Targeted therapy reduces off-target inhibitor effects by releasing payloads specifically at the site of disease like tumors or cancer microenvironments. Current strategies for release include reduction, enzyme-assisted release, and other very stable linkers that require internalization. This research is focused on the design of a release strategy dependent on reactive oxygen species (ROS). These entities are common at cancer microenvironments sites at high levels and thus can lead to selective release of a prodrug. Using a delivery vehicle such as an aptamer, antibody or short targeting peptide is possible to target a particular type of cancer for the delivery, doubling the specificity features for a selective drug release at tumor site.<br/>In my design, I will use a ROS-activatable self-cyclizing molecule that will be attached to a leukemia targeting peptide and a poly ADP ribose polymerase (PARP) inhibitor, NU1025 as the cytotoxic payload. The linker carrying the drug will first be synthesized with an available alkene and then conjugated with the delivery vehicle, a cysteine terminated peptide, via thiol-ene click chemistry. In vitro and in cellulo studies will then be carried to show the release of the cytotoxic payload under oxidative stress (ROS) conditions and the increased cell cytotoxicity and selectivity to the targeted cancerous cells.

Reactive oxygen species (ROS)-dependent release of an anticancer drug from a targeting peptide

2019 Fall National Meeting

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