Galactose Polymeric Based Nano-prodrugs And Their Applications In Anti-hepatoma Research

Liver cancer is the fourth common malignant tumor.It seriously threatens human life and health.Studies have shown that the surface of liver cancer cells specifically exposed the asialoprotein receptor(ASGPR),which could be used as a target for targeting liver cancer cells.Used the recognition between galactose and AGSPR,and combined with the characteristics of nanomedicines in improving the efficacy of drug treatment and reducing toxic and side effects,two kinds of liver-targeted nanoprodrugs were designed and prepared in this study,which have a response to the acidic environment and high levels glutathione(GSH)in tumor cells.It may be used for precise therapy of liver cancer.This paper mainly includes the following systems:(1)Regulation the self-assembly of amphiphilic galactose polymersUsing Reversible Addition-Fragmentation chain Transfer(RAFT)polymerization technology to obtain galactose polymer,regulate the number of galactose,and obtain three kinds of galactose macromolecules PGal25,PGal35,and PGal50 with different segment lengths.Three self-assemblies PGal25 D,PGal35D,and PGal50 D are obtained by connecting the same hydrophobic molecules at the end of polymer.Results showed that the self-assembly behavior of galactose polymers was affected by the proportion of hydrophilic and hydrophobic segments.In detail,with the increase of hydrophilic segments,the self-assembly changed from sphere to vermicular.(2)Reductive liver-targeted sugar-containing polymeric nanoprodrugsA doxorubicin prodrug was successfully prepared,which contained a disulfide bond self-eliminating linker;three reduction-responsed liver-targeted galatose polymeric nanoprodrugs were prepared.The drug loading amounts of PGal25 D,PGal35D,and PGal50 D were 6.6%,6.2% and 4.7%.Through the cell uptake studies,PGal25 D had the better ability to enter HepG2 cells compared with COS 7 cells.Using PGal25 D as a drug carrier,it showed a smart release behavior in the condition of high level GSH.Within 24 h,the cumulative release rate of DOX in 10 mmol/L GSH PBS was 2.5 times higher than no GSH PBS.Compared with the survival rate of free DOX,PGal25 D increased 2.2 times in normal cells.(3)Core cross-linked triblock galactose polymeric doxorubicin nanoprodrugsA highly efficient and stable core cross-linked triblock galactose polymeric doxorubicin nanoprodrug(GPDs)was successfully prepared.The DOX prodrugis linked to glycopolymer via a portion of the fluorenyl group on the nonylphenylboronic acid,and the other part of the nonylphenylboronic acid crosslinked with each other to form the core.Taking GPD4 as an example,it had a good drug loading and performed excellent particle size stability.Its cumulative drug release rate in 72 hours increased 10-fold at both pH 5.5 and 10 mmol/L GSH condition.The study of cellular uptake and intracellular distribution showed that GPD4 rapidly entered the liver cancer cells and distributed in lysosomes,and then it disassembled into the nucleus within 24 hours.Cytotoxicity evaluation of GPD4 and free DOX showed that they had similar toxicity to each other at high concentrations;besides it significantly reduced the toxicity of free DOX to normal cells.