The Design,Synthesis And Research Of Tumor Targeting Fluorescence Probe And Bioreductive Prodrug

The improving of targetability plays a key role in the tumor diagnosis and therapy.It can not only help to make more promptly,accurate and sensitive diagnosis of the generation,proliferation,canceration and metastasis,but also improve the therapeutical effect,survival rate and cure rate of patients.Usualy there are two strategies to improve the targetability,including active targeting and passive targeting.For the active targeting strategy,there are a lot of targets that have been studied,such as protein/peptide receptors,antibodies,folate receptors and lectins.Asialoglycoprotein receptor(ASGPr),a natural lectin existing in human body,is a specific target on the surface of hepatoma cells.For the passive targeting strategy,hypoxia in tumor tissues can be the target for drug delivery.The hypoxia-activited prodrugs can produce cytotoxic molecules through metabolisation under hypoxia condition,thus to achieve the targeted releasing of drug.The studies in this thesis are related to two fields,including fluorescence tumor probe and bioreductive anti-tumor prodrug,described brieftly as the following:1.Three kinds of positively charged conjugated polyelectrolyte composed of poly(para-phenyleneethynylene)backbone,galactose-attached side chains and quartenary ammonium-including side chains with different lengths have been synthesized,their physical properties have been characterized and their biological application have been researched.Three polymers all exhibit excellent optical properties and low cytotoxicity;they have the ability of adhering to Hep G2 hepatoma cells specifically and can only weakly adhere to cells with low ASGPr expressing such as He La,sh-ASGPr and A549,thus to achieve the distinguish Hep G2 from other cells and to prove the targeted marking ability of the polymers in the tumor cell imaging.The mechanism of the adhering between polymers and Hep G2 cells has also been researched through the fluorescence polarization experiment,the fluorescence quenching-recovery experiment,the galactose-polymer competitive cell imaging and the determination of sugar content of polymers.The results above show the potentiality of our polymers as in vivo cell imaging probes.2.Meanwhile,six kinds of small molecules with nitrified heterocycle group have been designed as prodrug bilding blocks,and two of them have been used in the modification of four deoxynucleoside(d T,d A,d C,d G)to synthesize nucleoside as monomer in the synthesis of bioreductive oligonucleotide prodrugs.During the synthesis progress,a “one pot” method with high yield and low side reaction rate has been developed for the preparation of nucleoside monomers.Oligonucleotides with modifications at different mucleoside positions have also been designed for the evaluation of their bioactivity.