2022 Annual Meeting

Synthetic Optimization of 2T-T for Targeted Drug Delivery

Camptothecin is a bioactive molecule with potent anticancer properties but effective use in treatment is hindered by its poor aqueous solubility. Researchers have developed derivatives with moieties to increase solubility–some of which are currently used in clinical applications, though still with issues of acute toxicity, low circulation time, and pH-dependent activity. The lactone structure in these drugs exist in two forms—open and closed—depending on pH. Acidic pH favors the closed and more potent form, while physiological, neutral pH favors the hydrolyzed, open lactone form that binds to bloodstream proteins resulting in enhanced filtration–therefore short circulation times and ineffective treatment. This effect can be mitigated by integration of drugs into nanoparticle delivery vehicles. This may be accomplished by chemical conjugation of drugs with phospholipids, resulting in prodrugs to be incorporated into liposome delivery vehicles. Liposomes enter the cell through endocytosis then intracellular enzymatic processing of packaged prodrugs induce apoptosis. Liposome delivery has the advantages of reducing protein binding to increase circulation time and using enhanced accumulation in tumors for a targeted effect. Multiple camptothecin derivatives are under investigation for this conjugation and delivery method in our laboratory. One of them–topotecan–has shown great potential in this application. The project’s overall goal is to produce topotecan-phospholipid prodrug, named 2T-T, and optimize its synthesis and purification. Conjugation synthesis may be done with varying reagent equivalence, affecting 2T-T yield. The purification, done by preparatory thin-layer chromatography, has demonstrated effectiveness that is dependent on mobile phase composition. Yields of up to 12% have been obtained through our process, validated by nuclear magnetic resonance spectroscopy. With evident potential in the isolation of 2T-T, experiments are underway to further increase yields and improve purification for future applications in liposome processing and biological testing.