| In recent years, breast cancer has become a major killer which threatened women's health and life, and its incidence continues to rise by 3% per year in China. The deterioration of modern living environment and increasing social stress led to breast cancer. Surgery, radiotherapy and chemotherapy are the major methods used in breast cancer therapy. Gene silencing, as an emerging technology, has been rapidly developed,which inhibits the expression and function of genes. Therefore,this technology shows promising preclinical potential. Breast cancer is correlated with multiple genes.Therefore, it is limited to silence single gene for therapy of breast cancer. In addition,breast cancer is not only a mammary gland disease,but also it will become a systemic disease with further development. Recently, chemotherapy is a common way to systemic treatment of breast cancer. But many factors will influence the effect of chemotherapy, and these are the main reasons which make the chemotherapy failure.Among these, multidrug resistance of breast cancer ranks the first. Therefore, it is of great significance to develop multiple genes simultaneous silencing and reduce the drug resistance of tumor cells for enhancing the therapeutic effect of breast cancer.Traditional delivery of genes and drugs has problems of low intake, uncontrolled release, and unreasonable distribution. As nanocarrier can increasing biological membrane permeability, adjust the release rate and prevent the degradation before they reach targets, the researches of nanocarrier for delivering genes and drugs are more and more widespread. Cobalt oxyhydroxide (CoOOH) and graphene oxide (GO) become ideal nanocarriers due to their easy modificability, well biocompatibility and huge specific surface for deliverying genes and drugs.Based on the above, we designed a series of nanocomposites for therapy of breast cancer. It mainly includes the following sections:1. We demonstrated a novel DNAzymes-based nanocomposite that can simultaneously silence three types of genes in living cells and in vivo. The nanocomposite composes of amino functionalized cobalt oxyhydroxide (CoOOH)nanoflakes modified by three DNAzymes that target to three different genes. When the nanocomposite encounters the intracellular glutathione (GSH), CoOOH was reduced to Co2+ ions, which can be employed as cofactors of 10-23 DNAzyme for gene knockdown. The nanocomposite exhibits great nuclease stability, low toxicity,high selectivity and good biocompatibility. The synergetic effect of three DNAzymes for corresponding mRNAs significantly enhanced the gene silencing efficacy, which can effectively inhibit the proliferation, migration and invasion of breast cancer cells, as well as inhibit tumor progression in vivo. The current approach could offer new insights in designing of multiplexed gene silencing systems for cancer therapy.2. We designed a drug-loaded nanosystem based on GO/MB. GO was modified with MDR1 MB and ETS1 MB, and Doxorubicin (Dox) was embedded into the stem of MB. Free Dox is also adsorbed on the GO for high drug loading purpose.P-glycoprotein (P-gp) on the cell membrane, encoded by the MDR1 gene, could cause drug efflux,and ETS1 as upstream of MDR1 can positively regulate the expression of MDR1. Therefore,simultaneously silencing two genes could inhibit the expression of P-gp much more effectively compared to only one, which will further reduce the efflux of Dox and increase the content of intracellular Dox to enhance the effect of chemotherapy. The drug-loaded nanosystem exhibits great selectivity, nuclease stability and good biocompatibility. And it solved multidrug resistance in breast cancer by effectively inhibiting the efflux of Dox. Compared with traditional chemotherapy, multimodal therapy that achieve the combination of gene therapy and chemotherapy has a better therapeutic effect. |
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