Ferritin-Mannose纳米粒通过糖代谢影响乳腺癌放疗敏感性及其机制研究

放射治疗是乳腺癌常规治疗手段，而乳腺癌的放射抵抗作用限制了放射治疗的广泛应用。铁蛋白(Ferritin)是一种普遍存在细胞内的铁储存蛋白，其重链（FTH1）亚基能够自组装成纳米级药物载体，且具备良好的生物相容性、降解性和低毒性。肿瘤细胞的糖代谢异常是其主要特征之一，我们前期研究发现甘露糖能增强电离辐射对乳腺癌的抑制作用；电离辐射可使乳腺癌细胞内磷酸甘露糖异构酶（PMI）的表达水平减少。本项目将在预实验研究的基础上，拟采用原核表达FTH1构建铁蛋白包裹甘露糖的纳米粒（Ferritin-Mannose）；进而采用体外细胞和体内动物模型深入研究Ferritin-Mannose在乳腺癌放射敏感性中的作用及分子机制。研究结果无疑为提高乳腺癌放射敏感性及临床放射治疗效果提供新的理论和实验依据。因此，本研究无论对提高临床乳腺癌放射治疗疗效和预后评估的基础研究以及临床应用研究都具有重要的价值和意义。

Breast cancer is the most common malignancy in the world. In china, the morbidity and mortality of breast cancer ranks first in terms of female tumors. Radiotherapy is one of the frequently-used methods for breast cancer. However, the radioresistance of breast cancer limits the clinical application of radiotherapy. A common feature of cancer cell metabolism is the ability to acquire necessary nutrients from a frequently nutrient-poor environment and utilize these nutrients to both maintain viability and build new biomass. Altered glucose metabolism is common in cancer. Otto Warburg observed a peculiar phenomenon in 1924, which tumor cells derived the energy required for uncontrolled replication from proteolysis and lipolysis, not to rapidly consume glucose, converting it to lactate. The significance of this finding is termed the Warburg effect. Accordingly, the development of specific molecular blockers targeting abnormal glucose metabolism in cancer cells can starve the cancer cells to death through reducing the intake of glucose by cancer cells, which make little effect on normal cells. Mannose is not only a kind of monosaccharide, but also a kind of six-carbon sugar, which is an isomer of glucose. It has been reported that mannose plays an important role in the glycosylation of some proteins. Mannose shows the inhibitory effect of on tumor cells depends on the expression level of intracellular mannose phosphate isomerase (PMI). In our preliminary studies, we found that mannose was able to reduce the radioresistance of breast cancer cell for gamma irradiation. The mRNA and protein expression level of PMI in MCF-7 cells and MDA-MB-231 cells treated with 2Gy γ-ray radiation were tested using qRT-PCR and Western blot. We found that the expression level of PMI was decreased in these cells after 2Gy γ-ray radiation, which provided potential evidence that mannose might improve the radiation sensitivity of breast cancer cells. So, we speculate that mannose may regulate the radiosensitivity of breast cancer through glucose metabolism pathway. However, mannose can also be absorbed by normal cells when it is used in animal models and even human bodies. Because the expression level of PMI in normal cells is lower compared to cancer cells, mannose can affect the glucose metabolism pathway of normal cells. Therefore, mannose must be specifically targeted into tumor cells in order to prevent normal cells from being affected. Ferritin is a ubiquitous multi-subunit iron storage protein formed by 24 polypeptide chains. Functionally, ferritin performs iron sequestration and is highly conserved in evolution. As an endogenous protein, ferritin is able to self-assemble into a hollow, roughly spherical protein cage and has good biocompatibility, biodegradability and low toxicity, which are very ideal properties of nano-carriers in clinical application. Moreover, the heavy chain binding receptor-transferrin receptor 1 (TFRC) of ferritin is highly expressed in many kinds of tumor cells, including breast cancer. This provides a theoretical basis for using ferritin as a carrier to deliver mannose into breast cancer. In this study, we propose to prepare encapsulation of mannose with ferritin (Ferritin-Mannose) and investigate the critical effect of Ferritin-Mannose on radiosensitivity of breast cancer and its molecular mechanism in vitro and in vivo. Our coming results will provide a new approach for radiosensitivity of breast cancer.