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.
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.
