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

• DOI: 10.1021/acsami.8b10521
• Publication Date: 2018-08-01T13:20:03Z
• Authors: Jinsheng Huang; Chaowen Lin; Jintao Fang; Xiaoxia Li; Jin Wang; Shaohui Deng; Sheng Zhang; Wanhan Su; Xiaoreng Feng; Bin Chen; Du Cheng; Xintao Shuai
• Keywords: 0301 basic medicine; Simvastatin; 03 medical and health sciences; Bone Regeneration; Osteogenesis; Cell Differentiation; Hydrogen-Ion Concentration; RNA, Small Interfering

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.