Study On The Nanomicelles Based On A Boronate Ester-linked Diblock Copolymer

Cancer has become one of the major diseases affecting human health and life. There are a variety of therapeutics against cancer, including surgery therapy, radiation therapy, chemotherapy and biological treatment. Conventional chemotherapy has achieved great success in cancer therapy but remains limited by drug resistance and other side effects. To overcome these limitations, substantial efforts has been devoted to the development of anticancer drug delivery carriers because of their prolonged circulation time and high passive targeting ability to tumor sites via the enhanced permeability and retention (EPR) effect. For cancer therapy, it is desirable to achieve a sufficient drug concentration at tumor tissues, which may enhance the therapeutic efficacy and reduce the probability of drug resistance in cells. Therefore, various stimuli-sensitive drug carriers have been designed in recent years based on the physiological properties of the tumor microenvironment or the expression of tumour-associated receptors. The difference in the pH value between tumor and normal tissue is often used as a stimulus factor. The pH at both primary and metastasized tumors (pH 6.6-6.8) is slightly lower than the pH of normal tissue (pH 7.35-7.45), and intracellular components such as the endosomes (pH 6.0-6.5) or lysosomes (pH 5.0-5.5) are more acidic. Previously designed pH-sensitive carriers are relatively stable in normal blood circulation but can degrade when they accumulate at target tumours.In this thesis, the research process of the drug delivery system has been discussed and the theory of its anti-tumor therapy has been introduced in the first chapter. We described recent advances in nanocarriers and their payload in clinical and preclinical study. In Chapter Ⅱ, the formation of PEG-BC@PBLG micelles was confirmed based on critical micelle concentration (CMC), particle size, and morphology observations. It was observed that these micelles were spherical with an average particle size of approximately 80 nm, as measured by dynamic laser scattering (DLS), suggesting their passive targeting to tumor tissue and endocytosis potential. Dox-loaded PEG-BC@PBLG micelles (PEG-BC@PBLG·Dox) showed sustained drug release profiles over 9 h, and their cumulative drug release was dependent on the pH value of the environment. Remarkably, cellular uptake ability of PEG-BC@PBLG micelles was found to be higher than that of non-boronate ester-linked PEG@PBLG micelles due to boronic acid-mediated endocytosis, as revealed by confocal laser scanning microscopy (CLSM) imaging of fluorescein isothiocyanate (FITC) green-conjugated micelles, thereby providing higher cytotoxicity against HepG2 cells. The antitumor activity and toxicity of PEG-BC@PBLG·Dox micelles in vivo were evaluated in BLAB/c mice against HepG2 cell-derived tumors. Compared with Dox, PEG-BC@PBLG·Dox showed reduced toxicity, whereas its tumor growth inhibition rate was 17% higher than that of free Dox. These results indicate the great potential of PEG-BC@PBLG micelles as a carrier of various lipophilic anticancer drugs with improved anti-tumor efficacy.