Godeshala Sudhakar, Nitiyanandan Rajeshwar, Thompson Brian, Goklany Sheba, Nielsen David R, Rege Kaushal
Chemical Engineering Arizona State University Tempe AZ 85287.
Biological Design Program Arizona State University Tempe AZ 85287.
Bioeng Transl Med. 2016 Oct 21;1(2):220-231. doi: 10.1002/btm2.10038. eCollection 2016 Jun.
Targeted delivery of anticancer therapeutics can potentially overcome the limitations associated with current chemotherapeutic regimens. Folate receptors are overexpressed in several cancers, including ovarian, triple-negative breast and bladder cancers, making them attractive for targeted delivery of nucleic acid therapeutics to these tumors. This work describes the synthesis, characterization and evaluation of folic acid-conjugated, aminoglycoside-derived polymers for targeted delivery of transgenes to breast and bladder cancer cell lines. Transgene expression was significantly higher with FA-conjugated aminoglycoside-derived polymers than with Lipofectamine, and these polymers demonstrated minimal cytotoxicty. Competitive inhibition using free folic acid significantly reduced transgene expression efficacy of folate-targeted polymers, suggesting a role for folate receptor-mediated uptake. High efficacy FA-targeted polymers were employed to deliver a plasmid expressing the TRAIL protein, which induced death in cancer cells. These results indicate that FA-conjugated aminoglycoside-derived polymers are promising for targeted delivery of nucleic acids to cancer cells that overexpress folate receptors.
抗癌治疗药物的靶向递送有可能克服当前化疗方案的局限性。叶酸受体在包括卵巢癌、三阴性乳腺癌和膀胱癌在内的多种癌症中过度表达，这使得它们成为将核酸治疗药物靶向递送至这些肿瘤的有吸引力的靶点。这项工作描述了叶酸共轭的、氨基糖苷衍生的聚合物的合成、表征和评估，用于将转基因靶向递送至乳腺癌和膀胱癌细胞系。与脂质体转染试剂相比，叶酸共轭的氨基糖苷衍生聚合物的转基因表达显著更高，并且这些聚合物表现出最小的细胞毒性。使用游离叶酸的竞争性抑制显著降低了叶酸靶向聚合物的转基因表达效率，表明叶酸受体介导的摄取发挥了作用。高效的叶酸靶向聚合物被用于递送表达TRAIL蛋白的质粒，该质粒可诱导癌细胞死亡。这些结果表明，叶酸共轭的氨基糖苷衍生聚合物有望将核酸靶向递送至过度表达叶酸受体的癌细胞。
