Fast release of lipophilic agents from circulating PEG-PDLLA micelles revealed by in vivo Förster resonance energy transfer imaging

Understanding the in vivo behavior of nanoparticles is critical for the translation of nanomedicine from laboratory research to clinical trials. In this work, in vivo Förster resonance energy transfer (FRET) imaging was employed to monitor the release of hydrophobic molecules from circulating polyethylene glycol)-poly(D,L-lactic acid) (PEG-PDLLA) micelles. A lipophilic FRET pair (DiIC₁₈ and DiOC₁₈) was physically entrapped into micelle cores by mimicking the loading of hydrophobic drugs. The FRET efficiency was found significantly reduced within 15 min after intravenous injection, implying that DiIC₁₈ and DiOC₁₈ quickly escaped from the circulating micelles. FRET spectroscopy studies further demonstrated that α- and β-globulins were major factors for the observed fast release, while γ-globulins, albumin, and red blood cells played minor roles. These results provide useful information for developing blood-stable micelles to deliver hydrophobic drugs to the target site via prolonged circulation and extravasation from the vascular system.