Synthesis, Physicochemical Analysis, and Side Group Optimization of Degradable Dipeptide-Based Polyphosphazenes as Potential Regenerative Biomaterials

We report the synthesis and physicochemical analysis of mixed-substituent dipeptide-based polyphosphazene polymers, poly[(glycineethylglycinato)x(phenylphenoxy)yphosphazene] (PNGEGxPhPhy) and poly[(ethylphenylalanato)x(glycineethylglycinato)yphosphazene] (PNEPAxGEGy), using glycylglycine ethyl ester (GEG) as the primary substituent side group and cosubstituting with phenylphenol (PhPh) and phenylalanine ethyl ester (EPA), respectively. The suitability of the cosubstituted polyphosphazenes to regenerative engineering was evaluated. The physicochemical evaluation revealed that the molecular weights, glass transition temperatures, hydrophilicity, and mechanical properties could be modulated by varying the compositions of the side groups to obtain a variety of properties. The PNEPA25GEG75 and PNGEG75PhPh25 polymers exhibited the most promising physicochemical properties. These two polymers were further subjected to in vitro hydrolysis and cell proliferation studies using poly(lactic-co-glycolic acid) (PLAGA) as a control. The hydrolysis experiments revealed that the two polymers hydrolyzed to near-neutral pH media (μ5.3 to 7.0) in a relatively slow fashion, whereas a pH value as low as 2.2 was obtained for the PLAGA media over 12 weeks of degradation study. Furthermore, the two polymers showed continuous MC3T3 cell proliferation and growth in comparison to PLAGA over a 21-day culture period. These findings establish that cosubstitution of different side groups of polyphosphazenes and exploitation of the hydrogen-bonding capacity of peptide bonds in GEG offer a flexible tool that can be employed to make new and fascinating polymeric biomaterials with different and tailored properties that can suit different regenerative needs.