Functionalized, biodegradable hydrogels for control over sustained and localized siRNA delivery to incorporated and surrounding cells.
Functionalized, biodegradable hydrogels for control over sustained and localized siRNA delivery to incorporated and surrounding cells.
复制标题
DOI：
10.1016/j.actbio.2012.08.012
复制
发表时间：
2013-01
影响因子：
9.7
通讯作者：
Alsberg, Eben
中科院分区：
文献类型：
--
作者：
Khanh Nguyen;Phuong Ngoc Dang;Alsberg, Eben
目前，应用RNA干扰(RNAi)技术最严重的限制是传递，包括将分子定位到特定的感兴趣位置以靶向特定的细胞群体，并在受控的一段时间内保持这些分子的呈现。在这项研究中，我们设计了一种功能化的可生物降解体系，通过可生物降解的酯键将阳离子线性聚乙烯亚胺(LPEI)共价掺入到光交联葡聚糖(DEX)水凝胶中。该体系的关键创新是实现了对短干扰RNA(SiRNA)持续释放的控制，因为LPEI可以与siRNA静电相互作用以保持水凝胶中的siRNA，并且LPEI和水凝胶之间的共价酯键的降解导致LPEI/siRNA复合物的可调释放。LPEI的共价连接不影响水凝胶的溶胀或降解性能，而siRNA和LPEI的加入对其力学性能影响很小。这些水凝胶对人胚胎肾293细胞(HEK293)表现出较低的细胞毒性。不同浓度的地塞米松(8%和12%w/w)和LPEI(0，5，10μg/100μL凝胶)的释药曲线在第9天(8%w/w凝胶)和第17天(12%w/w凝胶)达到近100%的累积释放。释放的siRNA在延长的时间内与水凝胶周围和内部的细胞显示出高的生物活性。这种可控制和持续的siRNA传递水凝胶系统允许定制的siRNA释放曲线，可能对指导再生医学和其他治疗应用(如癌症)的细胞命运有价值。
Currently, the most severe limitation to applying RNA interference (RNAi) technology is delivery, including localizing the molecules to a specific site of interest to target a specific cell population and sustaining the presentation of these molecules for a controlled period of time. In this study, we engineered a functionalized, biodegradable system created by covalent incorporation of cationic linear polyethyleneimine (LPEI) into photocrosslinked dextran (DEX) hydrogels through a biodegradable ester linkage. The key innovation of this system is that control over the sustained release of short interference RNA (siRNA) was achieved, as LPEI could electrostatically interact with siRNA to maintain siRNA within the hydrogels and degradation of the covalent ester linkages between the LPEI and the hydrogels led to tunable release of LPEI/siRNA complexes over time. The covalent conjugation of LPEI did not affect the swelling or degradation properties of the hydrogels, and the addition of siRNA and LPEI had minimal effect on their mechanical properties. These hydrogels exhibited low cytotoxicity against human embryonic kidney 293 cells (HEK293). The release profiles could be tailored by varying DEX (8 and 12 %w/w) and LPEI (0, 5, 10 μg/ 100 μl gel) concentrations with nearly 100% cumulative release achieved at day 9 (8 %w/w gel) and day 17 (12 %w/w gel). The released siRNA exhibited high bioactivity with cells surrounding and inside the hydrogels over an extended time period. This controllable and sustained siRNA delivery hydrogel system that permits tailored siRNA release profiles may be valuable to guide cell fate for regenerative medicine and other therapeutic applications such as cancer.
登录
查看更多内容
影响因子：
4.6
作者：
Minh Khanh Nguyen;Lee, Doo Sung
通讯作者：
Lee, Doo Sung
影响因子：
41.2
作者：
Kong, HJ;Liu, JD;Mooney, DJ
通讯作者：
Mooney, DJ
影响因子：
4.6
作者：
vanDijkWolthuis, WNE;Tsang, SKY;Hennink, WE
通讯作者：
Hennink, WE
影响因子：
14
作者：
Patterson J;Siew R;Herring SW;Lin AS;Guldberg R;Stayton PS
通讯作者：
Stayton PS
影响因子：
10.8
作者：
Moret, I;Peris, JE;Aliño, SF
通讯作者：
Aliño, SF