The natural product artemisinin is a sesquiterpene endoperoxide with known anti-malarial activity against both chloroquine-sensitive and chloroquine-resistant strains of the parasite Plasmodium falciparum. In addition to its anti-malarial activity, artemisinin was reported to have cytotoxic activity against several different tumor cell lines. Recently, artemisinin work conducted by our group has been extended to the preparation of a series of dihydroartemisinin dimers (DHA dimers) and the testing of these dimers against protozoal infections, as well as collaborative work with the National Cancer Institute (NCI) and the anti-tumor screening program. The analog DHA dimer oxime and its hemisuccinate ester (HS) have shown very promising results in the NCI screening program and strong activity against malaria in our initial in vitro and in vivo studies. However, the oral antimalarial dose needed was approximately 10-fold higher than the intraperitoneal dose. Several factors could be responsible for the observed limited oral absorption. These could include degradation of the drug/prodrug in the gastrointestinal tract, poor solubility in the gastrointestinal fluids, limited permeability across the gastro-intestinal walls or first-pass metabolism. Thus, the overall objective of this proposal is to elucidate the factor(s) behind the limited oral absorption and to develop formulation(s) that has high oral bioavailability, through strategies to overcome the challenges faced in oral absorption. This will be accomplished through a set of specific aims which include: 1: Synthesis of DHA dimer oxime and DHA dimer oxime hemisuccinate: These are the two compounds characterized as the lead dimers for oral bioavailability studies. 2: Evaluation of the biopharmaceutical characteristics of these DHA dimers: These studies will include solubility, logP, pH stability profile, metabolic stability in te presence of gastrointestinal and hepatic enzymes and in vitro permeability of the compounds. The data obtained will help identify the constraints in oral bioavailability of these compounds. 3: Development of formulation approaches: Based on the findings in Aim 2 various strategies to overcome the challenges including solubilization and stabilization approaches, inclusion of permeation enhancers and nanoparticle dosage forms will be investigated through in vitro permeability experiments. 4: Delineation of oral bioavailability in rats: Finally, promising formulations will be tested in vivo. The oral PK data will be compared to the intraperitoneal PK data. Blood samples will be analyzed using LC/MS/MS. It is anticipated that at least one formulation containing one of the dimers will be identified with high oral bioavailability and willbe progressed to developmental studies during phase II. This STTR application represents a collaborative effort between ElSohly Laboratories, Inc. (ELI), and the Department of Pharmaceutics at the University of Mississippi (UM).

Public Health Relevance

This proposal is directed towards improving the oral bioavailability of DHA dimers with potential therapeutic applications in malaria. This novel class of compounds also shows a lot of promise in other infectious diseases and in several forms of cancer. Development of an orally bioavailable formulation will significantly improve its therapeutic utility and will have a tremendous impact on public health.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
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Special Emphasis Panel (ZRG1-IDM-U (10))
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Rogers, Martin J
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Elsohly Laboratories, Inc.
United States
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