The Antiangiogenic Effect Of Two Drugs Loaded Nanocarriers And Its Potential Application For Cancer Metronomic Treatment.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Purpose: To synthesize and evaluate the antiangiogenic effect of individual and mixed paclitaxel (PTX) and rapamycin (RAP) conjugated micelles Methods: RAP or PTX were conjugated to poly(ethyleneglycol)-block-poly(aspartate-hydrazide) utilizing a pH-sensitive linker based on hydrazone prodrug strategy. The synthesized drug-polymer conjugates were characterized using NMR and gel permeation chromatography (GPC). RAP and PTX polymer conjugates, PEG-RAP and PEG-PTX respectively were assembled into individual and mixed micelles. The size of these micelles was determined using dynamic light scattering. The micelle drug content was quantified by RP-HPLC. The antiangiogenic effect of individual and mixed micelles was evaluated in in vitro Human Umbilical Vein Endothelial Cells (HUVEC) model through proliferation, tube formation and migration assays. The HUVEC cell proliferation was evaluated by the CellTiter-Blue® Cell Viability Assay, the tube formation was evaluated by measuring the total area covered by the HUVEC capiliary formation while the HUVEC cell migration was determined by xCELLigence System. Results: PEG-RAP and PEG-PTX were successfully synthesized and the molecular weight of the polymers was determined by GPC and NMR. The number of drug molecules attached to the polymer for RAP and PTX were 22 and 25 respectively. PEG-RAP and PEG-PTX were assembled into individual and mixed micelles as mono dispersed populations in the range of 40-100nm. The IC50 of PEG-RAP and PEG-PTX individual micelles were 12μM and 2nM respectively. The mixed micelles showed synergistic effect in inhibiting the HUVEC cell proliferation. Individual and mixed micelles inhibited HUVEC tube formation and migration with the mixed micelles showing a synergistic effect. Conclusions: We were successful in synthesizing new conjugates of RAP and PTX with a pH-sensitive linker. These polymers were formulated into individual and mixed micelles. Antiangiogenic effect was observed with individual and mixed micelles. The antiangiogenic effect was synergistically enhanced with the use of mixed micelles. Citation Format: Adam G. Alani, Gyan Mishra. The antiangiogenic effect of two drugs loaded nanocarriers and its potential application for cancer metronomic treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5664. doi:10.1158/1538-7445.AM2013-5664