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Nanoparticle-based drug delivery to ease anticancer therapy relies primarily on the enhanced permeability and retention effect (EPR). The leaky vascular structure in tumors allows extravasation of nanoparticles, often termed passive targeting. Long term retention of nanoparticles is attributed to the lack of lymphatic drainage, and unidirectional extravasation has been implied.Fluorescent liposomes with a plasma half-life of 29 h were injected into tumor-bearing rats, and biodistribution in tumor, skin, paws and ears was monitored via in vivo fluorescence measurements. To calculate tissue accumulation, an algorithm was developed to subtract the blood signal from the total fluorescence recorded. Accumulation in tumor tissue was much higher than that in other tissues monitored, initially exhibiting very rapid accumulation followed by a long plateau phase with little change. Discontinuous plasmapheresis was established that was as effective as highly sophisticated clinical plasmapheresis. We observed no difference in the tumor tissue's accumulation when plasmapheresis was performed 22 h after liposome injection. In contrast, plasmapheresis led to a significant inhibition of further accumulation in other tissues. When the liposomes' blood concentration was rapidly lowered, we detected no drop in tumor fluorescence. Thus extravasation via EPR is most likely a route of no return. These data support the emerging view of a more dynamic model of EPR, where gaps or entire vessels may open and close over time, or accumulated liposomes become entangled within the pores, hampering further accumulation.