| Although advances had been made among tumor biology and chemo-therapy fields, cancer is still a prevalent and lethal disease. During the treating process, the major obstacles are complex structures of malignant cells, multiple drug resistance, small anticancer molecules toxic to normal cells etc.. With the research doing, scientists discover that nanoscale particles could be wildly employed as one of drug deliveries to improve the antitumor efficiency. Due to the development of nano-technology, a salvo of nano-systems not only owned the ability of drug delivery, but also had smart functions, such as p H sensitiveness, target properties etc., at the time of improving tumor inhibition, could reduce side effects at best.In this thesis, using greatly biocompatible polysaccharides, dextran, as main chain, benzimidazole molecules have been grafted on dextran(benzimidazole-g-dextran), which as backbone, designed polymer based nano-sized drug delivery materials to inhibit tumor cells. The thesis includes following three parts:1. Benzimidazole-g-dextran(Dex-g-BM) has been successfully synthesized by one step method. This kind of amphiphilic material owned p H sensitiveness which could be used as intracellular drug delivery. Through NMR, IR, we confirmed the chemical structure of Dex-g-BM including ratio of grafting. TEM, DLS, CMC, in vitro release as well as intracellular assays demonstrated its p H sensitiveness. Amphiphilic Dex-g-BM could be self-assembly under p H 7.4 conditions and be regarded as drug holdings; and under acidic(p H=5.3) conditions, amphiphilic polymer could expand or even dis-assembly to achieve drug release behaviors. This kind of nano-sized drug delivery fits the ability that holding drugs under physiological environments and rapidly release drug in the vicinity of malignant cells, which could be employed as a smart drug delivery for tumor inhibition.2. The introducing of thiol-β-cyclodextrin molecules was attributable to successful synthesis of nanogels, which were made up of supramolecular crosslinked Dex-g-BM. This kind of nanogels owned dual sensitive extent, which could significantly improve the efficiency of tumor inhibition. Due to the combination of thiols under p H 7.4 conditions to achieving disulfide bonds. Having happened supramolcular interactions between β-cyclodextrin and benzimidazole, nano-micelles of Dex-g-BM could be crosslinked to form nanogels. The functions of crosslinking not only improve the stability of nanogels, but also improve the capacity of drugs. Through in vitro release and intracellular experiments indicated, under low p H conditions and presenting GSH, generally regarded as tumor cells nearby, the break of disulfide bonds promote the expanding of nanogels, or even dis-assembly to efficiently release drugs. This dual responsive(p H and GSH) supramolecular nanogels for intracellular drug delivery not only are biocompatible but also reduces tumor growing ratio.3. The effect of tumor inhibition is one of the evaluation factors among drug deliveries. To improve the efficiency of tumor inhibition, we not only used smart molecules, but also introduced photosensitizer for achieving photo-dynamic therapy. The synergistic therapeutics of chemo-photo dynamic therapy would show significant application future. We still used Dex-g-BM as backbone materials, by employing 3-carboxy-5-nitrophenylboronic acid to modify porphyrins for achieving photosensitizer to crosslink amphiphilic Dex-g-BM micelles. Due to the hydroxyl groups of dextran could be reacted towards phenylboronic acid to synthesize p H sensitive boronate esters. By using in vitro release and intracellular, we confirmed that this kind of nanogels, compared with sole chemotherapy, showed great advantages among synergistic chemo-photo dynamic therapeutics. |
PDF Full Text Request