Zwitterionic Nanocarrier Surface Chemistry Improves siRNA Tumor Delivery and Silencing Activity Relative to Polyethylene Glycol.
Zwitterionic Nanocarrier Surface Chemistry Improves siRNA Tumor Delivery and Silencing Activity Relative to Polyethylene Glycol.
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DOI：
10.1021/acsnano.7b01110
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发表时间：
2017-06-27
期刊：
影响因子：
17.1
通讯作者：
Duvall CL
中科院分区：
文献类型：
--
作者：
Jackson MA;Werfel TA;Curvino EJ;Yu F;Kavanaugh TE;Sarett SM;Dockery MD;Kilchrist KV;Jackson AN;Giorgio TD;Duvall CL
尽管基于siRNA的纳米药物有望用于癌症治疗，但常规的siRNA-聚合物复合物（polyplex）纳米载体系统在静脉内递送后具有较差的药代动力学，阻碍了肿瘤积累。在这里，我们确定了表面化学对siRNA复合物的体内药代动力学和肿瘤递送的影响。合成了二嵌段聚合物的文库，其全部含有相同的pH响应性、内体溶解性多聚复合物核心形成嵌段，但不同的冠嵌段：5 kDa（基准）和20 kDa线性聚乙二醇（PEG）、10 kDa和20 kDa刷状聚（低聚乙二醇）以及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，并且在阻断蛋白质吸附方面最有效。静脉内给药后，20 kDa PEG和PMPC冠状动脉都延长了循环半衰期5倍相比，5 kDa PEG。然而，在小鼠原位异种移植肿瘤中，基于两性离子PMPC的复合物显示出最高的体内荧光素酶沉默（用单次IV lmg/kg剂量敲低>75%持续10天）和比5 kDa PEG复合物高3倍的平均肿瘤细胞摄取（20 kDa PEG复合物仅比5 kDa PEG高2倍）。这些结果表明，当与传统PEG结构相比时，高分子量两性离子聚合物冠显著增强siRNA聚合物药代动力学，而不牺牲肿瘤内的聚合物摄取和生物活性。
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.
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DOI：
10.1016/j.jconrel.2011.06.013
发表时间：
2011-10-30
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Crownover E;Duvall CL;Convertine A;Hoffman AS;Stayton PS
通讯作者：
Stayton PS
影响因子：
4.9
作者：
Alexis F;Pridgen E;Molnar LK;Farokhzad OC
通讯作者：
Farokhzad OC
DOI：
10.1016/j.jconrel.2008.10.004
发表时间：
2009-02-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Convertine AJ;Benoit DS;Duvall CL;Hoffman AS;Stayton PS
通讯作者：
Stayton PS
影响因子：
6.4
作者：
Eliyahu, Galit;Kreizman, Tamar;Degani, Hadassa
通讯作者：
Degani, Hadassa
影响因子：
16.1
作者：
Aggarwal P;Hall JB;McLeland CB;Dobrovolskaia MA;McNeil SE
通讯作者：
McNeil SE