| Due to short half-lifes, antitumor drugs need to be frequently administered for chemotherapy. The inhibitory effect of antitumor drugs on tumor growth can be improved by frequent dosing, whereas the plasma concentration would increase exponentially, leading to serious systemic side effects and susceptibility of drug resistance. Gene therapy is the delivery of a target gene into the body's cells or tissues through a carrier system, and the expression of curative products would play the role of curing diseases in the body. Because of the synergistic effects of genes and drugs, combination chemotherapy is expected to reduce the dose of chemotherapy drugs, reduce the side effects, reverse drug resistance phenomenon in tumor, and improve the sensitivity of tumor cells to chemotherapy drugs. On the other side, the use of chemotherapy drugs can improve the efficiency of gene expression in tumor cells, induce death receptor activation and trigger apoptosis mechanism further.One of the key technologies for gene therapy is to establish an efficient and safe gene carrier, with low side effects. Polyethyleneimine (PEI), as one of the most typical cationic polymer, has been widely used as a carrier of gene transfection, but its cytotoxicity, blood compatibility and other disadvantages restrict its further applications. As direct application of PEI in the body would lead to the accumulation of red blood cells and nonspecif binding with blood albumin, leading to the formation of supermolecules, PEI modification is warranted for gene delivery.The spatial structure of ?-cyclodextrin makes it recognize a series of substrates and form inclusion complex in aqueous solution. Because of its low cost and good biocompatibility, ?-cyclodextrin has been widely recognized as an important host molecule in supramolecular chemistry and applied in a series of areas, such as catalysis, self-assembly, molecular recognition, and drug transport.In this thesis p53/BPEI-?-CD/AD-DOX complex was fabricated and employed to investigate the interaction manner between p53 and doxorubicin (DOX). Briefly, branched polyethylenimine (BPEI) was conjugated with ?-cyclodextrin hydrate (?-CD) to form BPEI-?-CD backbone, and p53 plasmid was condensed by positively charged BPEI via electrostatic interaction, while Dox was first conjugated with adamantine and then assembled with BPEI-?-CD backbone via the host-guest interaction. It was found that the BPEI-?-CD backbone possessed high endocytosis efficiency but low cytotoxicity. Moreover, p53/BPEI-?-CD/AD-DOX complex released DOX and enabled the expression of p53 gene in a sequential manner, and the released DOX and expressed p53 gene showed successive inhibition of the growth of HeLa cells in vitro. With the ability to co-deliver chemical drug and therapeutic gene and exert their inhibitory actions on tumor cell growth in a sequential manner, this DNA/BPEI-?-CD/AD-drug complex via electrostatic interaction and host-guest assembly not only achieved long-term efficacy in inhibiting tumor cell growth but also can be employed as a platform to investigate the coordination pattern between chemical drugs and therapeutic genes for other purposes. |
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