In vivo fate mapping of a paclitaxel-loaded polymeric micelle and its components

Paclitaxel (PTX) has poor aqueous solubility and vehicle-related toxicity. Polymeric micelles (PMs) can improve solubility and leverage the enhanced permeability and retention (EPR) effect for tumor targeting. However, a comprehensive understanding of their in vivo fate remains limited, due to the inability to distinguish between encapsulated and released drug. We developed a novel method integrating stable isotope tracing, ultrafiltration, and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to quantify free, released, and total PTX, the polymeric carriers methoxy-poly(ethylene glycol) (molecular weight ∼2000 Da) (mPEG2K) and methoxy-poly(ethylene glycol)-block-poly(d,l-lactic acid) (mPEG block MW ∼2000 Da, PLA block MW ∼2000 Da) (mPEG2K-PLA2K) in rats following administration of PTX injection and paclitaxel-loaded polymeric micelles (PTX-PMs). PTX-PMs significantly altered the pharmacokinetics, reducing the initial dose-normalized initial plasma concentration (C ₀/Dose) of free PTX to 27.0% of that from the injection. Altered tissue distribution was observed, with high accumulation in reticuloendothelial system (RES) organs and more complete clearance by 48 h. Excretion studies revealed a substantially higher cumulative fecal excretion of PTX after PTX-PMs administration, while the polymer carrier was predominantly excreted renally as mPEG2K. These findings provide critical insights into the in vivo disposition of PTX nanoformulations, supporting the rational design of PMs-based delivery systems.