Synthesis And Application Of Theranostic Anticancer Prodrugs Based On Camptothecin

Three small molecular theranostic anticancer prodrugs based on camptothecin(CPT) were designed and synthesized. The results of our research indicate that drug released from the theranostic prodrugs can be triggered by the special environment of cancer cells or regulating the exogenous conditions. The theranostic anticancer prodrugs can realize real-time cells imaging for monitoring drug release processes. The theranostic anticancer prodrugs we synthesized can kill cancer cells selectivity. The main points and results of this thesis are as follows:(1) A DT-diaphorase responsive theranostic prodrug was designed and demonstrated. The theranostic prodrug containing an anticancer drug CPT, a cleavable linker and a quinone propionic acid moiety. In this theranostic prodrug, the anticancer drug CPT serves as the reporter of itself-release processe via the change of fluorescence signal. The prodrug shows good response to DT-diaphorase, and as a result of the response, active CPT released from the prodrug rapidly. In contrast with normal cells, the prodrug shows much higher cytotoxicity towards DT-diaphorase overexpressed cancer cells. This strategy may offer an approach for the development of enzyme-catalyzed theranostic anticancer therapeutics.(2) A light-activated small molecular theranostics prodrug was designed and demonstrated. The prodrug containing an anticancer drug CPT, a self-immolative linker and a light activated coumarin moiety. The fluorescence of coumarin and CPT is quenched by fluorescence resonance energy transfer(FRET). The DCM moiety shows red emission which can be used to visualize the drug localization before irradiation. The theranostics prodrug can be activated by blue light(> 400 nm, one-photon) and near infrared light(NIR, 800 nm, two-photon) irradiation. Upon irradiation, drug releasing can be monitoring via the turn-on fluorescence of CPT and coumarin. As a result, this system realize monitoring drug release processes via three fluorescence channel. The drug release processes can be regulated by light irradiation effectively. Our theranostics prodrug exhibited high controllable phototoxicity toward cancer cells.(3) A biothiol-activated 2,4-dinitrobenzenesulfonyl-based small molecular theranostics prodrug was designed and demonstrated. The prodrug consists of four parts: a 2,4-dinitrobenzenesulfonyl as biothiol responsive group, a CPT as pharmacophore, a DCM dye as fluorescence reporter and a self-immolative linker which links in front of three part together covalently. The fluorescence of CPT and DCM dye is quenched by 2,4-dinitrobenzenesulfonyl via photoinduced electron transfer(PeT) and intramolecular charge transfer(ICT). Upon exposure to GSH, CPT and DCM dye releasing from the prodrug simultaneously, which provide double fluorescence channel for drug release monitoring. The DCM release form the prodrug system can be used in one- and two-photon cells imaging for visualizing the drug release processes. The prodrug can be activated in cancer cells preferentially, and shows much higher cytotoxicity towards cancer cells, which lead to improve the therapy efficacy and reduce side effect.In summary, the theranostic prodrugs can realize real-time and visually monitoring drug release processes. The prodrugs show much higher cytotoxicity towards cancer cells rather than normal cells, which make them useful in improving the therapy efficacy and reducing side effect. Our strategies in this thesis may offer new approachs for design and application of theranostic anticancer prodrug.