PROJECT SUMMARY/ABSTRACT Development of dormant hypnozoites in the hepatic tissues, which may cause malaria relapse weeks to months after the initial infection, poses the major challenge for treatment & control of vivax malaria. 8- Aminoquinolines (8-AQs) are the only antimalarial drugs active against Plasmodium vivax hypnozoites. However, the utility of 8-AQs has been limited due to a dose-limiting hemolytic toxicity in individuals with glucose-6- phosphate dehyrogenase (G6PD) deficiency. G6PD deficiency affects more than 400 million people worldwide Lipid/polymeric nanoparticle formulations have recently been shown to have significant oral bioavailability. This approach, along with targeted delivery to the hepatic tissues may be applied for improving therapeutic index of 8-AQs. The goal of this project would be to develop stable lipid nanoparticles [solid lipid nanoparticles (SLNs) or nanostructured lipid carriers (NLCs)] loaded with primaquine or NPC1161B, which can permeate across the intestinal epithelia, reach the blood circulation and distribute in the tissues intact following oral administration. Targeted and non-targeted nano-carrier formulations (polymeric, lipid based and micellar) of PQ and NPC1161B will be prepared and optimized for pharmaceutical properties. Lipid-based nanoparticles will be prepared by high-pressure homogenization technique using glyceryl stearate, glyceryl distearate, glyceryl behenate, miglyol and other GRAS listed, biocompatible and biodegradable lipids, and their combinations. The formulations will be evaluated with respect to drug loading, loading efficiency, particle size and size distribution, zeta potential, resistance to lipolysis, in vitro drug release rates, physical and chemical stability, uptake and metabolism by primary human hepatocytes. In vivo pharmacokinetics and tissue distribution in rodents will assess the liver/blood ratios of the drugs and characterize their metabolism and plasma/liver pharmacokinetics. The formulations with desired PK and metabolism profiles would be progressed to in vivo efficacy in rodent malaria blood and liver stage causal prophylaxis models. In vivo hemotoxicity will be evaluated in the recently developed humanized NOD-SCID mouse model engrafted with human G6PD deficient blood. Targeted orally bioavailable nano-carrier formulations of PQ and NPC1161B will reduce total dose of the drug required for complete efficacy, which presumably would translate to a higher total dose of active metabolite in parasitized liver cells required to clear vivax hypnozoites. Reduced exposure of erythrocytes to the drug or the metabolites would improve therapeutic index of these drugs and allow their safe use in G6D deficient individuals. This would also allow application of these drugs for public health and malaria control programs.