(681f) A Model-Based Approach to Investigate the Differential Tumor Delivery of Nab-Paclitaxel (Abraxane) and CrEL-Paclitaxel (Taxol)

nab-Paclitaxel (nab-PTX, or Abraxane®) is a nanoparticle composed of paclitaxel and albumin that exploits unique properties of the albumin protein for stabilization of the formulation and for transport within the body. Instead of solubilizing the hydrophobic paclitaxel molecule in micelles using solvent mixtures containing Cremophor EL and ethanol (CrEL-PTX, or Taxol®), nab-PTX relies on the natural drug-binding capacity of albumin to help drive formation of nanoparticles suitable for intravenous administration. Preclinical and clinical studies have indicated that nab-PTX achieves a higher intratumoral paclitaxel concentration relative to CrEL-PTX. Several proposed mechanisms to explain the benefits of nab-PTX over CrEL-PTX center around the manner in which albumin is naturally transported within the body. Albumin can be actively extravasated through gp60-mediated transcytosis, and this may drive the rapid tumor accumulation of albumin-bound paclitaxel. Moreover, tumors demonstrate enhanced catabolism of plasma proteins, such as albumin, to satisfy their metabolic requirements. The increased accumulation and internalization of albumin by tumors may thereby contribute to the tumor delivery of albumin-bound paclitaxel. Here, a physiologically based mathematical model is used to investigate potential mechanisms driving the experimentally observed differences in the delivery of nab-PTX and CrEL-PTX to solid tumors.

The mathematical model uses an arterial input function derived from experimentally determined plasma concentration vs. time profiles for nab-PTX and CrEL-PTX. Simple ordinary differential equations are used to capture the transport of free paclitaxel, albumin-bound paclitaxel, and CrEL micelle-encapsulated paclitaxel from the tumor vasculature, through the tumor interstitium, and into the individual tumor cells comprising the solid tumor. Parameter values not available in the literature were estimated through fitting to experimental data of the total tumor drug concentration vs. time for nab-PTX and CrEL-PTX in tumor-bearing mice. Model calculations demonstrate that active transport through the gp60 pathway can significantly increase the peak concentration of drug in the tumor for nab-PTX but not for micelle-encapsulated CrEL-PTX. Furthermore, a preferential partitioning of albumin-bound paclitaxel into the tumor was necessary to fit the experimental tumor concentration vs. time profiles, indicative of an additional mechanism through which albumin-bound paclitaxel is sequestered within the tumor via extracellular binding or cellular internalization. It has previously been suggested that albumin binding proteins (e.g., SPARC) may be responsible for such a sequestration. In addition to offering mechanistic insights into the delivery of nab-PTX and CrEL-PTX to solid tumors, this study demonstrates the utility of quantitative, physiologically based models for the rational design and experimental evaluation of drug delivery vehicles in general.