Common biodegradable polyesters such as poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA) and poly(ε-caprolactone) (PCL) are used as drug delivery vehicles for tissue regenerative applications. However, they are typically bioinert, with drug loading limitations. Polymerizing the active agent or precursor into its respective biodegradable polymer would control drug loading via molar ratios of drug to initiator used for synthesis. Simvastatin was chosen due to its favorable anti-inflammatory, angiogenic, and osteogenic properties. In addition, its lactone ring lends itself to ring-opening polymerization and, consequently, the synthesis of poly(simvastatin) with controlled simvastatin release.
Simvastatin was first polymerized with a 5kDa methyl-terminated poly(ethylene glycol) (mPEG) initiator and catalyzed via stannous octoate to form poly(simvastatin)-block-poly(ethylene glycol). Molecular weights ranged from 9.5kDa, with a polydispersity index (PDI) of 1.1 at 150 °C, to 75kDa with a PDI of 6.9 at 250 °C. First-order propagation rates were seen. Infrared spectroscopy showed carboxylic and methyl ether stretches unique to simvastatin and mPEG in the copolymer, respectively. Slow degradation was seen in neutral and alkaline conditions, with simvastatin, simvastatin-incorporated macromolecules, and mPEG identified as degradation products.
Alternatively, triazabicyclodecene (TBD) was used to mediate simvastatin polymerization. A lower temperature of 150°C led to successful polymerization using 5kDa mPEG, compared to at least 200 °C via stannous octoate. TBD was also successful for reactions using 2 or 0.55kDa mPEG. The biodegradability of poly(simvastatin)-block-poly(ethylene glycol) via TBD improved, losing twice more mass in phosphate-buffered saline, pH 7.4, than the copolymer synthesized via stannous octoate. Release rates of three different copolymers synthesized demonstrated tunable simvastatin release.
To further modulate degradation, poly(simvastatin)-block-poly(ethylene glycol) was blended with 5, 2, or 0.55kDa mPEG-initiated PLA copolymers. The blends showed a compressive elastic modulus ranging from 26 to 44MPa, within the magnitude of trabecular bone (approximately 50MPa). Tunability in mass loss and release was also seen due to varied ratios of incorporated PLA copolymers.
Lastly, copolymer degradation byproducts inhibited HMG-CoA reductase and showed possible enhancement of osteoblastic activity in vitro. A pilot study using a rodent calvarial onlay model showed tolerability of the polymers and potential for long-term evaluations of bioactivity. Poly(simvastatin) may be useful in regenerative applications.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:cbme_etds-1049 |
| Date | 01 January 2017 |
| Creators | Asafo-Adjei, Theodora |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations--Biomedical Engineering |
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