Synthesis of star-branched PLA-b-PMPC copolymer micelles as long blood circulation vectors to enhance tumor-targeted delivery of hydrophobic drugs in vivo

Star-branched amphiphilic copolymer nanocarriers with high-density zwitterionic shell show great promise in drug delivery due to their controllable small size and excellent anti-biofouling properties. This gives the hydrophobic cargo with high stability and long blood circulation in vivo. In the present study, star-branched polylactic acid and poly(2-methacryloyloxyethyl phosphorylcholine) copolymers with (AB3)3–type architecture (PLA-b-PMPC3)3 were conceived as drug vectors, and the copolymers were synthesized by an “arm-first” approach via the combination of ring opening polymerization (ROP), atom transfer radical polymerization (ATRP) and the click reaction. The self-assembled star-branched copolymer micelles (sCPM) had an average diameter of about 64.5 nm and exhibited an ultra-hydrophilic surface with an ultralow water contact angle of about 12.7°, which efficiently suppressed the adhesion of serum proteins. In vivo experiments showed that the sCPM loading strongly enhanced the blood circulation time of DiI and the plasma half-life of DiI in sCPM was 19.3 h. The relative accumulation concentration in tumor of DiI delivered by sCPM was 2.37-fold higher than that of PLA-PEG, at 4 h after intravenous injection. These results demonstrated that the star-branched copolymer (PLA-b-PMPC3)3 is a promising alternative carrier material for intravenous delivery versus classic PEG-modified strategies. [Display omitted] •Star-branched amphiphilic copolymer micelles (sCPM) with zwitterionic shells were prepared.•sCPM possess an ultra-hydrophilic surface and thus inhibited the protein absorption.•sCPM can effectively prolong the cargo’s plasma circulation time.•sCPM can enhance the cargo’s passive tumor-targeted delivery.