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Acid Degradable Cationic Galactose-Based Hyperbranched Polymers as Nanotherapeutic Vehicles for Epidermal Growth Factor Receptor (EGFR) Knockdown in Cervical Carcinoma
Biomacromolecules ( IF 5.5 ) Pub Date : 2018-08-29 00:00:00 , DOI: 10.1021/acs.biomac.8b01066 Yi-Yang Peng 1 , Diana Diaz-Dussan 2 , Piyush Kumar 2 , Ravin Narain 1
Biomacromolecules ( IF 5.5 ) Pub Date : 2018-08-29 00:00:00 , DOI: 10.1021/acs.biomac.8b01066 Yi-Yang Peng 1 , Diana Diaz-Dussan 2 , Piyush Kumar 2 , Ravin Narain 1
Affiliation
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Strong signaling cascades derived from upregulation and overexpression of growth factors such as the EGF-family (epidermal growth factors) have been crucially related to cancer pathogenesis. Gene silencing techniques to modulate the expression of oncogenes and tumor suppresor genes are a strategy that shows great promise for cancer management but still faces some limitations in the design of biocompatible and effective vectors. In this study, we synthesized, by reversible addition–fragmentation chain transfer (RAFT) polymerization, several acid degradable galactose-based hyperbranched cationic polymers with varying molecular weights (10 to 20 kDa) and compositions with 2-lactobioamidoethyl methacrylamide [LAEMA] and 2-aminoethyl methacrylamide hydrochloride [AEMA] at different ratios (2.0, 1.0, and 0.5). These polymers were then evaluated for their ability to enhance Epidermal Growth Factor Receptor (EGFR) knockdown in cervical carcinoma. All the polymer constructs have enhanced capabilities to condensate siRNA (small interfering RNA), showing low toxicity at higher LAEMA:AEMA ratios (1.0 and 2.0). Western blot assays were conducted to quantify the EGFR expression of each treatment group demonstrating superior gene knockdown efficiency for the polymers having a LAEMA:AEMA ratio of 2.0 than the lower ratio counterparts; while maintaining low toxicity levels. Gene silencing of EGFR of up to 60% was achieved with acid degradable polymers having 10 kDa molecular weight and a LAEMA:AEMA ratio of 2.0. The superior stability of the polyplexes under physiological conditions and the low cytotoxicity observed in the 48 h post-transfection demonstrated the high potential of these acid degradable galactose-based hyperbranched cationic polymers for EGFR silencing treatment applications at the clinical level.
中文翻译：
酸可降解阳离子半乳糖基超支化聚合物作为宫颈癌表皮生长因子受体（EGFR）基因敲除的纳米治疗载体。
源于生长因子（例如EGF家族）（表皮生长因子）的上调和过表达的强大信号级联与癌症的发病机理至关重要。基因沉默技术可调节癌基因和肿瘤抑制基因的表达，是一种在癌症治疗方面显示出巨大希望的策略，但在设计生物相容性和有效载体方面仍存在一些局限性。在这项研究中，我们通过可逆的加成-断裂链转移（RAFT）聚合反应，合成了几种具有不同分子量（10至20 kDa）的酸可降解半乳糖基超支化阳离子聚合物，以及具有2-乳酸生物酰胺乙基甲基丙烯酰胺[LAEMA]和2的组合物-氨乙基甲基丙烯酰胺盐酸盐[AEMA]的比例不同（2.0、1.0和0.5）。然后评估这些聚合物在宫颈癌中增强表皮生长因子受体（EGFR）抑制的能力。所有聚合物构建体均具有增强的siRNA（小干扰RNA）浓缩能力，在较高的LAEMA：AEMA比值（1.0和2.0）下显示出低毒性。进行了蛋白质印迹分析以量化每个治疗组的EGFR表达，证明其LAEMA：AEMA比率为2.0的聚合物比低比率的同类物具有更高的基因敲除效率。同时保持较低的毒性水平。用分子量为10 kDa且LAEMA：AEMA比为2.0的可酸降解的聚合物可达到EGFR的60％的基因沉默。
更新日期：2018-08-29
中文翻译：
酸可降解阳离子半乳糖基超支化聚合物作为宫颈癌表皮生长因子受体（EGFR）基因敲除的纳米治疗载体。
源于生长因子（例如EGF家族）（表皮生长因子）的上调和过表达的强大信号级联与癌症的发病机理至关重要。基因沉默技术可调节癌基因和肿瘤抑制基因的表达，是一种在癌症治疗方面显示出巨大希望的策略，但在设计生物相容性和有效载体方面仍存在一些局限性。在这项研究中，我们通过可逆的加成-断裂链转移（RAFT）聚合反应，合成了几种具有不同分子量（10至20 kDa）的酸可降解半乳糖基超支化阳离子聚合物，以及具有2-乳酸生物酰胺乙基甲基丙烯酰胺[LAEMA]和2的组合物-氨乙基甲基丙烯酰胺盐酸盐[AEMA]的比例不同（2.0、1.0和0.5）。然后评估这些聚合物在宫颈癌中增强表皮生长因子受体（EGFR）抑制的能力。所有聚合物构建体均具有增强的siRNA（小干扰RNA）浓缩能力，在较高的LAEMA：AEMA比值（1.0和2.0）下显示出低毒性。进行了蛋白质印迹分析以量化每个治疗组的EGFR表达，证明其LAEMA：AEMA比率为2.0的聚合物比低比率的同类物具有更高的基因敲除效率。同时保持较低的毒性水平。用分子量为10 kDa且LAEMA：AEMA比为2.0的可酸降解的聚合物可达到EGFR的60％的基因沉默。
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