Release of hydrophobic molecules from polymer micelles into cell membranes revealed by Förster resonance energy transfer imaging

Hongtao Chen, Sungwon Kim, Li Li, Shuyi Wang, Kinam Park*, Ji Xin Cheng

*Corresponding author for this work

Research output: Contribution to journalArticle

312 Scopus citations

Abstract

It is generally assumed that polymeric micelles, upon administration into the blood stream, carry drug molecules until they are taken up into cells followed by intracellular release. The current work revisits this conventional wisdom. The study using dual-labeled micelles containing fluorescently labeled copolymers and hydrophobic fluorescent probes entrapped in the polymeric micelle core showed that cellular uptake of hydrophobic probes was much faster than that of labeled copolymers. This result implies that the hydrophobic probes in the core are released from micelles in the extracellular space. Förster resonance energy transfer (FRET) imaging and spectroscopy were used to monitor this process in real time. A FRET pair, DiIC18(3) and DiOC 18(3), was loaded into monomethoxy poly(ethylene glycol)-block- poly(D,L-lactic acid) micelles. By monitoring the FRET efficiency, release of the core-loaded probes to model membranes was demonstrated. During administration of polymeric micelles to tumor cells, a decrease of FRET was observed both on the cell membrane and inside of cells, indicating the release of core-loaded probes to the cell membrane before internalization. The decrease of FRET on the plasma membrane was also observed during administration of paclitaxel-loaded micelles. Taken together, our results suggest a membrane-mediated pathway for cellular uptake of hydrophobic molecules preloaded in polymeric micelles. The plasma membrane provides a temporal residence for micelle-released hydrophobic molecules before their delivery to target intracellular destinations. A putative role of the PEG shell in the molecular transport from micelle to membrane is discussed.

Original languageEnglish (US)
Pages (from-to)6596-6601
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number18
DOIs
StatePublished - May 6 2008

ASJC Scopus subject areas

  • General

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