2022 Annual Meeting
Synthetic Optimization of Camptothecin Derivative SN38-Lipid Prodrugs for Targeted Chemotherapeutic Delivery
Camptothecin is an effective anticancer drug but is not easily administered due to its hydrophobicity causing poor solubility. One of the hydrophobic derivatives of camptothecin is SN38. This drug is not used clinically but it is the active metabolite of the clinically-used irinotecan. SN38 has a lactone ring that has two forms: open or closed. The open form, at neutral pH, is easily protein bound and cleared from circulation, effectively reducing efficacy. The closed form, at low pH, is the active state which induces apoptosis upon intracellular uptake through topoisomerase I inhibition. The pH dependency is problematic as the neutral pH of the blood promotes the open form which then gets filtered out of the body without treating the tumor. This issue can be minimized by integrating these drugs into liposomal delivery vehicles which improve circulation time and provide a privileged pathway, upon utilizing the enhanced permeability and retention effect, into tumor cells so that a smaller dose can be utilized. To do this, a lipid tail is chemically conjugated to the drug so that the resulting prodrug can be incorporated into the lipid bilayer of a liposome and enzymatically released in lysosomes when liposomes are endocytosed. The lipid tails are able to attach at various hydroxyl groups of the SN38, which can lead to multiple tail conjugation. The multiple attached tails can affect the packaging of the prodrug into a liposome. Upon modification of testing parameters, multiple attachment-prodrugs have been collected and the single attachment yield was 31.4%.