Release of hydrophobic molecules from polymer micelles into cell membranes revealed by Förster resonance energy transfer imaging
Open accessAbstract
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, DiIC(18(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.
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By loading both DiO and Dil, it was possible to confirm by FRET that the two dyes were first released to plasma membranes and then entered the cells afterward; a high FRET signal was observed outside the cells, while a low FRET was observed on membrane and inside the cells.
“Additionally, by loading both DiO and Dil, it was possible to confirm by FRET that the two dyes were first released to plasma membranes and then entered the cells afterward; indeed a high FRET signal was observed outside the cells, while a low FRET was observed on membrane and inside the cells.”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [234]
Results highlighted that cellular uptake of the probe was much faster than that of the labeled copolymers, indicating that the hydrophobic probe in the core was released from micelles in the extracellular space.
“The results highlighted that cellular uptake of the probe was much faster than that of the labeled copolymers, indicating that the hydrophobic probe in the core was released from micelles in the extracellular space.”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [234]
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- Authors
- Chen, H., Kim, S., Li, L., Wang, S., Park, K., & Cheng, J.-X.
- Affiliations
- Purdue University West Lafayette (US)
- University of Shanghai for Science and Technology (CN)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-05-06
- Volume
- 105
- Issue
- 18
- Pages
- 6596-6601
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2373326
- OpenAlex
- W2033486390
- Cited by
- 394
- References
- 45
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 4 · 2023: 6 · 2022: 17 · 2021: 18 · 2020: 28 · 2019: 27 · 2018: 31 · 2017: 30 · 2016: 28 · 2015: 31 · 2014: 37 · 2013: 32 · 2012: 36
- FWCI
- 7.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Purdue e-Pubs (Purdue University System) (submittedVersion)
- Funders
- National Science Foundation (0416785)
- Purdue University
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL078715, R56HL078715, HL078715)
- National Institute of General Medical Sciences (R01GM065284, GM065284)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- polymeric micelles, hydrophobic drug release, cellular uptake, plasma membrane, paclitaxel, cancer cells
- MeSH terms
- Caproates, Cell Membrane, Endocytosis, HeLa Cells, Humans, Lactones, Micelles, Microscopy, Fluorescence, Polyethylene Glycols, Polymers, Molecular Probes, Paclitaxel, Lactic Acid, Fluorescence Resonance Energy Transfer, Hydrophobic and Hydrophilic Interactions
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