Drug Diffusion

A free drug can diffuse across the cell membrane following disassembly of the micelles or release of the drug from intact micelles. The extent and rate of diffusion of the free molecules across the cell membrane will depend largely on the physico-chemical properties of the drug (water solubility, charge, molecular weight, and partition coefficient). Small hydrophobic molecules can easily permeate the membrane and enter the intracellular space. Studies have shown that the rate of cell uptake of a free drug (non-micelle-incorporated) is faster than that of drug incorporated in micelles.103-105 In this way, the release profile of the drug from the micelles can have a significant influence on the rate of cellular uptake of the drug. As the drug is released from the micelles, there is an increase in the gradient between the concentrations of free drug on the exterior and interior of the cell that, in turn, drives diffusion of the drug into the intracellular compartment. A micelle system with a slow drug release profile will only have a limited pool of free drug available for diffusion into the cell. For example, Maysinger et al. demonstrated that for PEG-b-PCL micelles loaded with benzo[a]pyrene that has an apparent partition coefficient (Kv) of 690, the rate of cell uptake of the micelle formulated probe was similar to that of the rate of uptake of free benzo[a]pyrene. In contrast, for micelles loaded with DiI that has a Kv of 5800, a much lower degree of cell uptake of the micelle formulated probe was observed when compared to free DiI.45,103 Therefore, at the site of interest, an increase in the rate of drug release from the micelles can result in a greater extent of intracellular drug accumulation if the drug can easily diffuse across the cell membrane. Micelle systems that respond to external stimuli as a means to promote drug release at the tumor have also been designed and are discussed further in Section 17.6. Another route for the entry of micelle-formulated drug into cells includes the internalization or endocytosis of the drug-loaded micelles.103'104'106

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