Mechanistic Study on the Degradation of Hydrolysable Core-Crosslinked Polymeric Micelles

Core-crosslinked polymeric micelles (CCPMs) are an attractiveclassof nanocarriers for drug delivery. Two crosslinking approaches toform CCPMs exist: either via a low-molecular-weight crosslinking agentto connect homogeneous polymer chains with reactive handles or viacross-reactive handles on polymers to link them to each other (complementarypolymers). Previously, CCPMs based on methoxy poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate](mPEG-b-PHPMAmLac (n) ) modifiedwith thioesters were crosslinked via native chemical ligation (NCL,a reaction between a cysteine residue and thioester resulting in anamide bond) using a bifunctional cysteine containing crosslinker.These CCPMs are degradable under physiological conditions due to hydrolysisof the ester groups present in the crosslinks. The rapid onset ofdegradation observed previously, as measured by the light scatteringintensity, questions the effectiveness of crosslinking via a bifunctionalagent. Particularly due to the possibility of intrachain crosslinksthat can occur using such a small crosslinker, we investigated thedegradation mechanism of CCPMs generated via both approaches usingvarious analytical techniques. CCPMs based on complementary polymersdegraded slower at pH 7.4 and 37 & DEG;C than CCPMs with a crosslinker(the half-life of the light scattering intensity was approximately170 h versus 80 h, respectively). Through comparative analysis ofthe degradation profiles of the two different CCPMs, we conclude thatpartially ineffective intrachain crosslinks are likely formed usingthe small crosslinker, which contributed to more rapid CCPM degradation.Overall, this study shows that the type of crosslinking approach cansignificantly affect degradation kinetics, and this should be takeninto consideration when developing new degradable CCPM platforms.