Introduction: Polymers derived from lactic/glycolic acid have been extensively used for various biomedical applications such as sutures and implants due to their biocompatibility and biodegradability. The ability to modify the physiochemical properties (e.g., degradability, hydrophobicity/philicity) of these polymers is a key to expand their application spectrum. Conventional approaches usually involve copolymerization and block copolymer preparations. In contrast, few studies report the use of lactic/glycolic acid derivatives as monomers for preparing polylactides/glycolides[1],[2]. This study provides a process for synthesis and characterizations of fluorine-substituted polylactides. Fluoropolymers demonstrate excellent inertness in various biological environments and good blood compatibility. They have been used in various biomedical applications such as prosthetics[3] and drug delivery[4]. Here, our strategy involves substitution of hydrogen or methyl group of the glycolide/lactide repeat unit with fluorocarbon (CF3) moiety. Applying established polymerization methods generates fluorine-substituted polylactides/glycolides. The structure of polymer backbone remains unchanged; due to their analogy to the polylactides, we believe that such substituted polymers retain their hydrolysis characteristics, but with a reduced rate of hydrolysis which is a key factor for long-term performance in biological environments.
Materials and Methods: Materials: 3, 3,3-Trifluorolactic acid (TFLA) and 2-bromopropionyl bromide (2-BPB) were purchased from Matrix Scientific (Columbia, USA) and Sigma-Aldrich, respectively and were used as received. Proton nuclear magnetic resonance (1H-NMR) analyses were carried out at room temperature in deuterated chloroform (CDCl3) on a Bruker AV-300 spectrometer with the solvent proton signals being used as chemical shift standards. Monomer synthesis: Under an argon atmosphere, equal molar of TFLA and 2-BPB were mixed and heated at 75 ˚C for 6 days. The evolved HBr was directed to a saturated solution of NaHCO3 for neutralization. At the end of reaction time samples were cooled and dissolved in ethyl acetate and filtered through silica gel. Then solvent was distilled off and remaining crude product was analyzed by 1H-NMR.
Results and Discussion: The fluorine-substituted lactide monomer was prepared using the reaction outlined in Fig.1.
The 2-BPB was first condensed with TFLA to form an intermediate ester, followed by ring closure under basic condition to yield cyclic dimer. The proceeding of the reaction was monitored by thin layer chromatography. 1H-NMR (300 MHz, CDCl3) spectrum of crude reaction mixture of intermediate ester and cyclized monomer is shown in Fig.2.
The spectrum shows characteristic peaks related to both intermediate ester and cyclized monomer. The methyl and methine protons can be identified as a doublet and quartet near δ 1.9 and 4.5, respectively. The peak related to CF3 group in intermediate ester overlaps by the same group in cyclic dimer at 5.55 ppm and clearly indicates the formation of fluorine-substituted monomer. Further optimization of the reaction and the development of effective purification techniques will enable us to obtain monomer in high yield. Our ongoing studies are aimed at investigating the ring-opening polymerization of the substituted monomer and evaluation of their physiochemical properties such as degradability.
Conclusions: Here, we report a versatile approach for synthesis of fluorine-substituted lactide monomer. Subsequent polymerization will be carried out by adopting similar procedures used for synthesis of polylactides. We expect that incorporation of hydrophobic CF3 moieties to substituted-polylactide, will result in higher hydrophobicity and slower degradation rates compared with polylactides. This approach can potentially widen the scope of physiochemical properties and open up new biomedical applications for polylactides/glycolides.
Funding by Abbott Vascular
References:
[1] Trimaille, T.; Muller, M.; Gurny, R., J. Polym. Sci. A Polym. Chem. 2004; Vol. 42, p 4379.
[2] Yin, M.; Baker, G. L., Macromolecules; ACS 1999; Vol. 32, p 7711.
[3] Kannan, R. Y.; Salacinski, H. J.; Butler, P. E.; Hamilton, G.; Seifalian, A. M., J. Biomed. Mater. Res. Part B Appl. Biomater. 2005; Vol. 74, p 570.
[4] Riess, J. G.; Krafft, M. P., Biomaterials 1998; Vol. 19, p 1529.