基于可降解聚乙二醇（PEG）的水凝胶，用于时空控制siRNA /纳米颗粒的输送。,Journal of Controlled Release

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基于可降解聚乙二醇（PEG）的水凝胶，用于时空控制siRNA /纳米颗粒的输送。
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2018-08-03 , DOI: 10.1016/j.jconrel.2018.08.002
Yuchen Wang ₁ , Sue Zhang ₂ , Danielle S W Benoit ₃

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尽管具有巨大的治疗潜力，并且开发了解决降解和细胞摄取限制的各种给药方法，但小的干扰RNA（siRNA）却显示出组织特异性定位控制不佳。为了克服这一障碍，将siRNA与嵌入聚（乙二醇）-聚（乳酸）-二甲基丙烯酸酯（PEG-PLA-DM）水凝胶中的纳米颗粒（siRNA / NP）进行了复合，并提出了PLA中酯键的水解降解的假设。交联将提供可调的，持续的siRNA / NP释放。研究了由具有增加的PLA重复序列（例如，0或不可降解为5个PLA重复序列，位于PEG核心旁）的大分子单体形成的水凝胶，以及不可降解PEG-DM（0 PLA）和可降解PEG-PLA5-DM大分子单体的混合物。仅形成具有完全可降解交联的水凝胶可在6-14天之内迅速降解，而对siRNA / NP释放的控制却有限。但是，由不可降解的大分子单体与20％，50％和100％的可降解大分子混合物形成的水凝胶会导致siRNA / NP在3到28天内释放。随后，由释放自20％和50％可降解水凝胶的siRNA / NP介导的基因沉默持续约28天。此外，体内成像显示水凝胶降解可控制siRNA / NP定位，并在28、21和15天内从0％，20％和50％的可降解水凝胶中持续释放siRNA / NP。建立了一个模型，该模型考虑了水凝胶的降解速率和siRNA / NP扩散，从而能够合理设计siRNA / NP递送库。全面的，

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Degradable poly(ethylene glycol) (PEG)-based hydrogels for spatiotemporal control of siRNA/nanoparticle delivery.

Despite great therapeutic potential and development of a repertoire of delivery approaches addressing degradation and cellular uptake limitations, small interfering RNA (siRNA) exhibits poorly controlled tissue-specific localization. To overcome this hurdle, siRNA was complexed to nanoparticles (siRNA/NP) embedded within poly(ethylene glycol)-poly(lactic acid)-dimethacrylate (PEG-PLA-DM) hydrogels with the hypothesis that hydrolytic degradation of ester bonds within the PLA crosslinks would provide tunable, sustained siRNA/NP release. Hydrogels formed from macromers with increasing PLA repeats (e.g., 0 or non-degradable to 5 PLA repeats flanking PEG cores) and mixtures of nondegradable PEG-DM (0 PLA) and degradable PEG-PLA5-DM macromers were investigated. Hydrogels formed only with fully degradable crosslinks degraded rapidly over 6-14 days with limited control over siRNA/NP release. However, hydrogels formed with mixtures of nondegradable and 20%, 50%, and 100% degradable macromers resulted in siRNA/NP release over 3 to 28 days. Subsequently, gene silencing mediated by released siRNA/NP from 20% and 50% degradable hydrogels was sustained for ~28 days. Furthermore, in vivo imaging showed that hydrogel degradation controlled siRNA/NP localization, with sustained siRNA/NP release from 0%, 20% and 50% degradable hydrogels over 28, 21, and 15 days. A model, which accounts for hydrogel degradation rate and siRNA/NP diffusion, was developed to enable rational design of siRNA/NP delivery depots. Overall, this study shows that siRNA/NP release can be sustained via encapsulation in hydrogels with tunable degradation kinetics and modeled for a priori design of delivery depots.

更新日期：2018-08-03

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