(184a) Thermodynamic Limits on Drug Loading in Nanoparticle Cores

Recently, biodegradable nanoparticles have attracted a great deal of attention as effective drug delivery vehicles for various reasons. Particle size is considered to be a critical design parameter as particles with diameter less than 200 nm and having poly(ethylene glycol), PEG, shell avoid entrapment by the reticuloendothelial system (RES) [1]. Moreover the core-shell architecture formed by amphiphilic copolymers ensures the entrapment of hydrophobic solutes such as drug and protection from protein adsorption at the same time. Maximizing the amount of drug loaded into particle is the desired goal, but experimental results find loading only between 3 to about 25 wt% drug (for Paclitaxel). The reasons for the low loading and variability in loading have not been fully explained.

In this study, we present a model that explains quantitatively the observed phenomena. We model the thermodynamic limit of drug loading based on the molar free energy of the drug, which depends on the block copolymers size (entropic term), the interaction parameter between the drug and the hydrophobic core (enthalpic term), and the pressure-volume work. The pressure-volume work, related directly to the interfacial tension between the core and the outer-core region, is usually not considered. We have extensively studied the effect of each parameter on the loading. To validate the model, we did representative calculations for different organic solutes and Paclitaxel with poly(ethylene glycol)-b-poly(ε-caprolactone), PEG/PCL, as the block copolymer. The model developed was found to predict the loading values in close agreement with experiments reported in literature [2, 3]. To study the effect of the interaction parameter on the loading, we calculated the loading of Taxol in poly(ethylene glycol)-b- poly(D, L-lactide) nanoparticles as poly (D, L-lactide) is more compatible with Taxol than PCL. The results obtained compare well with experimental findings [4]. The presented model is based on the equilibrium solubilization of drugs in Nanoparticle cores. This process, however, gives low loading compared to the ?Flash precipitation? process [5], which tunes the kinetics of pure drug precipitation and block copolymer self-assembly. The later process however, is kinetically driven and was found to control the particles size more effectively.

[1] Tochilin VP. J. Controlled Release 2001, 73, 137-172.

[2] Kim SY and Lee YM. Biomaterials 22 (2001) 1697-1704.

[3] Shuai X, Merdan T, Schaper AK, Xi F and Kissel T. Bioconjugate Chem. 2004, 15, 441-448.

[4] Burt HM, Zhang X, Toleikis P, Embree L and Hunter WL. Colloids and Surfaces B: Biointerfaces16 (1999) 161 ? 171.

[5] Johnson BK and Prud'homme RK. AIChE Journal 2003 Vol. 49, No. 9 2264-2282.