Anticancer agents that modify DNA are a mainstay of chemotherapy regimens, but development of new classes of these agents has slowed because of the modification of DNA in non-cancerous cells, known as off-target reactivity, which gives rise to serious side effects and poor selectivity. We have designed a means to achieve specificity by translating the finding that levels of reactive oxygen species (ROS) are elevated in acute myeloid leukemia (AML) cells into a therapeutic modality termed ROS-Activated Cytotoxic DNA-modifying agents. Therefore, only upon ROS activation, DNA modification occurs. Our most effective agent, RAC1, has an IC<sub>50</sub> against AML cells of 750 nM. In addition, this compound is exquisitely specific with an order of magnitude lower potency for closely related CD34+ blood stem cells. Data indicate signs of efficacy in a realistic mouse model. This study aims to improve the selectivity and delivery by adding a specifically designed aptamer as a selective transporter. The developed aptamers are selective against AML cancer and not against normal CD34+ cord blood cells. The aptamer is conjugated to RAC1 via a cleavable hydrolysable linker. The anticancer activity and selectivity of the aptamer conjugate has also been tested.

Design of a nucleic acid aptamer to achieve localization of a ROS-activated anti-cancer agent

253rd National Meeting (2017)

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