Polymer-drug conjugates: Manipulating drug delivery kinetics using model LCST systems

Model studies of the kinetics of hydrolysis of side chain substituted polymers exhibiting a lower critical solution temperature (LCST) were undertaken. Copolymers of N-isopropyl acrylamide (NiPAm) and N-acryloxy succinimide (AS) were prepared by radical polymerization of the monomers or by reaction of isopropylamine with poly(N-acryloxy succinimide). The LCSTs of the copolymers were measured by DSC and shown to depend on both the NiPAm/AS ratio and the copolymer microstructure. The kinetics of hydrolysis of the succinimide side chain were measured at temperatures below, at, and above the LCST of the copolymers. The LCST increased on conversion of the acryloxy succinimide groups to acrylic acid groups during the hydrolysis process. At temperatures below the LCST, the polymers were water soluble throughout the hydrolysis and exhibited first order kinetics. Above the LCST, the polymers were initially insoluble but became soluble as hydrolysis caused a progressive increase in the LCST. The rate of hydrolysis accelerated on dissolution. As a result, the kinetics exhibited either a zero order or an S-shaped profile. In the latter case the initial slow phase was dependent on the difference between the reaction temperature and the initial LCST.