Microparticle resiquimod for the treatment of visceral leishmaniasis

瑞西莫德微粒治疗内脏利什曼病

基本信息

批准号：
9091911
负责人：
Kristy M Ainslie
金额：
$ 19.93万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9091911
关键词：
Acetone Adjuvant Affect Agonist 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 Immune Immune response Immunotherapy Infection Kinetics Leishmania Leishmania donovani Life Ligands Liposomes Liver Lysosomes Maximum Tolerated Dose Measures Metabolic Methods Military Personnel Miltefosine Nature Organ Outcome Parasites Particle Size 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 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

项目摘要

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）是由强制性的细胞内寄生虫Donovani（L. donovani）的E型电子威胁性的全球健康关注的疏忽）我们假设用AMP和R-848处理抗药性L.被感染的巨噬细胞居住，由于以下原因，我们将使用Toparticles作为Toreat VL。）治疗抗药性寄生虫3。 3到几个月，用于封装的药物的连续释放。 ACE-DEX MPS中的AMP（R-848/AMP/MPS）。骨髓，肝脏和脾脏的靶向。