Biodegradable mPEG-b-poly(MDO-co-vinyl esters) block copolymers as a viable nanocarrier platform with tuneable disassembly

Xanthate-based copolymerisations of 2-methylene-1,3-dioxepane (MDO) and vinyl acetate-derivative monomers were conducted using a versatile mPEG macroCTA to create degradable amphiphilic block copolymers that can undergo self-assembly and crosslinking reactions. Two different block copolymer systems were synthesised; one from vinyl bromobutanoate (VBr) that, after modification, would exhibit permanent crosslinking, and the other from vinyl levulinate (VL) that would have labile crosslinks under acidic pH. The copolymerisations of VBr exhibited excellent control over molecular weight, monomer incorporation and end-group retention, and were able to undergo nucleophilic substitution of the bromo-side chains to form azide-functional copolymers. Conversely, the VL copolymers tended to show less control over molecular weight and end group retention. However, both sets of copolymers were able to undergo self-assembly and with subsequent crosslinking under controlled conditions into micellar nanoparticles via strain promoted azide–alkyne cycloaddition (SPAAC) or hydrazone formation for the azide and ketone functional copolymers, respectively. These nanoparticle systems showed differing stabilities under hydrolytic degradation conditions though they contained a similar amount of degradable ester units in the polymer backbone. Depending on the crosslinking density, the reversible hydrazone linkages destabilized within a few days under physiological conditions (PBS, pH 7.4, 37 °C) as opposed to the stable SPAAC linkages which were intact over many days. Moreover, these materials resembling clinically relevant polycaprolactone (PCL) showed insignificant cytotoxicity towards mouse NIH-3T3 fibroblast and RAW264.7 macrophage cell lines, and displayed unique cellular drug delivery behaviour depending on the crosslinking system.