Biomedical Applications Of Anticancer Prodrug Based On Mitochondrial Apoptosis Strategy

As the most threatening cancer among east Asia population,hepatic carcinoma has become a worldwide challenge for life science researchers.Even though general cancer mortality has been plummeting in the last two decades,mortality of hepatic carcinoma still bucked that trend.The underlying reason of this difficulty can be ascribed to the lacks the chemotherapeutic strategy:The first generation of chemotherapy drugs were demonstrated incapable in overcoming both high-level intrinsic or acquired resistance of hepatoma carcinoma cell,Meanwhile,most published clinical research of systemic chemotherapy ended up in low response rates.Hence one can see the necessity and urgency to develop novel chemotherapy drugs with both good therapeutic effect and biocompatibility.To meet the requirement,this study develop two kinds of novel chemotherapy prodrugs,t-AsPt and t-AsDox.The prodrugs were all developed based on clinically approved chemotherapeutics,cisplatin and doxorubicin.We proposed a efficacy enhancement strategy aimed at triggering mitochondrial dysfunction,and innovatively employed a mitochondrial-targeting arsenic functional group.This molecular designing endowed the prodrug with capacity to initiated a mitochondria mediated apoptosis pathway and better anti-tumor activities.Chapter 1 will be a brief introduction of the cancer disease.In especial the challenge of liver cancer therapy.Moreover,the developing history of arsenic compound in drug is mentioned.We will also elaborate biological mechanism of apoptosis and mitochondrial mediated apoptosis pathway.Chapter 2 will focus on the prodrug design.We will describe the consideration factor during designing of t-AsPt and t-AsDox,including molecular screening,response mode selection and targeting ability evaluation.Some in vivo experiment will be involved to monitor the cellular behavior of the prodrug.Chapter 3 will be a systematic assessment for antitumor efficiency.The evidence will span from sub-cellular level to xenograft tumor bearing mouse.Several aspect will be mentioned in this chapter to prove a mitochondrial mediated apoptosis process,including ROS,mtDNA,mitochondrial membrane potential and Cyt-C.Chapter 4 will discuss pharmacological mechanisms of t-AsPt.Combining traditional molecular biology methods and novel bioinformatics approach,we further demonstrated regulation of key protein.An integrated pathway mapping will also be provided at the end of this chapter.In a word,this study design an activatable mitochondrial-targeting organoarsenic prodrugs for bioenergetic cancer therapy while demonstrated mitochondrial-mediated apoptosis pathway could be a new method in therapy of liver cancer.