Reexamining in vivo fate of paclitaxel-loaded polymeric micelles

Polymeric micelle (PM) is one of the most promising drug delivery systems for therapeutic agents with poor solubility. Yet the in vivo fate of PM remains unclear due to the limitations in separation and detection methods. Herein we established a facile method for PEGylated PM separation by combining a single-chain variable antibody fragment against polyethylene glycol (PEG) with Ni-NTA agarose beads. Complete micelle separation was accomplished by mild centrifugation (2000 x g) at 4 degree celsius. In virtue of this method, we surprisingly discovered that paclitaxel (PTX) was not completely trapped in the hydrophobic cores of micelles in PTX-loaded PMs, and the portion of unencapsulated PTX further increased either with the dilution of micelle solutions or in the presence of serum ascribing to the high binding affinity between PTX and serum proteins. After entering the bloodstream, PTX-loaded PMs rapidly released PTX to form plasma protein-bound form, leaving the empty micelles circulating for a while. Moreover, anti-PEG antibodies, whether stimulated by the administration of PEGylated therapeutics or pre-existing in serum with unknown origin, could exacerbate the accelerated blood clearance phenomenon and induce anaphylactoid reactions via complement activation, which persuaded us to be more cautious in the clinical medication of PEGylated micelles.