CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China.
CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China; High Magnetic Field Laboratory of CAS, University of Science and Technology of China, Hefei, Anhui 230026, China.
Biomaterials. 2014 Aug;35(26):7622-34. doi: 10.1016/j.biomaterials.2014.05.050. Epub 2014 Jun 11.
Systemic delivery of small interfering RNA (siRNA) into cancer cells remains the major obstacle to siRNA drug development. An ideal siRNA delivery vehicle for systemic administration should have long circulation time in blood, accumulate at tumor site, and sufficiently internalize into cancer cells for high-efficiency of gene silence. Herein, we report a core-shell Micelleplex delivery system that made from block copolymer bearing poly(ethylene glycol) (PEG), matrix metalloproteinase 2 (MMP-2)-degradable peptide PLG*LAG, cationic cell penetrating peptide polyarginine r9 and poly(ε-caprolactone) (PCL) for siRNA delivery. We show clear evidences in vitro and in vivo to prove that the micelle carrying siRNA can circulate enough time in blood, enrich accumulation at tumor sites, shed the PEG layer when triggered by tumor overexpressing MMP-2, and then the exposing cell penetrating peptide r9 enhanced cellular uptake of siRNA. Accordingly, this design strategy enhances the inhibition of breast tumor growth following systemic injection of this system carrying siRNA against Polo-like kinase 1, which demonstrating this Micelleplex can be a potential delivery system for systemic siRNA delivery in cancer therapy.
系统地将小干扰 RNA（siRNA）递送到癌细胞中仍然是 siRNA 药物开发的主要障碍。用于系统给药的理想 siRNA 递药载体应在血液中有长循环时间，在肿瘤部位聚集，并足够地内吞到癌细胞中以实现高效的基因沉默。在此，我们报告了一种核壳型胶束复合物递药系统，它由带有聚乙二醇（PEG）的嵌段共聚物、基质金属蛋白酶 2（MMP-2）可降解肽 PLG*LAG、阳离子细胞穿透肽多聚精氨酸 r9 和聚（ε-己内酯）（PCL）组成，用于 siRNA 的递送。我们在体外和体内都提供了明确的证据，证明载有 siRNA 的胶束在血液中有足够长的循环时间，在肿瘤部位有富集，当肿瘤过度表达 MMP-2 时，胶束会触发 PEG 层脱落，然后暴露的细胞穿透肽 r9 增强了 siRNA 的细胞摄取。因此，这种设计策略增强了携带针对 Polo 样激酶 1 的 siRNA 的这种系统在全身注射后的抑制乳腺癌肿瘤生长的效果，这表明这种胶束复合物可以成为癌症治疗中全身 siRNA 递药的潜在递药系统。
