Miryala Bhavani, Zhen Zhuo, Potta Thrimoorthy, Breneman Curt M, Rege Kaushal
Chemical Engineering, School for Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, Arizona 85287-6106, United States.
Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York 12180, United States.
ACS Biomater Sci Eng. 2015 Aug 10;1(8):656-668. doi: 10.1021/acsbiomaterials.5b00045. Epub 2015 Jul 1.
We describe the parallel synthesis of lipopolymers generated by conjugating alkanoyl chlorides to polymers derived from aminoglycoside antibiotic monomers as novel vehicles for transgene delivery and expression in mammalian cells. Parallel screening of lipopolymers led to the identification of six leads that demonstrated higher transgene expression efficacies in several cancer cells, when compared to the parental polymers as well as 25 kDa poly(ethylene imine), a current standard for polymer-mediated transgene expression. Quantitiative structure-activity relationship (QSAR)-based cheminformatics modeling was employed in order to investigate the role of lipopolymer physicochemical properties (molecular descriptors) on transgene expression efficacy. The predictive ability of the QSAR model, investgated using lipopolymers not employed for training the model, demonstrated excellent agreement with experimentally observed transgene expression. Our findings indicate that lipid substitution on aminoglycoside-derived polymers results in high levels of transgene expression compared to unsubstituted polymers. Taken together, these materials show significant promise in nonviral transgene delivery with several applications in biotechnology and medicine.
我们描述了通过将烷酰氯与源自氨基糖苷类抗生素单体的聚合物共轭而生成的脂聚合物的平行合成，作为用于转基因在哺乳动物细胞中递送和表达的新型载体。对脂聚合物进行平行筛选，鉴定出六种先导物，与亲本聚合物以及25 kDa聚乙烯亚胺（聚合物介导的转基因表达的当前标准）相比，这六种先导物在几种癌细胞中表现出更高的转基因表达效率。采用基于定量构效关系（QSAR）的化学信息学建模，以研究脂聚合物物理化学性质（分子描述符）对转基因表达效率的作用。使用未用于训练模型的脂聚合物对QSAR模型的预测能力进行研究，结果表明其与实验观察到的转基因表达具有极好的一致性。我们的研究结果表明，与未取代的聚合物相比，氨基糖苷类衍生聚合物上的脂质取代导致高水平的转基因表达。综上所述，这些材料在非病毒转基因递送方面显示出巨大潜力，在生物技术和医学中有多种应用。
