Developing polymer micelles as drug delivery systems requires an in-depth understanding of how they interact with cells and deliver drugs across the cell membrane; however, this investigation faces many problems. In this study, we attempt to show how polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles deliver drugs across cell membranes by using a series of fluorescence techniques, including de-quenching, FRET and multi-labeling. We demonstrate that PEG-PE copolymers transfer to the cell membrane from micelles due to their amphiphilic properties, and are then internalized through nonspecific endocytosis and distributed in the endoplasmic reticulum and Golgi apparatus without affecting cellular ATP and viability. Hydrophilic drugs and/or hydrophobic dyes can be encapsulated in PEG-PE micelles, which are maintained in an intact form in culture medium before and after incubation with cells. These micelles disassemble and release their payloads at the cell membrane; released agents are accelerated to enter cells due to the increased membrane fluidity caused by PEG-PE insertion. Encapsulation of drugs in micelles does not change their intracellular distribution but increases their cellular accumulation. This investigation provides new insights into the mechanism of polymer micelle delivering drugs into cells, which are helpful for designing a true site-specific delivery carrier.
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