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 struc ture was evaluated. A series of model copolymers with different propor tions of N-acryloyl morpholine (AM) and p-nitrophenyl acrylate (PAC) w as prepared by free radical polymerization or by reaction of morpholin e 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 line arly 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 cop olymers exhibited an increasing divergence from first order kinetics a s the coil expansion coefficient of the hydrolyzed product increased, consistent with increasing reactivity as the chain expanded. Copolymer ization of omega-methoxypoly(ethylene glycol) monoacrylamide (PEGA) an d PAC permitted incorporation of a higher proportion of hydrophobic PA C units without loss of water solubility. The kinetics of solvolysis o f these copolymers with a higher PAC content reflected neighbouring gr oup participation by carboxylate groups, and could be interpreted as t he sum of solvolyses of PAC sequences of different block lengths.