Amphiphilic copolymer brush with random pH-sensitive/hydrophobic structure: synthesis and self-assembled micelles for sustained drug delivery

A random hydrophobic/pH-sensitive copolymer brush poly(polylactide methacrylate-co-methacrylic acid)-b-poly(poly(ethylene glycol) methyl ether methacrylate) [P(PLAMA-co-MAA)-b-PPEGMA] and its self-assembled micelles were developed for oral administration of hydrophobic drugs. The polymer was synthesized by the combination of activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and ring opening polymerization (ROP). The CMC of P(PLAMA-co-MAA)-b-PPEGMA in aqueous solution was extremely low (about 1.5 mg L-1). The self-assembled blank and drug-loaded micelles were spherical in morphology and had an average size of 160-220 nm, determined by DLS and SEM. Ibuprofen (IBU) was selected as the model drug and encapsulated into the core of micelles via a dialysis method. The in vitro release behavior of IBU from these micelles was pH-dependent. In simulated gastric fluid (SGF, pH 1.2), the cumulative release of IBU was less than 25% of the initial drug content over 24 h, suggesting that the drug can be well protected from the harsh environment in stomach. While in simulated intestinal fluid (SIF, pH 7.4), the ionization of carboxyl groups of MAA contributed to the swelling of the micelle structure, which could accelerate the IBU release from the micelles. 35-45% of IBU was released in 8 h, 60% in 24 h, and 100% after 56 h for P(PLAMA(6.3k)-co-MAA(3k))-b-PPEGMA(4k) micelles, and it was 50% in 2 h, 90% in 10 h, and 100% after 14 h for P(PLAMA(6.3)k-co-MAA(4.5k))-b-PPEGMA(4k) micelles with an increased content of MAA. All the results indicate that the pH-sensitive P(PLAMA-co-MAA)-b-PPEGMA micelles may be a potential oral drug delivery carrier for hydrophobic drugs with sustained release.