Microparticle resiquimod for the treatment of visceral leishmaniasis

 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L.恰加斯病是一种危及生命的被忽视的热带疾病，引起全球卫生关注。我们提出了一种治疗耐药L。使用对病原体特异性的化学治疗剂（两性霉素B（Amphotericin））和增加针对病原体的免疫应答的佐剂（瑞喹莫特（resiquimod）（R-848））治疗donovani。我们推测，用R848和R100治疗将协同治疗耐药L。donovani。R848是一种直接作用于寄生虫的化学治疗剂，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，咪唑喹啉类药物与寄生虫特异性化疗药物协同清除皮肤利什曼病。由于我们可以将R-848和RP 4配制成醋酸葡聚糖（Ace-DEX）微粒（MP），这些微粒可以潜在地靶向受感染的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。这是一项创新性的补助金，原因如下：（1）靶向宿主的佐剂和抗寄生虫药物的共包封可以协同治疗感染以及其他致命感染; 2.）治疗耐药寄生虫的能力。3.）第三章Ace-DEX MP可以在巨噬细胞吞噬体内释放包封的货物，这允许药物靶向感染的细胞内; 4.）Ace-DEX聚合物具有pH中性降解产物，这与常规生物材料不同; 5.）Ace-DEX聚合物具有可调的降解动力学，其范围可以从数小时到数月，允许包封药物的连续释放; 6.）先前的研究表明，Ace-DEX中的包封导致化合物的剂量节省; 7）Ace-DEX封装在冷链外储存时提供封装保护。为了检验我们的假设，我们提出了以下两个具体目标。具体目标1涉及R-848与Ace-DEX MP中的β-内酰胺酶的共包封（R- 848/β-内酰胺酶/MP）。具体目标2侧重于MP的生物分布和随后用L. donovani。最初，我们将开发一种对骨髓、肝脏和脾脏具有最佳靶向的颗粒。如果成功的话，将化疗药物与佐剂一起递送的概念可以应用于其他病原性感染。

 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.