Manipulation of the rate of hydrolysis of polymer-drug conjugates: The secondary structure of the polymer

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 degrees 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 omega-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.