Novel nanoparticles function as chemo- and adjunctive-therapy against experimental cerebral malaria

新型纳米颗粒可作为实验性脑型疟疾的化疗和辅助疗法

• 批准号: 10308498
• 负责人: HENRI C VAN DER HEYDE
• 金额: $ 26万
• 依托单位: LA JOLLA INFECTIOUS DISEASE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308498
• 关键词: 3-Dimensional; Adult; Affect; African; Albumins; Antiparasitic Agents; Artemisinins; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Coagulation Disorders; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Brain; Brain Edema; CD8-Positive T-Lymphocytes; Cerebral Malaria; Child; Clinic; Clinical; Complex; Complication; Data; Development; Drug Carriers; Drug Delivery Systems; Drug resistance; Dyes; Erythrocytes; Evans blue stain; Exhibits; FDA approved; Flow Cytometry; Fluorescence; Future; Glutathione Disulfide; Goals; Grant; Guidelines; Histologic; Human; Immune response; Impairment; Infection; Inflammation; Inflammatory; Investigational Therapies; Label; Life; Magnetic Resonance Imaging; Malaria; Measures; Modeling; Mus; Neurologic; Neurologic Dysfunctions; Neuronal Dysfunction; Osmotic Pressure; Parasitemia; Parasites; Pathogenesis; Pathogenicity; Patients; Persons; Pharmaceutical Preparations; Plasmodium; Plasmodium berghei; Plasmodium falciparum; Process; Reporter; Reproducibility; Research; Saline; Serum Albumin; Syndrome; Testing; Therapeutic; Treatment Efficacy; Weight; artemether; chemotherapy; cytokine; disability; drug development; extracellular; high reward; high risk; in vivo; mortality; motor deficit; nanoparticle; nanoparticle drug; nanoscale; neuron loss; novel; novel strategies; novel therapeutics; oxidant stress; stroke patient; uptake; vasogenic edema

Neurological dysfunction is an important complication of blood stage Plasmodium falciparum (Pf) infection and the syndrome is called cerebral malaria (CM). We have developed human serum albumin (HSA) nanoparticles (NPs) that are nanoscale aggregates of albumin as a carrier for drug delivery and conjugated anti-bloodstage Plasmodium drugs, including artemether (A) and artemisinin to these NPs. Our preliminary data indicate that our novel artemether-conjugated NPs (A-NPs) provide complete protection against experimental CM (eCM). A-NPs exhibit anti-parasite activity and are preferentially targeted to infected red blood cells (iRBCs) over uRBCs. Our control NPs (C-NPs), which are NPs without drug, provide significant (p<0.05) protection against eCM without affecting parasitemia. These findings suggest that A-NPs may exhibit both anti-parasite- and adjunctive-therapy effects in a single, easy to administer compound. There is currently no FDA-approved adjunctive therapy of CM to ameliorate the pathogenic host response during CM and to decrease mortality in the 15-30% of CM patients who die after adequate anti-parasite chemotherapy. In addition, this adjunctive therapy to ameliorate the pathogenic host response may also decrease the neurological impairment after Pf infection that results in life-long disability for African children who survive CM. We use the well-defined, reproducible P. berghei ANKA infection of mice as our model for CM (i.e., eCM). We hypothesize that our novel nanoparticles protect from development of eCM by decreasing pathogenic processes leading to eCM, i.e., vasogenic edema, oxidant stress, inflammation, sequestration, and coagulopathy. The efficacy of NPs as adjunctive therapy against eCM is tested in Aim 1. Mechanism(s) of action of NPs as adjunctive therapy are tested in Aim 2. Cerebral malaria is a syndrome comprised of multiple pathogenic processes that includes brain edema, Pf- infected red blood cell sequestration, oxidant stress, coagulopathy, and inflammation. Vasogenic edema is observed by magnetic resonance imaging in African children with CM; the vasogenic edema occurs in Indian adults with CM but is less pronounced. Our preliminary data indicate that C-NPs significantly (p<0.05) decrease vascular leak measured by Evans Blue dye extrusion into brain during eCM compared with vehicle controls. A-NPs decreased vascular leak even further than C-NPs to levels similar to those in uninfected mice. Our preliminary data therefore suggest that NPs function as adjunctive therapy in eCM by reducing vascular leak. We will also assess the extent to which other key pathogenic mechanisms in eCM are affected by our eCM-protective NPs. Patients with CM and mice with eCM both exhibit oxidant stress, parasite sequestration, coagulopathy, and inflammation as possible pathogenic processes, so defining which mechanisms are significantly decreased by our eCM-protective A-NPs highlights targetable processes for additional future drug development. This proposal meets R21 exploratory grant guidelines because it is focused on assessing the efficacy of a new drug with undefined mechanisms for which there is little experimental support beyond our preliminary data. Follow-on studies will use the generated data for in-depth studies of mechanisms and to move the NPs to the clinic.

神经功能障碍是血级恶性疟原虫（PF）感染的重要并发症 该综合征称为脑疟疾（CM）。我们已经开发了人血清白蛋白（HSA）纳米颗粒 （NPS）是白蛋白的纳米级聚集体，作为药物输送和共轭抗血管的载体 这些NP的疟原虫药物，包括氨基氨酸（a）和青蒿素。我们的初步数据表明 我们的新型辅助NP（A-NP）提供了针对实验CM（ECM）的完全保护。 A-NP具有抗寄生虫活性，优先针对感染的红细胞（IRBC） urbcs。我们的对照NP（C-NP）是没有药物的NP，可对 不影响寄生虫血症的ECM。这些发现表明A-NP可能同时表现出抗寄生虫和 单个易于施用化合物的辅助治疗效果。 目前尚无对CM的FDA批准辅助治疗来改善致病性宿主反应 在CM期间，在足够的抗寄生虫后死亡的15-30％的CM患者中的死亡率降低 化学疗法。此外，这种改善致病宿主反应的辅助疗法也可能 减少PF感染后的神经系统损害，导致非洲儿童终身残疾 幸存CM。我们使用明确的，可重现的P. berghei Anka感染小鼠作为CM的模型 （即ECM）。我们假设我们的新型纳米颗粒可以防止ECM的发展 减少导致ECM的致病过程，即血管水肿，氧化剂应激，炎症， 隔离和凝血病。 NP作为针对ECM的辅助治疗的功效在AIM 1中测试。 在AIM 2中测试了NP作为辅助疗法的作用机制。 脑疟疾是一种由多种致病过程组成的综合征，包括大脑水肿，PF- 感染的红细胞固执，氧化剂应激，凝血病和炎症。血管生成水肿是 通过磁共振成像观察到非洲CM儿童；血管生成性水肿发生在印度 CM的成年人，但不太明显。我们的初步数据表明C-NP显着（P <0.05） 与媒介物相比，在ECM期间通过Evans蓝色染料挤出到大脑中测量的血管泄漏减少 控件。 A-NPS将血管泄漏降低到与未感染小鼠相似的水平相似的水平。 因此，我们的初步数据表明，NP通过减少血管在ECM中起辅助治疗的作用 泄露。我们还将评估ECM中其他关键的致病机制受我们的影响的程度 ECM保护NP。患有ECM的CM和小鼠的患者均表现出氧化应激，寄生虫隔离， 凝血病和炎症是可能的致病过程，因此定义哪些机制是 我们的ECM保护A-NPS显着降低 发展。 该提案符合R21探索性赠款指南，因为它重点是评估新的功效 具有不确定机制的药物，除了我们的初步数据之外，几乎没有实验支持的药物。 后续研究将使用生成的数据进行深入的机制研究，并将NPS移至 诊所。