Introduction: This work encompasses the synthesis of an array of biodegradable, crosslinked polyesters with independently tailored degradation, mechanical, release and bioactive properties for biomedical applications. Diacids and polyols endogenous to the body are used as precursors to minimize immune responses to degradation products. The motivation of the present work is to develop a combinatorial strategy to synthesize a library of polymers where synthesis parameters can control various polymer properties independently. Furthermore, it is important to impart bioactivity to the polymers to reduce immunogenicity and susceptibility for microbial infection. Thus, the objective is to chemically incorporate salicylates (salicylic acid and p-aminosalicylic acid) and a benzofuran derivative (usnic acid) by esterification onto the polyester backbone to ensure pharmacological activity. Unlike conventional entrapment of drugs in delivery vehicles, this chemical incorporation allows higher loading, better processability and controlled release.
Materials and Methods: Diacids (succinic, adipic, suberic and sebacic acid) and a penta-functional (-OH) alcohol xylitol are used for synthesis. A simple melt condensation polymerization at 150˚C in N2 environment and vacuum is performed. This is followed by a post polymerization step where the prepolymer is thermally cured by under high temperature (120˚C) and high vacuum (60 mm Hg). To incorporate the drugs in the matrix, the drug is attached to the diacyl chlorides of the acids mentioned by simple esterification at 35˚C [3]. This drug loaded diacid is then melt polymerized with xylitol and cured under same conditions as above.
Results and Discussion: Tuning of the properties involves simple modifications to the synthesis, including a systematic variation of the diacid chain length, post polymerization time and molar stoichiometric ratio. Upon drug incorporation the hydrolytically labile ester bonds cleave under physiological conditions to release the drug moiety with a simultaneous degradation of the matrix. The polyesters synthesized by this approach have a diverse spectrum of degradation (ranging from ∼4 to 100% degradation in 7 days), mechanical strength (from 0.5 to ∼15 MPa) and controlled release properties. The degradation is a first-order process and the rate constant of degradation decreases linearly as the hydrophobicity of the polyester increases[1]. In controlled release studies, the release rate constant decreases with the hydrophobicity and curing time[1]. The integration in the polymer backbone also ensures a higher stability to these otherwise low half-life drugs. These drugs impart anti-inflammatory, anti-bacterial and/or anti-mycobacterial properties to these cytocompatible polymers[2].
Conclusion: These results present a versatile strategy to design immunomodulatory biomaterials with modulated physico-chemical properties and bioactivity. The mechanical properties of these polyesters are comparable to those of aorta (Young’s modulus: 2.0−6.5 MPa) and articular cartilage (Young’s modulus: 2.1−11.8 MPa) and may be used as replacement for these tissues. An almost-linear dependence of the degradation and mechanical characteristics to the chain length and curing time allows us to presage these properties of the polymers. We demonstrate that this particular combinatorial synthesis strategy can be leveraged to prepare optimally tuned biomaterials.
References:
[1] Dasgupta, Q.; Chatterjee, K.; Madras, G. Combinatorial Approach to Develop Tailored Biodegradable Poly (xylitol dicarboxylate) Polyesters. Biomacromolecules 2014, 15, 4302-4313.
[2] Dasgupta, Q.; Chatterjee, K.; Madras, G., Controlled Release of Salicylic Acid from Biodegradable Crosslinked Polyesters. Molecular pharmaceutics 2015.
[3] Schmeltzer, R. C.; Schmalenberg, K. E.; Uhrich, K. E. Synthesis and cytotoxicity of salicylate-based poly (anhydride esters). Biomacromolecules 2005, 6, 359-367.