Design,Synthesis,and Biomedical Applications Of Multifunctional Anticancer Prodrug Molecules

In the treatment of cancer,chemotherapy is one of the most ubiquitous and economical treatments.Even if new treatments emerge in an endless stream,it will still be treated with combination chemotherapy because chemotherapy as a systemic therapy has advantages that other therapies do not have.However,chemotherapy has its severe liminations.Its target specificity is poor,causing toxic side effects on the normal tissues and organs of the body.It rarely cures metastatic solid tumors.Currently,chemotherapy is rarely used as an only monotherapy in clinic.Chemotherapy will be combined with radiotherapy,phototherapy,immunotherapy,and so on.In this thesis,we focus on the urgent need to improve the therapeutic effect of chemical drugs,design and synthesize two prodrug molecules.The first one is a targeting prodrug combined diagnosis and therapy.The later one is a type of multifunctional prodrugs with cascade cancer treatment containing chemotherapy and later immunotherapy.Chapter 1:A brief introduction to the status quo of cancer and traditional chemotherapeutic methods and the recent rise of chemical immunotherapy are reported.Moreover,a brief introduction to the status quo of the integration of treatment and the relationship between indole 2,3-dioxygenase and immunotherapy are summarized.Finally,the basis and research content of this thesis are elaborated.Chapter 2:We designed and synthesized a prodrug based on Gadolinuim complex for in vivo tumor imaging.We designed a prodrag(la)that contains the nmagnetic resonance imaging molecule Gd-DOTA,the targeting group biotin and the traditional chemotherapy drug camptothecin(CPT)and the disulfide bond of the GSH response.The structural properties of the prodrug and the effect of tumor cell targeting and tuimor in vivo treatment were examined.The resul+ts show that the prodrugcan selectively target tumor cells and tissues,effectively release dr!gs through GSH,enhance anticancer effect,and can be accurately diagnosed and monitored in real time in vivo by magnetic resonance imaging.Chapter 3:We designed and synthesized two prodrug molecules,DOX-NLG and DOX-IND,combined with chemotherapy and immunotherapy.The prodrug molecule contains traditional chemotherapy drug Doxorubicin(DOX)and immunotherapeutic molecules,NLG919 or Indoximod,and the cleaved tetrapeptide responds to the apoptotic enzyme Caspase 3.The prodrug molecules first release the chemotherapeutic drug through the acid response and induce the cell apoptosis,which causes the h igh increase of expression of Caspase 3,thereby releasing the immunotherapeutic molecules.Therefore,there is a time interval between the action of the chemotherapeutic drug and the action of the immunotherapeutic molecules.This interval is determined by the apoptosis effect caused by the chemotherapeutic drug.We examined the structural properties and immunotherapeutic effects of two prodrug molecules by characterization experiments,response release experiments,cell experiments,and animal experiments.In vitro experiments have shown that prodrug molecules can efficiently release drugs in sequence in the desired response.In vivo experiments showed that both prodrug molecules showed superior immunotherapeutic effects compared to the combination of free chemotherapic drugs and immunologic molecules.In a word,this paper focuses on how to improve the anticancer activity of drug molecules.We have established a platform for the integration of diagnosis and treatment at the level of small molecules,and explored the effects on anticancer and its mechanism.after apply of chemotherapy and immunotherapy sequentially.