Dual location disulfide degradable interlayer-crosslinked micelles with extended sheddable coronas exhibiting enhanced colloidal stability and rapid release†
Amphiphilic block copolymer-based micellar nanocarriers hold great promise as a drug delivery platform; however, the colloidal stability of nanoassemblies upon intravenous injection remains a significant challenge. Further, enhanced/controlled release of encapsulated drugs by cleavage of dynamic covalent linkages in response to external stimuli is highly desired. Herein, we report new polylactide (PLA)-based triblock copolymers (PssDL) possessing thiol-responsive dynamic disulfide linkages at dual locations using a combination of ring opening polymerization and controlled radical polymerization techniques. These well-defined PssDL copolymers are designed to self-assemble to form aqueous micellar aggregates having multiple pendant disulfide linkages in a hydrophobic interlayer as well as single disulfides at interfaces of the interlayer and PLA core, surrounded by hydrophilic coronas. Through thiol-responsive cleavage of these dually located disulfide linkages, novel interlayer-crosslinked micelles (ICMs) with a crosslinkable and sheddable extended corona can be formed, thus combining the enhanced colloidal stability of crosslinked nanocarriers with rapid destabilization or disintegration of micelles typically found with sheddable systems. This dual location degradation process results in enhanced colloidal stability, along with controlled release of encapsulated anticancer drugs to promote the inhibition of cell proliferation after internalization into cancer cells.