Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA.
Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Utah, Salt Lake City 84132, USA.
J Control Release. 2014 Jun 10;183:1-8. doi: 10.1016/j.jconrel.2014.03.025. Epub 2014 Mar 21.
The major drawback hampering siRNA therapies from being more widely accepted in clinical practice is its insufficient accumulation at the target site mainly due to poor cellular uptake and rapid degradation in serum. Therefore, we designed a novel polymeric siRNA carrier system, which would withstand serum-containing environments and tested its performance in vitro as well as in vivo. Delivering siRNA with a system combining an arginine-grafted bioreducible polymer (ABP), microbubbles (MBs), and ultrasound technology (US) we were able to synergize the advantages each delivery system owns individually, and created our innovative siRNA-ABP-MB (SAM) complexes. SAM complexes show significantly higher siRNA uptake and VEGF protein knockdown in vitro with serum-containing media when compared to naked siRNA, and 25k-branched-polyethylenimine (bPEI) representing the current standard in nonviral gene therapy. SAM complexes activated by US are also able to improve siRNA uptake in tumor tissue resulting in decelerating tumor growth in vivo.
阻碍 siRNA 疗法在临床实践中更广泛应用的主要障碍是其在靶部位的蓄积不足，主要是由于细胞摄取不良和在血清中快速降解。因此，我们设计了一种新型的聚合物 siRNA 载体系统，该系统能够耐受含血清的环境，并在体外和体内测试其性能。我们将携带 siRNA 的系统与精氨酸接枝的生物可还原聚合物 (ABP)、微泡 (MB) 和超声技术 (US) 相结合，从而协同发挥每个输送系统各自的优势，创造了我们的创新 siRNA-ABP-MB (SAM) 复合物。与裸 siRNA 相比，SAM 复合物在含血清的培养基中显示出更高的 siRNA 摄取和 VEGF 蛋白敲低，而 25k-支化聚乙烯亚胺 (bPEI) 则代表了当前非病毒基因治疗的标准。经 US 激活的 SAM 复合物还能够提高肿瘤组织中的 siRNA 摄取，从而减缓体内肿瘤生长。
