-glutamylglutamine)–paclitaxel (PGG–PTX) is of interest as a novel drug delivery system for PTX for several reasons. First, it is unique in being a polymer-based system that spontaneously forms nanoparticles in aqueous environments. Ongoing molecular modeling studies suggest that the hydrophobic interactions between the PTX molecules randomly distributed along the PGG polymer cause collapse of the polymer strand to form a particle with a hydrophilic surface and a hydrophobic core. Second, the size of the nanoparticles as determined by dynamic light scattering is substantially smaller than those in the Abraxane formulation (~20 vs. 80–120 nm). The large difference in size is likely to translate into important differences in the behavior of the drugs both in the plasma and in tissues. Third, pharmacokinetic studies in nu/nu mice bearing NCI-H460 tumors indicate that conjugation of PTX to the PGG polymer increased plasma and tumor Cmax
, prolonged plasma half-life and the period of accumulation in tumor, and reduced washout from the tumor. The plasma exposure to total taxane produced by PGG–PTX, measured over the first 340 h after injection, was 23-fold greater than that produced by unconjugated PTX, and the tumor exposure was increased by a factor of 7.7-fold [27
]. In contrast, Abraxane increased tumor exposure by only 33% relative to that attained with Cremophor-based paclitaxel (3632 vs. 2739 nCi h/g) in the MX-1 xenograft model reported by Desai et al. [3
]. The results of the current study provide an additional reason for interest in PGG–PTX. In all 3 of the models tested in this study in which a single dose of drug was used, PGG–PTX out-performed Abraxane with respect to inhibition of tumor growth when both drugs were given at doses that produced similar degrees of acute weight loss. In addition, the magnitude of the increase in effectiveness was quite substantial and statistically significant in all 3 models. Perhaps even more importantly, when given every 7 days for 3 doses, PGG–PTX produced greater inhibition of tumor growth while at the same time causing much less toxicity than Abraxane. Even while being less effective, the 40 mg PTX/kg dose of Abraxane produced progressive weight loss and was not tolerated on a weekly schedule.
Part of the explanation for the difference in efficacy of PGG–PTX and Abraxane, and for the delayed recovery of body weight in the mice treated with a single dose of PGG–PTX, likely lies in their quite different pharmacokinetics both in the plasma and in normal and malignant tissues. PGG–PTX was found to be somewhat less potent than Abraxane with respect to acute toxicity when given on a single dose schedule. Whereas the MTD for PGG–PTX was 300–350 mg PTX/kg in all 3 models, the single dose MTD for Abraxane varied from 150 mg PTX/kg in the B16 model to 250 mg PTX/kg in the NCI H460 lung cancer model. It appears that the type of tumor modulates the toxicity of Abraxane to a greater extent than that of PGG–PTX, an effect most likely related to the specific vascular anatomy of each tumor type. The plasma half-life of Abraxane in mice has not been reported but in the rat it was found to be 19.0 h; the plasma clearance was 517 ml/h/kg [26
]. In contrast, in pharmacology studies carried out in nu/nu mice bearing NCI H460 tumors executed in parallel with the efficacy studies reported here, the plasma half-life of PGG–PTX was found to be 296.2 h and the clearance only 11.5 ml/h/kg [27
]. Whereas Abraxane increased the total tumor exposure to PTX by only 33% above that produced by an equitoxic dose of PTX formulated as Taxol in the MX1 tumor model [3
], PGG–PTX increased exposure for the NCI H460 tumors by a factor of 7.7-fold in the NCI H460 model [27
]. Studies directly comparing the tumor exposure to PTX following injection of equitoxic doses of PGG–PTX and Abraxane in the same tumor model have yet to be performed. Nevertheless, these data are consistent with the concept that PGG–PTX is more efficient at targeting PTX to tumors than Abraxane largely due to differences in their pharmacokinetics.
Abraxane has an established role in the treatment of breast cancer. We conclude from these studies that PGG–PTX has the potential to out-perform Abraxane in enhancing the delivery of PTX to such tumors while at the same time further reducing the toxicity of both single dose and weekly treatment regimens.