Fate of Polymeric Micelles In Vivo

The MPS serves as one of the major mechanisms for the elimination of nanosized drug delivery systems such as liposomes, nanoparticles, and micelles.131-133 Clearance by the MPS is first mediated by an array of blood components that interact with the delivery vehicle or other foreign bodies present within the systemic circulation, a process termed opsonization134-136 Following intravenous injection, the micelles quickly distribute into various tissues and organs by way of the blood and lymphatic system. The primary elimination route for micelles is postulated to include uptake by the liver and spleen followed by clearance through the kidneys via the excretion of urine35,76,137-139 and/or hepatobiliary excretion in the feces.131,140 In this process, various plasma proteins play an important role because they adsorb to the surface of a delivery vehicle within the first few minutes of exposure, especially if the surface is charged or hydrophobic (Figure 17.6a). The protein adsorption could cause opsonization, leading to rapid clearance of both carrier and encapsulated drug by the MPS.10,142,143 As a result, a reduction in the extent of protein adsorption to delivery vehicles such as micelles has been considered to be one of the key strategies to increase the circulation lifetime of the vehicles in vivo.

Various efforts to prolong the lifetime of micelles in vivo have been explored, including optimization of micelle size, size distribution, and surface properties. To this point, the micelles explored for applications in drug delivery have mostly been formed from copolymers that include PEG as the hydrophilic block. The presence of PEG at the surface of a delivery vehicle is known to impart stealth properties.1,2,10 Good correlations have been found between the length of the PEG block and the extent of stabilization provided.137 The degree of stabilization is largely determined by the thickness of the PEG layer. The PEG chains are present in a coil-like conformation on the surface of the micelles. The thickness of the surface layer (dh) may be calculated from the PEG block length using the following equation: dh = a0 84where a is the number of PEG units.144 In a study by Gref et al. in Balb/C mice, a significant increase in the circulation lifetime of PEG-b-PLGA nanospheres was observed when the length of the PEG block was increased from 0 to 20,000 g/mol, and the length of the PLGA block was held constant. The increased thickness of the protective PEG layer likely provides complete coverage of the more hydrophobic PLGA components. In the same study, the increase in the PEG length also resulted in a significant reduction in the extent of liver uptake of the particles that provided further evidence that PEG could effectively decrease the extent of opsonization and, therefore, limit MPS elimination.

For materials to be eliminated by glomerular filtration through the kidneys, they must have a molecular weight of less than 50,000 g/mol.17 The total molecular weight of a block copolymer micelle is typically on the order > 200,000 g/mol, and the molecular weight of the individual copolymers ranges between 3000 and 25,000 g/mol. Therefore, it may be postulated that only the copolymer single chains rather than intact micelles are eliminated by renal excretion.

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