesized by activators regenerated by electron transfer (ARGET) ATRP to develop an efficient gene delivery nanosystem. The glycoplexes generated had suitable physicochemical properties and showed high ASGPR specificity and high transfection efficiency. Moreover, the HSV-TK/GCV suicide gene therapy strategy, mediated by PAMA--PLAMA-based nanocarriers, resulted in high antitumor activity in 2D and 3D culture models of HCC, which was significantly enhanced by the combination with small amounts of docetaxel. Overall, our results demonstrated the potential of primary-amine polymethacrylate-containing-glycopolymers as HCC-targeted suicide gene delivery nanosystems and highlight the importance of combined strategies for HCC treatment.
阳离子糖聚合物因其固有生物相容性和对过度表达于肝癌 (HCC) 细胞的去唾液酸糖蛋白受体 (ASGPR) 的高结合亲和力而成为基因传递纳米系统。然而，其合成过程仍然繁琐复杂，存在溶解性问题，需要保护/脱保护步骤。在这里，通过电子转移 (ARGET) ATRP 合成了一组具有明确结构的聚(2-氨基乙基甲基丙烯酸盐酸盐-聚(2-乳酰氨乙基甲基丙烯酸酯)(PAMA-PLAMA)糖聚合物的小型文库，以开发高效的基因传递纳米系统。所生成的糖复合物具有合适的物理化学性质，表现出高 ASGPR 特异性和高转染效率。此外，基于 PAMA-PLAMA 的纳米载体介导的 HSV-TK/GCV 自杀基因治疗策略，在 HCC 的 2D 和 3D 培养模型中表现出高抗肿瘤活性，并且与小剂量多西他赛联合使用时，抗肿瘤活性显著增强。总体而言，我们的结果表明含有伯胺的聚甲基丙烯酸酯糖聚合物作为 HCC 靶向自杀基因传递纳米系统的潜力，并强调了联合策略在 HCC 治疗中的重要性。
