Wang Leo L, Sloand Janna N, Gaffey Ann C, Venkataraman Chantel M, Wang Zhichun, Trubelja Alen, Hammer Daniel A, Atluri Pavan, Burdick Jason A
Department of Bioengineering, ‡Division of Cardiovascular Surgery, Department of Surgery, and §Department of Chemical and Biomolecular Engineering, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
Biomacromolecules. 2017 Jan 9;18(1):77-86. doi: 10.1021/acs.biomac.6b01378. Epub 2016 Dec 20.
While siRNA has tremendous potential for therapeutic applications, advancement is limited by poor delivery systems. Systemically, siRNAs are rapidly degraded, may have off-target silencing, and necessitate high working concentrations. To overcome this, we developed an injectable, guest-host assembled hydrogel between polyethylenimine (PEI) and polyethylene glycol (PEG) for local siRNA delivery. Guest-host modified polymers assembled with siRNAs to form polyplexes that had improved transfection and viability compared to PEI. At higher concentrations, these polymers assembled into shear-thinning hydrogels that rapidly self-healed. With siRNA encapsulation, the assemblies eroded as polyplexes which were active and transfected cells, observed by Cy3-siRNA uptake or GFP silencing in vitro. When injected into rat myocardium, the hydrogels localized polyplex release, observed by uptake of Cy5.5-siRNA and silencing of GFP for 1 week in a GFP-expressing rat. These results illustrate the potential for this system to be applied for therapeutic siRNA delivery, such as in cardiac pathologies.
虽然小干扰RNA（siRNA）在治疗应用方面具有巨大潜力，但进展受到不良递送系统的限制。在全身给药时，siRNAs会迅速降解，可能存在脱靶沉默现象，并且需要高工作浓度。为了克服这一问题，我们开发了一种可注射的、在聚乙烯亚胺（PEI）和聚乙二醇（PEG）之间通过客体-主体组装形成的水凝胶，用于局部递送siRNA。经客体-主体修饰的聚合物与siRNAs组装形成多聚体，与PEI相比，其转染效果和细胞活力得到改善。在较高浓度下，这些聚合物组装成剪切变稀的水凝胶，能迅速自我愈合。通过siRNA包封，组装体以多聚体形式侵蚀，这些多聚体具有活性并能转染细胞，这在体外通过Cy3-siRNA摄取或GFP沉默得以观察到。当注射到大鼠心肌中时，通过Cy5.5-siRNA摄取以及在表达GFP的大鼠中对GFP进行1周的沉默观察到水凝胶实现了多聚体的局部释放。这些结果说明了该系统应用于治疗性siRNA递送（如在心脏疾病中）的潜力。
