A Novel Colon-specific Bi-functional Amebicidal Therapeutics: Gal-Dextran-MM

描述(申请人提供)：E.溶组织寄生虫是一种原生动物肠道寄生虫，能够入侵和破坏人体组织，导致潜在威胁生命的疾病，如肠源性结肠炎和肝脓肿。阿米巴感染影响了大约10%的世界人口，每年导致约5000万人患上侵袭性疾病，并导致10万人死亡。寄生虫通过半乳糖/N-乙酰氨基半乳糖凝集素与宿主肠道上皮细胞的黏附，是导致宿主细胞死亡和全身侵袭的重要病理机制。严重的肠道阿米巴感染需要用混合阿米巴唑治疗，甲硝唑对肠道和全身阿米巴病都有效。甲硝唑的一个局限性是它在上消化道的高吸收，这可能导致治疗浓度无法到达结肠，并产生全身副作用。本建议的目的是开发一种新型的双功能聚合物阿米巴杀菌治疗药物，半乳糖-葡聚糖-甲硝唑(Gal-Ddexan-MM)前药，用于甲硝唑和半乳糖的结肠定位给药。这种阿米巴杀菌疗法旨在通过两种机制阻止疾病进展和根除潜在感染，1)输送阿米巴杀菌剂甲硝唑，以杀死阿米巴；2)输送半乳糖，可能抑制寄生虫与宿主细胞的黏附。中心假设是半乳糖葡聚糖MM将稳定通过上消化道，释放药物和半乳糖后，葡聚糖解聚存在于结肠的微生物内切酶，并抑制阿米巴病的进展。本研究的具体目的是：1)合成并表征半乳糖葡聚糖-MM作为结肠定位的双功能阿米巴前药；2)体外评价半乳糖葡聚糖-MM的阿米巴杀菌活性和黏附抑制作用；3)评价半乳糖-葡聚糖-MM在小鼠阿米巴溃疡模型中的药效和毒性。公共卫生相关性：如果寄生阿米巴寄生在大脑和肝脏等敏感器官上，感染会导致轻微到严重的肠道疾病，并可能威胁生命的疾病。因为世界上10%的人口都受到这种感染的影响。由于容易传播和感染，奥美巴也被认为是潜在的生物恐怖分子。因此，为应对大规模暴发，仍有必要继续开发溶组织埃希氏菌的创新治疗策略。本项目致力于开发一种新型的结肠特异性双功能阿米巴病治疗药物，半乳糖-葡聚糖-甲硝唑(Gal-葡聚糖-甲硝唑)前药，用于治疗阿米巴病。

DESCRIPTION (provided by applicant): E. histolytica is a protozoal enteric parasite that is capable of invading and destroying human tissues, leading to potentially life-threatening diseases such as enteric colitis and liver abscess. Amoebic infection affects approximately 10% of the world's population, causing invasive disease in about 50 million people and resulting in 100,000 deaths annually. Parasite adhesion to host intestinal epithelial cells, through a glactose/N-acetyl galactosamine lectin, is a critical mechanism of pathology, which can lead to host cell death and systemic invasion. Severe intestinal amoebic infection requires treatment with the mixed amebicide, metronidazole, which is effective against both intestinal and systemic amebiasis. One limitation of metronidzole is its high absorption in the upper GI tract , that may result in failure to reach the colon in therapeutic concentrations and in systemic side effects. The objective of this proposal is to develop a novel bi-functional polymeric amebicidal therapeutic, Galactose-Dextran- Metronidazole (Gal-Dextran-MM) prodrug, for colon-specific delivery of metronidazole and galactose. This amebicidal therapeutic is designed to block disease progression and eradicate the underlying infection through two mechanisms, 1) delivery of the amebicidal agent, metronidazole, to kill the amoebae, and 2) delivery of galactose which may inhibit adhesion of the parasite to host cells. The central hypothesis is that Gal-dextran-MM will stably pass through the upper GI tract, release drug and galactose following dextran depolymerization by microbial endodextranases present in the colon, and inhibit the progression of amebiasis. The specific aims are 1) to synthesize and characterize Gal- Dextran-MM as a colon-specific bi-functional polymeric amebicidal prodrug, 2) to evaluate the amebicidal activity and adhesion inhibition effect of Gal -Dextran -MM in vitro, and 3) to evaluate the efficacy and toxicity of Gal-Dextran-MM in a mouse amoebic ulcer model in vivo. PUBLIC HEALTH RELEVANCE: Infection by parasitic amoeba results in mild to severe bowel disorders and potentially life threatening diseases if the organism colonizes sensitive organs such as the brain and the liver. As many of 10% of the world population are affected by this infection. Due to the ease of transmission and infection, aomeba are also considered potential bioterrorism agents. Therefore, there is a continued need for the development of innovative therapeutic strategies for E. histolytica in order to counter large scale outbreaks. This project is focused on development of a novel colon-specific bi-functional amebicidal therapeutic, Galactose-Dextran-Metronidazole (Gal-Dextran-MM) prodrug, for treatment of amebiasis.