Release of pharmaceutical cocktails from small polymeric micelles

Abstract

Here we model release of multidrug cocktails from small micelles. As most emerging anticancer agents remain sparingly soluble in water, they require carriers such as poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) micelles to enhance their delivery. These micelles have been used as vectors for multidrug cocktails (e.g., the hydrophobic anticancer agents paclitaxel, 17-allylamino-17-demethoxygeldanamycin, and rapamycin). Empirically determined agent release takes hours and half-lives depend on oil-water partition coefficients, a representative thermodynamic parameter. This contrasts with the assertion that the cocktail release rate is diffusion controlled, with diffusion time scales less than a millisecond. Here we resolve this inconsistency in mechanism using a “lumped capacitance” method. The two parameter equation that results provides excellent agreement with experimental release profiles. Model time scales depend on the micelle radius, external mass transfer coefficient, and lumped partition coefficient. These findings enable tuning of release rates of multidrug mixtures from micelles, which will become increasingly important because many new drug candidates remain hydrophobic.