Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
ACS Nano. 2017 Jun 27;11(6):5680-5696. doi: 10.1021/acsnano.7b01110. Epub 2017 Jun 7.
Although siRNA-based nanomedicines hold promise for cancer treatment, conventional siRNA-polymer complex (polyplex) nanocarrier systems have poor pharmacokinetics following intravenous delivery, hindering tumor accumulation. Here, we determined the impact of surface chemistry on the in vivo pharmacokinetics and tumor delivery of siRNA polyplexes. A library of diblock polymers was synthesized, all containing the same pH-responsive, endosomolytic polyplex core-forming block but different corona blocks: 5 kDa (benchmark) and 20 kDa linear polyethylene glycol (PEG), 10 kDa and 20 kDa brush-like poly(oligo ethylene glycol), and 10 kDa and 20 kDa zwitterionic phosphorylcholine-based polymers (PMPC). In vitro, it was found that 20 kDa PEG and 20 kDa PMPC had the highest stability in the presence of salt or heparin and were the most effective at blocking protein adsorption. Following intravenous delivery, 20 kDa PEG and PMPC coronas both extended circulation half-lives 5-fold compared to 5 kDa PEG. However, in mouse orthotopic xenograft tumors, zwitterionic PMPC-based polyplexes showed highest in vivo luciferase silencing (>75% knockdown for 10 days with single IV 1 mg/kg dose) and 3-fold higher average tumor cell uptake than 5 kDa PEG polyplexes (20 kDa PEG polyplexes were only 2-fold higher than 5 kDa PEG). These results show that high molecular weight zwitterionic polyplex coronas significantly enhance siRNA polyplex pharmacokinetics without sacrificing polyplex uptake and bioactivity within tumors when compared to traditional PEG architectures.
尽管基于 siRNA 的纳米药物在癌症治疗方面具有广阔的应用前景，但传统的 siRNA-聚合物复合纳米载体系统在静脉注射后具有较差的药代动力学特性，阻碍了肿瘤的积累。在这里，我们确定了表面化学对 siRNA 多聚物纳米载体在体内药代动力学和肿瘤递释的影响。我们合成了一系列嵌段共聚物，所有共聚物都含有相同的 pH 响应性、内体溶酶体的多聚物核形成嵌段，但冠部嵌段不同：5 kDa（基准）和 20 kDa 线性聚乙二醇（PEG）、10 kDa 和 20 kDa 刷状聚（聚乙二醇）和 10 kDa 和 20 kDa 两性离子磷酸胆碱基聚合物（PMPC）。在体外，发现 20 kDa PEG 和 20 kDa PMPC 在盐或肝素存在下具有最高的稳定性，并且最有效地阻止蛋白质吸附。静脉注射后，与 5 kDa PEG 相比，20 kDa PEG 和 PMPC 冠部都将循环半衰期延长了 5 倍。然而，在小鼠原位异种移植肿瘤中，两性离子 PMPC 基多聚物显示出最高的体内荧光素酶沉默效果（单次静脉注射 1 mg/kg 剂量 10 天可达到>75%的敲低），并且肿瘤细胞摄取量比 5 kDa PEG 多聚物高 3 倍（20 kDa PEG 多聚物仅比 5 kDa PEG 高 2 倍）。这些结果表明，与传统的 PEG 结构相比，高分子量两性离子多聚物冠部可显著增强 siRNA 多聚物的药代动力学特性，而不会牺牲多聚物在肿瘤内的摄取和生物活性。
