Nano-carrier Formulations for Targeted Drug Delivery and Malaria Radical Cure

项目摘要/摘要 在肝组织中形成休眠的催眠体，这可能导致疟疾复发数周至 在最初感染几个月后，对间日疟的治疗和控制构成了主要挑战。八号 氨基喹啉类(8-AQS)是目前唯一有效的抗间日疟原虫催眠原虫的药物。然而， 由于8-水杨酸对患有葡萄糖-6-酮的个体具有剂量限制的溶血毒性，其应用受到了限制。 磷酸脱氢酶(G6PD)缺乏症。G6PD缺乏症影响全球超过4亿人 脂质/聚合物纳米颗粒制剂最近被证明具有显著的口服生物利用度。这 该方法结合肝组织靶向给药，可用于提高治疗指数。 8-AQS。该项目的目标是开发稳定的脂类纳米颗粒[固体脂类纳米颗粒(SLNS)或 纳米结构脂质载体(NLC)]负载伯喹或NPC1161B，可渗透到 肠道上皮细胞，到达血液循环，在口服后完好无损地分布在组织中。 PQ和PQ的靶向和非靶向纳米载体制剂(聚合物、脂类和胶束) NPC1161B将被制备并针对药物性能进行优化。以脂质为基础的纳米颗粒将被 采用高压均质技术，以硬脂酸甘油酯、硬脂酸甘油酯、甘油酯 山毛榉、米甘醇和其他GRAS上市、生物相容和可生物降解的脂类及其组合物。这个 将根据药物载量、载药效率、颗粒大小和粒度分布对制剂进行评价， Zeta电位，抗脂解性，体外释药速率，物理和化学稳定性，摄取和 原代人肝细胞的代谢。啮齿类动物体内药代动力学和组织分布 评估药物的肝脏/血液比率，并表征其代谢和血浆/肝脏的药代动力学。 具有期望的PK和代谢特征的制剂将在啮齿动物身上取得体内疗效 疟疾血液和肝脏阶段因果预防模型。体内血液毒性将在最近进行评估 建立人G6PD缺血型人源化NOD-SCID小鼠模型。 靶向口服生物利用度纳米载体制剂PQ和NPC1161B将减少 完全有效所需的药物，这可能会转化为“更高的活性代谢物总剂量” 在寄生的肝细胞中“需要清除间日疟原虫的催眠体。减少红细胞对药物或 这些代谢物将提高这些药物的治疗指数，并使它们在G6D缺乏时安全使用 个人。这也将允许将这些药物应用于公共卫生和疟疾控制项目。

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.