Executive Summary : | The level of reactive oxygen species (ROS) in cancer cells is generally higher than normal cells and the overproduction of ROS in cancer cells is caused primarily due to the dysregulation of multiple metabolic enzymes. For example, the expression of thymidylate synthase (TS), aldose reductase (AR), cyclooxygenase-2 (COX-2) and glutathione-S-transferase pi (GSTP1) are up-regulated in many organ-specific cancer cells. Moreover, these enzymes are found to be interconnected with the dysregulation of ROS level in malignant cells. Thymidylate synthase catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) and maintains DNA replication and repair. Similarly, aldose reductase catalyzes the reduction of ROS-induced lipid peroxidation-derived aldehydes and their glutathione-conjugates to the corresponding alcohols, which is responsible for the induction of inflammatory signals. Furthermore, it is well-established that cyclooxygenases (COX-1 and COX-2) induce and elevate the inflammatory signals with the generation of prostaglandin leading to the overproduction of ROS. A major concern of the chemotherapeutic drug effectiveness is associated with the chemoresistance, which is triggered by the over-expression of GSTP1 via glutathione conjugation. Therefore, selective and effective inhibition of one or more of these over-expressed enzymes is important for controlling the abnormal cellular proliferation of cancer cells. However, the existing strategies of direct administration of such inhibitors have several drawbacks/limitations with (a) lack of selectivity towards cancer cells over healthy normal cells, (b) more side-effects due to the sudden increase in drug concentration in the plasma level; (c) lack of real time monitoring for the drug targeting. Herein, we plan to develop bio-analyte-triggered turn-on fluorogenic delivery systems for the targeted and selective delivery of one of more active inhibitors of the above over-expressed enzymes. Moreover, an adjuvant delivery of a gasotransmitter will be considered to minimize the drug-resistance and the drug-induced side-effects. Suitable targeting groups will be incorporated for enhancing the selective drug delivery and the cancer cell-selective bio-analytes will be used for the activation process. Sequential self-immolative linkers are used in the delivery systems enabling a sustained release of the inhibitors. Upon the synthesis of fluorogenic delivery systems using multi-step organic synthesis, fluorogenic drug release profile will be studied in aqueous phase followed by cellular medium. Detailed biological studies will be performed to validate the targeted delivery of the specific inhibitors to cancer cells over healthy normal cells. With the success of our strategy, we expect to resolve the limitations with effective treatment strategies for cancer with high selectivity and minimized side-effects. |