Polymeric Micelles For Cancer Drug Delivery In Vivo Fate And Clearance Kinetics

Understanding the in vivo behavior of polymeric micelles is critical for the translation of nanomedicine from laboratory research to clinical trials. 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 used dual-labeled polymeric micelles containing a pair of near-infrared fluorescent probes Cy5and Cy5.5, which were conjugated in the polymeric micelle core via fluorescence resonance energy transfer (FRET) to provide insights into the dynamics of the polymeric micelles in different biological conditions. We find that the serum albumins, immunoglobulin (including alpha and beta) and shear stress have moderate effects on the integrity of self-assembled polymeric micelles of poly (ethylene glycol)-b-poly (caprolactone)(PEG-b-PCL) copolymers whereas dilution of the concentration lead the main reason for disassembly of the micelles. During the incubation with cancer cells, FRET spectroscopy showed that micelles stayed intact while extracellular or on the cell membrane and dissembled once inside cells. When the micelles were administrated into the blood stream, FRET imaging and spectroscopy were used to monitor this process in real time. A decrease of FRET efficiency was observed indicating a fast release of core-loaded molecules from micelles in blood circulation due to the loss of micelle integrity. Increasing the micelles dose, pre-treated with micelles and pre-injection with GdCl3could prolong the micelles’blood retention time, but have minor effects on the micelles integrity. The drug-loaded polymeric micelles are able to retain their assembly structure and have a slower decreased of FRET ratio. Moreover, although only a few micelles could finally reach to tumor sites via EPR effect, but the FRET spectroscopy showed micelles in tumor still retain intact and may release the loaded drug at the target site. Taken together, our results reveal that the fate of the injected micelles in vivo and the mechanism of micelle clearance. It may contribute to discovering the pharmacokinetic properties and improving the therapeutic outcome of polymeric micelles.