Comparison of Efficacy and Specificity in Cancer‐Targeting Prodrug Conjugates

Abstract

Current chemotherapy methods are non‐specific, killing cancerous and healthy cells alike. This drug‐related cytotoxicity results in many side effects such as hair loss or lower blood cell count. Prodrug conjugates have been developed with the goal of preferentially targeting diseased cells to minimize interactions with healthy cells, thereby mitigating deleterious off‐target effects. One powerful prodrug strategy exploits higher vitamin receptor expression levels in tumor cells. These abundant receptors drive their rapid, nutrient‐demanding growth rates. As such, a vitamin structural motif may be included in the prodrug conjugate design to target the ever‐growing tumor: a “targeting group” that acts as an appealing disguise for the drug. Biotin, folate, cyclic and acyclic RGD peptides have been found to be effective in targeting tumors over non‐cancerous cells. To systematically compare the selectivity and potency of these targeting groups, we intend to construct fluorogenic prodrug conjugates based on a previously established scaffold. The conjugates include one of the four respective targeting groups, the anticancer drug (camptothecin), a naphthalimide fluorophore component to track drug delivery, and an activatable disulfide linker that cleaves upon entering the reducing cellular environment, activating both the drug and the fluorophore. After these conjugates have been synthesized, comparisons of efficacy and specificity among targeting groups will be made to gain a better understanding of targeted cancer prodrug conjugates. Currently, these conjugates are still in the synthesis stages.