Antitumor activity of nexil in preclinical animal tumor models

2319 Background: Nexil, poly-(γ-L-glutamyl glutamine)-paclitaxel, is an innovative macromolecular taxane designed to increase the therapeutic index of paclitaxel by enhancing delivery via the enhanced permeability and retention mechanism. It is a water-soluble formulation of paclitaxel (PTX) made by conjugating PTX to poly(L-glutamate glutamate acid) via ester bonds. Nexil spontaneously forms nanoparticles in aqueous environments. In this study, we evaluated the activity of a Nexil by IV injection in mice bearing a human non-small cell lung cancer xenograft. Methods: The maximum tolerated dose (MTD) of Nexil was determined in tumor free and tumor-bearing nude mice. Therapeutic efficacy of Nexil as compared to Abraxane was evaluated in both the NCI-H460 non-small cell lung cancer xenograft and murine B16 melanoma models. Results: Nexil is ready soluble in 0.9% saline at 50 mg/ml. Analysis of particle size by light scattering demonstrated that 90% of the particles had a diameter between 7 and 10 nm. In NCI-H460 non-small cell lung cancer xenograft model, when given on a q7dx2 schedule, the MTD of Abraxane given IV was 200 mg/kg total cumulative dose; the MTD of Nexil given IV on the same schedule was 1100 mg/kg total cumulative dose. When both drugs were given on the q7dx2 schedule Nexil demonstrated antitumor activity that was significantly better than that of Abraxane while producing less weight loss (Nexil 12%, Abraxane 25%). Nexil increased tumor growth delay by 136% relative to that produced by Abraxane. In the B16 murine melanoma model, Nexil also demonstrated superior antitumor activity at 200 mg/kg/d on a qdx2 schedule given IV; Nexil produced a tumor growth delay 50% greater than that produced by Abraxane. Nexil has also shown activity HT-29 human colon carcinoma model. Conclusions: Covalent linkage of paclitaxel to the poly-(γ-L-glutamyl glutamine) backbone resulted in a formulation that retains high solubility and spontaneously forms nanoparticles in a range known to accumulate in tumors with hyperpermeable capillaries. The toxicity of Nexil was substantially lower than that of Abraxane as estimated from MTD. Nexil has activity in a murine and several human tumor models, and is superior to Abraxane in the NCI-H460 non-small cell lung cancer model. These results encourage the development of Nexil as a Cremophor-free polymer based formulation of paclitaxel for the treatment of malignant diseases.