Microparticle resiquimod for the treatment of visceral leishmaniasis

瑞西莫德微粒治疗内脏利什曼病

• 批准号: 9259909
• 负责人: Kristy M Ainslie
• 金额: $ 22.45万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259909
• 关键词: AIDS therapy; Acetates; Acetone; Adjuvant; Affect; Agonist; Alpha Particles; Amphotericin B; Antigens; Antimony; Antiparasitic Agents; Biocompatible Materials; Biodistribution; Biopolymers; Blood; Blood Circulation; Bone Marrow; Canis familiaris; Cells; Cessation of life; Cold Chains; Contracts; Cream; Cutaneous Leishmaniasis; Deposition; Dextrans; Disease; Disease model; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug resistance; Encapsulated; Endothelium; Ethanol; FDA approved; Formulation; Glycolates; Grant; Hamsters; Hour; Hydrophobicity; Immune; Immune response; Immunotherapy; Infection; Injectable; Kinetics; Leishmania; Leishmania donovani; Life; Ligands; Liposomes; Liver; Lysosomes; Maximum Tolerated Dose; Measures; Metabolic; Methods; Military Personnel; Miltefosine; Nature; Organ; Organ Size; Outcome; Parasite resistance; Parasites; Particle Size; Pathogenicity; Phagocytes; Phagosomes; Pharmaceutical Preparations; Physiological; Polymers; Reporting; Research; Resistance; Site; Spleen; Splenocyte; T-Cell Proliferation; TLR7 gene; Testing; Time; Tissues; Treatment Protocols; Visceral; Visceral Leishmaniasis; War; Work; Zoonoses; chemotherapy; cytokine; design; drug efficacy; effective therapy; global health; innovation; macrophage; neglected tropical diseases; novel; obligate intracellular parasite; parenteral administration; particle; pathogen; public health relevance; resiquimod; resistant strain; response; small molecule; targeted treatment; therapeutic target; trafficking; viral RNA

 DESCRIPTION: Visceral leishmaniasis (VL) is caused by the obligate intracellular parasites Leishmania donovani (L. donovani) or L. chagasi and is a life-threatening neglected tropical disease of global health concern. We present a method for the treatment of drug resistant L. donovani using both a chemotherapeutic specific for the pathogen (Amphotericin B (Amp)), and an adjuvant that increases the immune response against the pathogen (resiquimod (R-848)). We hypothesize that treating with Amp and R-848 will synergistically treat drug resistant L. donovani. Amp is a chemotherapeutic that works directly on the parasite, while R-848 is an adjuvant that activates infected macrophages that allows for the clearance of intracellular parasites. Prior research has shown that imidazoquinolines with parasite specific chemotherapies synergize in the clearance of cutaneous leishmaniasis. Since we can formulate both R-848 and Amp into Acetated Dextran (Ace-DEX) microparticles (MPs) that can potentially target tissues where infected macrophages reside, we will use these microparticles as a platform to treat VL. This grant is innovative for the following reasons: 1.) Co- encapsulation of both a host-targeted adjuvant and an antiparasitic drug could synergistically treat the infection as well as other lethal infections; 2.) Ability to treat drug resistant parasites. 3.) Ace-DEX MPs can release encapsulated cargo inside the macrophage phagosome which allows for drug targeting inside the infected cell; 4.) Ace-DEX polymer has pH neutral degradation products, unique from conventional biomaterials; 5.) Ace-DEX polymer has tunable degradation kinetics that can range from hours to months allowing for the continuous release of encapsulated drugs; 6.) Previous research has shown that encapsulation in Ace- DEX has resulted in dose sparing of compounds; 7.) Ace-DEX encapsulation offers protection of encapsulates when stored outside the cold chain. In order to test our hypothesis we propose the following two specific aims. Specific Aim 1 involves the co-encapsulation of R-848 with Amp in Ace-DEX MPs (R- 848/Amp/MPs). Specific Aim 2 focuses on the biodistribution of MPs and the subsequent treatment of infected hamsters with susceptible or Amp resistant strains of L. donovani. Initially we will develop a particle that has optimal targeting of the bone marrow, liver and spleen. If successful, the concept of delivering a chemotherapeutic with an adjuvant could be applied to other pathogenic infections.

 描述：内脏利什曼病 (VL) 是由专性细胞内寄生虫杜氏利什曼原虫 (L. donovani) 或恰加斯利什曼原虫引起，是一种危及生命、被忽视的热带疾病，引起全球健康关注。我们提出了一种治疗耐药杜氏乳杆菌的方法，使用针对病原体的特异性化疗药物（两性霉素 B (Amp)）和增强针对病原体的免疫反应的佐剂（瑞西莫德 (R-848)）。我们假设用 Amp 和 R-848 治疗将协同治疗耐药杜氏乳杆菌。 Amp 是一种直接作用于寄生虫的化疗药物，而 R-848 是一种佐剂，可以激活受感染的巨噬细胞，从而清除细胞内的寄生虫。先前的研究表明，咪唑喹啉与寄生虫特异性化疗在清除皮肤利什曼病方面具有协同作用。由于我们可以将 R-848 和 Amp 配制为醋酸右旋糖酐 (Ace-DEX) 微粒 (MP)，该微粒可以潜在地靶向感染巨噬细胞所在的组织，因此我们将使用这些微粒作为治疗 VL 的平台。这项资助具有创新性，原因如下：1.）将宿主靶向佐剂和抗寄生虫药物共同封装可以协同治疗感染以及其他致命感染； 2.) 能够治疗耐药寄生虫。 3.) Ace-DEX MP 可以释放巨噬细胞吞噬体内的封装物质，从而允许药物靶向感染细胞内； 4.) Ace-DEX聚合物具有pH中性的降解产物，这是传统生物材料所独有的； 5.) Ace-DEX聚合物具有可调节的降解动力学，其范围可以从数小时到数月不等，从而可以连续释放封装的药物； 6.) 先前的研究表明，封装在 Ace-DEX 中可以节省化合物的剂量； 7.) Ace-DEX 封装可在冷链外储存时提供封装保护。为了检验我们的假设，我们提出以下两个具体目标。具体目标 1 涉及将 R-848 与 Amp 共同封装在 Ace-DEX MP 中 (R-848/Amp/MP)。具体目标 2 侧重于 MP 的生物分布以及随后用杜氏乳杆菌易感或 Amp 抗性菌株治疗受感染的仓鼠。最初，我们将开发一种对骨髓、肝脏和脾脏具有最佳靶向性的颗粒。如果成功，用佐剂进行化疗的概念可以应用于其他病原体感染。