Abstract
The ability to manipulate the kinetics of hydrolysis of water soluble polymer-drug conjugates by programmed changes in their secondary structure was evaluated. A series of model copolymers with different proportions of N-acryloyl morpholine (AM) and p-nitrophenyl acrylate (PAC) was prepared by free radical polymerization or by reaction of morpholine with poly( p-nitrophenyl acrylate). The coil expansion coefficients of the hydrolyzed esters, poly( N-acryloyl morpholine-co-acrylic acid), were determined by viscosity measurements and shown to increase linearly with the acrylic acid content. The kinetics of solvolysis of the p-nitrophenyl group were measured at pH 9 or 10, 25°C. The copolymers exhibited an increasing divergence from first order kinetics as the coil expansion coefficient of the hydrolyzed product increased, consistent with increasing reactivity as the chain expanded. Copolymerization of ω-methoxypoly(ethylene glycol) monoacrylamide (PEGA) and PAC permitted incorporation of a higher proportion of hydrophobic PAC units without loss of water solubility. The kinetics of solvolysis of these copolymers with a higher PAC content reflected neighbouring group participation by carboxylate groups, and could be interpreted as the sum of solvolyses of PAC sequences of different block lengths.
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