Biodegradable polymerized simvastatin stimulates bone formation.

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.

Tuning Properties of Poly(ethylene glycol)-block-poly(simvastatin) Copolymers Synthesized via Triazabicyclodecene.

Simvastatin was polymerized into copolymers to better control drug loading and release for therapeutic delivery. When using the conventional stannous octoate catalyst in ring-opening polymerization (ROP), reaction temperatures ≥200 °C were required, which promoted uncontrollable and undesirable side reactions. Triazabicyclodecene (TBD), a highly reactive guanidine base organocatalyst, was used as an alternative to polymerize simvastatin. Polymerization was achieved at 150 °C using 5 kDa methyl-terminated poly(ethylene glycol) (mPEG) as the initiator. ROP reactions with 2 kDa or 550 Da mPEG initiators were also successful using TBD at 150 °C instead of stannous octoate, which required a higher reaction temperature. Biodegradability of the poly(simvastatin) copolymer in phosphate-buffered saline was also improved, losing twice as much mass than the copolymer synthesized via stannous octoate. The three copolymers exhibited modified rates of simvastatin release, demonstrating tunablity for drug delivery applications.

Synthesis and Characterization of a Poly(ethylene glycol)-Poly(simvastatin) Diblock Copolymer.

Biodegradable polyesters are commonly used as drug delivery vehicles, but their role is typically passive, and encapsulation approaches have limited drug payload. An alternative drug delivery method is to polymerize the active agent or its precursor into a degradable polymer. The prodrug simvastatin contains a lactone ring that lends itself to ring-opening polymerization (ROP). Consequently, simvastatin polymerization was initiated with 5 kDa monomethyl ether poly(ethylene glycol) (mPEG) and catalyzed via stannous octoate. Melt condensation reactions produced a 9.5 kDa copolymer with a polydispersity index of 1.1 at 150 °C up to a 75 kDa copolymer with an index of 6.9 at 250 °C. Kinetic analysis revealed first-order propagation rates. Infrared spectroscopy of the copolymer showed carboxylic and methyl ether stretches unique to simvastatin and mPEG, respectively. Slow degradation was demonstrated in neutral and alkaline conditions. Lastly, simvastatin, simvastatin-incorporated molecules, and mPEG were identified as the degradation products released. The present results show the potential of using ROP to polymerize lactone-containing drugs such as simvastatin.