聚乙二醇接枝到聚赖氨酸上可以延长其在血液循环中的半衰期并增加其在肿瘤中的积累，而不会丧失与 siRNA 结合的能力。

Grafting of poly(ethylene glycol) to poly-lysine augments its lifetime in blood circulation and accumulation in tumors without loss of the ability to associate with siRNA.

机构信息

Institute for Materials Chemistry and Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 812-8581, Japan.

出版信息

J Control Release. 2011 Jan 5;149(1):2-7. doi: 10.1016/j.jconrel.2009.12.007. Epub 2009 Dec 21.

DOI:10.1016/j.jconrel.2009.12.007

PMID:20005270

Abstract

Poly-lysine has been studied as a carrier for the delivery of drugs and nucleic acids for at least a decade. It is an especially attractive carrier for DNA and RNA, because of its condensed cationic charges. In our previous study, we showed that poly(ethylene glycol) (PEG) grafted to poly-L-lysine (PLL) remarkably increased the life time of a small interfering RNA (siRNA) in blood circulation. In this study, we prepared a new series of PEG-grafted PLL (PLL-g-PEG) with various lengths (PEG 2kDa, 5kDa, and 10kDa and PLL 28kDa and 40kDa), to evaluate masking effects of PEG on cationic charges of PLL in vivo and the structural implications for biodistribution and tumoral accumulation. The best in the series, 40K10P37 (40kDa of PLL, 10kDa of PEG, 37mol% grafting) with molecular weight of 10(6) as determined by Multi-Angle Laser Light Scattering (MALLS), accumulated in tumors at about 8% of the injected dose per gram of tissue. Interestingly, a PLL-g-PEG conjugate pre-mixed with murine sera prevented degradation of siRNA, suggesting that PLL-g-PEG preferentially associates with siRNA in sera. Our results indicate grafting of PEG to the side chains of PLL augments its lifetime in blood circulation and tumoral accumulation without loss of the ability to associate with siRNA and support further evaluation of these cationic delivery carriers.

摘要

聚赖氨酸作为药物和核酸的载体已被研究了至少十年。由于其带正电荷的缩合，它是 DNA 和 RNA 的一种特别有吸引力的载体。在我们之前的研究中，我们表明，聚乙二醇（PEG）接枝到聚-L-赖氨酸（PLL）上，显著延长了小干扰 RNA（siRNA）在血液循环中的半衰期。在这项研究中，我们制备了一系列具有不同长度（PEG 2kDa、5kDa 和 10kDa 和 PLL 28kDa 和 40kDa）的 PEG 接枝 PLL（PLL-g-PEG），以评估 PEG 在体内对 PLL 正电荷的掩蔽作用以及对生物分布和肿瘤积累的结构影响。在该系列中，分子量为 10(6)的最佳 40K10P37（40kDa 的 PLL、10kDa 的 PEG、37mol%的接枝）在肿瘤中的积累量约为每克组织注射剂量的 8%。有趣的是，与鼠血清预先混合的 PLL-g-PEG 缀合物可防止 siRNA 的降解，表明 PLL-g-PEG 优先与血清中的 siRNA 结合。我们的结果表明，PEG 接枝到 PLL 的侧链上可增加其在血液循环和肿瘤积累中的半衰期，而不丧失与 siRNA 结合的能力，并支持对这些阳离子递药载体的进一步评估。