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

用于靶向药物输送和疟疾根治的纳米载体制剂

• 批准号: 9366759
• 负责人: BABU L TEKWANI
• 金额: $ 58.05万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9366759
• 关键词: Address; Affect; Aminoquinolines; Antimalarials; Asialoglycoprotein Receptor; Bioavailable; Biological Assay; Biological Availability; Blood; Blood Circulation; Clinical; Development; Dose; Dose-Limiting; Drug Delivery Systems; Drug Efflux; Drug Kinetics; Drug Targeting; Drug or chemical Tissue Distribution; Erythrocytes; Evaluation; Formulation; Generations; Glucose-6-Phosphate; Goals; Hemolysis; Hepatic Tissue; Hepatocyte; Human; In Vitro; Individual; Infection; Lead; Ligands; Lipids; Lipolysis; Liver; Malaria; Medical; Metabolism; Methods; Modeling; NOD/SCID mouse; Nanostructures; Oral; Oral Administration; Parasites; Particle Size; Pharmaceutical Preparations; Pharmacologic Substance; Phase I Clinical Trials; Phenotype; Plasma; Plasmodium vivax; Polymers; Population; Pre-Clinical Model; Preparation; Primaquine; Property; Prophylactic treatment; Public Health; Relapse; Resistance; Rodent; Rodent Model; Safety; Solid; Stearates; System; Techniques; Testing; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Translating; Vivax Malaria; analog; base; biomaterial compatibility; chemical stability; clinical development; controlled release; cytotoxicity; efficacy testing; global health; improved; in vitro Assay; in vivo; intestinal epithelium; malaria infection; member; metabolic abnormality assessment; mouse model; nanocarrier; nanoparticle; nanoparticulate; nanostructured; pressure; programs; targeted delivery; tool; uptake; zeta potential

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.

项目概要/摘要 肝组织中休眠子虫的发育，可能导致疟疾在数周内复发 初次感染后数月，对间日疟疾的治疗和控制提出了重大挑战。 8- 氨基喹啉 (8-AQ) 是唯一对间日疟原虫休眠子具有活性的抗疟药物。然而， 由于葡萄糖-6-个体的剂量限制性溶血毒性，8-AQ 的效用受到限制 磷酸脱氢酶（G6PD）缺乏症。 G6PD 缺乏症影响着全球超过 4 亿人 脂质/聚合物纳米颗粒制剂最近已被证明具有显着的口服生物利用度。这 方法以及靶向递送至肝组织可用于提高治疗指数 8-AQ。该项目的目标是开发稳定的脂质纳米颗粒[固体脂质纳米颗粒（SLN）或 纳米结构脂质载体（NLC）]负载伯氨喹或NPC1161B，可以渗透穿过 口服后，肠上皮细胞完整地到达血液循环并分布在组织中。 PQ 和非靶向纳米载体制剂（聚合物、脂质和胶束） NPC1161B 将针对药物特性进行制备和优化。基于脂质的纳米粒子将 采用硬脂酸甘油酯、二硬脂酸甘油酯、甘油酯经高压均质技术制备而成 山嵛酸酯、miglyol 和其他 GRAS 列出的、生物相容性和可生物降解的脂质及其组合。这 将评估制剂的药物负载、负载效率、粒径和尺寸分布， Zeta 电位、抗脂解性、体外药物释放速率、物理和化学稳定性、摄取和 原代人肝细胞的代谢。啮齿类动物的体内药代动力学和组织分布将 评估药物的肝脏/血液比率并表征其代谢和血浆/肝脏药代动力学。 具有所需 PK 和代谢特征的制剂将在啮齿动物体内发挥功效 疟疾血液和肝脏阶段因果预防模型。最近将评估体内血液毒性 开发了植入人类 G6PD 缺陷血液的人源化 NOD-SCID 小鼠模型。 PQ 和 NPC1161B 的靶向口服生物可利用纳米载体制剂将减少总剂量 完全发挥功效所需的药物，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休眠子。减少红细胞与药物的接触或 代谢物将提高这些药物的治疗指数并允许它们在 G6D 缺乏症中安全使用 个人。这也将允许将这些药物应用于公共卫生和疟疾控制计划。