Biodegradable polymerized simvastatin stimulates bone formation

Abstract

Previous research from our labs demonstrated the synthesis of polymerized simvastatin by ring-opening polymerization and slow degradation with controlled release of simvastatin in vitro. The objective of the present study was to evaluate the degradation and intramembranous bone-forming potential of simvastatin-containing polyprodrugs in vivo using a rat calvarial onlay model. Poly(ethylene glycol)-block-poly(simvastatin) and poly(ethylene glycol)-block-poly(simvastatin)-ran-poly(glycolide) were compared with simvastatin conventionally encapsulated in poly(lactic-co-glycolic acid) (PLGA) and pure PLGA. The rate of degradation was higher for PLGA with and without simvastatin relative to the simvastatin polyprodrugs. Significant new bone growth at the circumference of poly(ethylene glycol)-block-poly(simvastatin) disks was observed beginning at 4 weeks, whereas severe bone resorption (4 weeks) and bone loss (8 weeks) were observed for PLGA loaded with simvastatin. No significant systemic effects were observed for serum total cholesterol and body weight. Increased expression of osteogenic (BMP-2, Runx2, and ALP), angiogenic (VEGF), and inflammatory cytokines (IL-6 and NF-ĸB) genes was seen with all polymers at the end of 8 weeks. Poly(ethylene glycol)-block-poly(simvastatin), with slow degradation and drug release, controlled inflammation, and significant osteogenic effect, is a candidate for use in bone regeneration applications. STATEMENT OF SIGNIFICANCE: Traditional drug delivery systems, e.g., drug encapsulated in poly(lactic-co-glycolic acid) (PLGA), are typically passive and have limited drug payload. As an alternative, we polymerized the drug simvastatin, which has multiple physiological effects, into macromolecules ("polysimvastatin") via ring-opening polymerization. We previously demonstrated that the rate of degradation and drug (simvastatin) release can be adjusted by copolymerizing it with other monomers. The present results demonstrate significant new bone growth around polysimvastatin, whereas severe bone loss occurred for PLGA loaded with simvastatin. This degradable biomaterial with biofunctionality integrated into the polymeric backbone is a useful candidate for bone regeneration applications.

Keywords: Controlled release; Degradable biomaterials; Osteogenesis; Prodrugs; Simvastatin.