Liposome Form?lations Containing A Novel Wnt Pathway Inhibitor C132

The compound CGX1321 was identified in our previous study as a potent inhibitor of the Wnt signal transduction pathway.Since Wnt pathway abnormality were involved in many cancer types including liver,colon,and gastric cancers,CGX1321 has the potential to become a potent anti-cancer drug with broad application areas.But the compound has very poor aqueous solubility at neutral PH.In addition,there are also concerns about its toxicity in colon and skin where there are high endogenous Wnt activities.In this study,we propose to develop a liposome formulation containing CGX1321 and to evaluate the in vivo pharmacokinetic behaviors and pharmacodynamics.We hope the new formulation can help to maximize drug concentration and efficacy in tumor while minimizing drug distribution in colon and skin tissues.The CGX1321 solubility and partition coefficient at various pH solutions were evaluated.Since it was very poorly soluble at pH 4.0 and up,various concentrations of Hydroxypropyl-?-Cyclodextrin(HPBCD)were added to reach desirable drug concentration.The drug solution was added to liposome formulations containing HSPC and cholesterol and loaded using the ammonium sulfate gradient method.The optimum liposome formulation,which contains high concentration of drug,was evaluated for in vivo pharmacokinetic properties and pharmacodynamics.Liposomes made of HSPE: Chol: DSPE-PEG2000 were prepared containing CGX1321 at up to 1mg/ml concentration.The in vivo PK & tissue distribution study indicated significantly different drug concentration profiles in tumor,skin,and colon.The drug clearance patterns were also different,suggesting the liposomal delivery and controlled release effects.The liposome formulation successfully improvements drug efficacy and reduces drug toxicities.The drug CGX1321 was successfully loaded in to liposomes using the ammonium sulfate gradient method.The drug dose range for intravenous injection was greatly improved.The pharmacokinetic profile and tissue distribution patterns were also more optimized based on the drug efficacy and toxicity mechanism.