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)或查加西利什曼原虫(L.chagasi)引起的，是一种危及生命的全球卫生问题被忽视的热带疾病。我们提出了一种治疗耐药杜氏杆菌的方法，既使用针对病原体的化疗特异性药物(两性霉素B(AMP))，又使用增强对病原体的免疫反应的佐剂(Requimod(R-848))。我们假设用Amp和R-848治疗将协同治疗耐药的杜诺瓦尼乳杆菌。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，咪唑并喹啉类药物与寄生虫特异性化疗药物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制成乙酰化葡聚糖(Ace-DEX)微粒(MPS)，这种微粒可能针对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。这笔赠款具有创新性，原因如下：1)共包裹宿主靶向佐剂和抗寄生虫药物可以协同治疗感染和其他致命感染；2)治疗抗药性寄生虫的能力。3.)ACE-DEX MPS可以在巨噬细胞吞噬体内释放包裹的货物，从而允许在受感染的细胞内进行药物靶向；ACE-DEX聚合物具有pH中性的降解产物，不同于传统的生物材料；ACE-DEX聚合物具有可调的降解动力学，可以从几个小时到几个月不等，从而允许胶囊药物的连续释放；先前的研究表明，在Ace-DEX中的封装导致了化合物的剂量节约；7)当储存在冷链之外时，ACE-DEX封装可提供胶囊保护。为了验证我们的假设，我们提出了以下两个具体目标。具体目标1涉及将R-848与Amp共封装在Ace-DEX MPS(R-848/AMP/MPS)中。具体目的2着重于MPS的生物分布以及随后用敏感或耐Amp的杜氏乳杆菌菌株治疗感染的仓鼠。最初，我们将开发一种对骨髓、肝脏和脾具有最佳靶向的颗粒。如果成功，提供带有佐剂的化疗药物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.