pH-Sensitive Nanocarrier-Mediated Codelivery of Simvastatin and Noggin siRNA for Synergistic Enhancement of Osteogenesis

• Published in: ACS applied materials & interfaces 2018-08, Vol.10 (34), p.28471-28482
• Main Authors: Huang, Jinsheng, Lin, Chaowen, Fang, Jintao, Li, Xiaoxia, Wang, Jin, Deng, Shaohui, Zhang, Sheng, Su, Wanhan, Feng, Xiaoreng, Chen, Bin, Cheng, Du, Shuai, Xintao
• Format: Article
• Language: English
• Subjects: Bone Regeneration; Cell Differentiation; Hydrogen-Ion Concentration; Osteogenesis; RNA, Small Interfering; Simvastatin - chemistry
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.8b10521

The inexpensive hypolipidemic drug simvastatin (SIM), which promotes bone regeneration by enhancing bone morphogenetic protein 2 (BMP-2) expression, has been regarded as an ideal alternative to BMP-2 therapy. However, SIM has low bioavailability and may induce the upregulation of the BMP-2-antagonistic noggin protein, which greatly limits the osteogenic effect. Here, a pH-sensitive copolymer, monomethoxy-poly­(ethylene glycol)-b-branched polyethyleneimine-b-poly­(N-(N′,N′-diisopropylaminoethyl)-co-benzylamino)­aspartamide (mPEG-bPEI-PAsp­(DIP-BzA)) (PBP), was synthesized and self-assembled into a cationic micelle. SIM and siRNA targeting the noggin gene (N-siRNA) were loaded into the PAsp­(DIP-BzA) core and the cationic bPEI interlayer of the micelle via hydrophobic and electrostatic interactions, respectively. The SIM-loaded micelle effectively delivered SIM into preosteoblast MC3T3-E1 cells and rapidly released it inside the acidic lysosome, resulting in the elevated expression of BMP-2. Meanwhile, the codelivered N-siRNA effectively suppressed the expression of noggin. Consequently, SIM and N-siRNA synergistically increased the BMP-2/noggin ratio and resulted in an obviously higher osteogenetic effect than did simvastatin or N-siRNA alone, both in vitro and in vivo.