Exploiting sequence to control the hydrolysis behavior of biodegradable PLGA copolymers.

Monomer sequence is a potentially powerful but underutilized tool for the control of copolymer properties. Sequence is demonstrated to dramatically affect the hydrolysis profile for the degradation of poly(lactic-co-glycolic acid) (PLGA), a member of the most widely used class of biodegradable polymers employed in biomedical applications. The nearly linear molecular weight loss profile and uniform thermal behavior throughout the course of the hydrolysis differ dramatically from the behavior that is exhibited by random copolymer controls with the same comonomer ratio.

Periodic incorporation of pendant hydroxyl groups in repeating sequence PLGA copolymers.

A series of repeating sequence poly(lactic-co-glycolic acid) copolymers (RSC PLGAs) has been prepared with the precise incorporation of a pendant benzyl-ether substituted monomer derived from serine. Copolymers were synthesized from the assembly of sequence-specific, stereopure dimeric, and trimeric segmers of lactic, glycolic, and (S)-3-benzyloxy-2-hydroxypropionic acids with controlled and varied tacticities. Deprotection of the hydroxyl groups was accomplished by catalytic hydrogenolysis to yield highly functionialized, hydrophilic polyesters. The (1)H and (13)C NMR spectra for all of the copolymers were consistent with sequence and stereochemical retention and lacked the signal broadening that is inherent with more random copolymers.

New insights into poly(lactic-co-glycolic acid) microstructure: using repeating sequence copolymers to decipher complex NMR and thermal behavior.

Sequence, which Nature uses to spectacular advantage, has not been fully exploited in synthetic copolymers. To investigate the effect of sequence and stereosequence on the physical properties of copolymers, a family of complex isotactic, syndiotactic, and atactic repeating sequence poly(lactic-co-glycolic acid) copolymers (RSC PLGAs) were prepared and their NMR and thermal behavior was studied. The unique suitability of polymers prepared from the bioassimilable lactic and glycolic acid monomers for biomedical applications makes them ideal candidates for this type of sequence engineering. Polymers with repeating units of LG, GLG and LLG (L = lactic, G = glycolic) with controlled and varied tacticities were synthesized by assembly of sequence-specific, stereopure dimeric, trimeric, and hexameric segmer units. Specifically labeled deuterated lactic and glycolic acid segmers were likewise prepared and polymerized. Molecular weights for the copolymers were in the range M(n) = 12-40 kDa by size exclusion chromatography in THF. Although the effects of sequence-influenced solution conformation were visible in all resonances of the (1)H and (13)C NMR spectra, the diastereotopic methylene resonances in the (1)H NMR (CDCl(3)) for the glycolic units of the copolymers proved most sensitive. An octad level of resolution, which corresponds to an astounding 31-atom distance between the most separated stereocenters, was observed in some mixed sequence polymers. Importantly, the level of sensitivity of a particular NMR resonance to small differences in sequence was found to depend on the sequence itself. Thermal properties were also correlated with sequence.