Formulating biomolecular crowns on micelles: A potential strategy for improving micelle stability

Abstract

The complex environment in blood circulation has a tremendous destabilizing effect on the micelles structure, which is a vital issue to be addressed in micelles design and application. Biomolecule crowns, quickly formed on the surface of nanocarriers in vivo, may alter the physicochemical properties of nanocarriers. In this study, bovine serum albumin (BSA) or fetal bovine serum (FBS) was formulated as the biomolecular crown of the bacterial lipase-responsive micelles encapsulating the hydrophobic antibiotics chloramphenicol (CHL) to investigate their stabilization effect on the micelles. Compared with BSA-crowned micelles (BSA/PM@CHL), FBS-crowned micelles (FBS/PM@CHL) reduced drug leakage by more than 90 % without masking their lipase responsiveness, it also inhibited 77 % of bacterial growth in in vitro antibacterial activity study and significantly increased the area under plasma concentration curve and in vivo half-life in pharmacokinetic study. Then the Förster resonance energy transfer (Fret) Effect was used to further explore the mechanisms responsible for the differences between the BSA-crown and FBS-crown. The in vitro anti-dilution tests below the critical micellar concentration showed that FBS-crown could improve the thermodynamic stability of the micelles, the micelle integrity of FBS/PM was 2 times higher than that of PM diluted with aqueous dilution and 6.5 times higher than that diluted with rat plasma dilution. In vivo optical imaging study showed that micelles with dual-labeled FBS/PM (mean value = 0.363) maintained better structural integrity than dual-labeled PM (mean value = 0.325) after 4 h of injection, explaining the ability of FBS-crowned micelles to improve pharmacokinetic parameters in terms of thermodynamic stability. Besides, the destruction of PM integrity slowed down after injection into the blood circulation for 4–8h, indicating that the baring of biomolecular-crown may be in the late cycle. Overall, the biomolecular-crowned micelles strategy presents a promising strategy for maintaining the structural and functional stability of micelles under physiological conditions.