1. 研究目的与意义
我国癌症疾病发病率高，影响面广，已成为严重危害国民健康的主要疾病之一，医药行业多年的研究发现，许多单体药物在抗肿瘤方面均具有一定的作用，而近现代研究表明，许多单体抗肿瘤药物通过联合载药可以达到不同于单体药物发挥的治疗作用，多药联合纳米药物系统有时可以高效的调节药物在肿瘤细胞中的分布，提高抗癌药物的靶向性，从而达到更好的治疗效果。
而如何发挥联合载药的靶向性，要通过药物本身的性质和联合用药的方法来实现。
阿霉素是临床化疗的一线用药，但其毒副作用较大。
2. 文献综述
参考文献：[1] 张波, 张娜. 纳米载体共递送化疗药物用于肿瘤联合治疗的研究进展.中国新药杂志, 2014, 23(21): 2514-2520.[2] 许秀丽, 黄园.联合用药在抗肿瘤纳米递药系统中的应用.华西药学杂志, 2014,29(6):720-722.[3] Huxford, R. C., et al. . Metal-organic frameworks as potential drug carriers. Curr Opin Chem Biol 2010 14(2): 262-268.[4] Carne, A., et al.. Nanoscale metal-organic materials. Chem Soc Rev 2011. 40(1): 291-305.[5] Taylor, J. M., Mahmoudkhani, A. H., Shimizu, G. K. H. A tetrahedral organophosphonate as a linker for a microporous copper framework[J]. Journal of Controlled Release, 2007, 46 (5): 795-798.[6] Liu,Y.,Eubank,J.F.,Cairns, A. J., etc.Assembly of metalorganicframeworks (MOFs) based on indium-trimer building blocks: a porous MOF with soc topology and high hydrogen storage[J]. Journal of Controlled Release, 2007, 46 (18): 3278-3283.[7] Kitagawa,S.,Kitaura,R., Noro,S.Functional porous coordination polymers [J]. Journal of Controlled Release, 2004, 43 (18): 2334-2375.[8] Shekhah,O.,Wang,H.,Paradinas,M.,etc.Controlling interpenetration in metalorganic frameworks by liquid-phase epitaxy[J]. Nature Materials, 2009,8 (6): 481-484.[9] Gould, S. L., Tranchemontagne, D., Yaghi, O. M., etc. Amphidynamic character of crystalline MOF-5:rotational dynamics of terephthalate phenylenes in a free-volume, sterically unhindered environment[J].Journalof the AmericanChemical Society, 2008, 130 (11): 3246-3247.[10] Gerweck, L. E., Seetharaman, K. Cellular pH gradient in tumor versus normal tissue:potential exploitation for the treatment of cancer[J]. Cancer Research, 1996, 56 (6):1194-1198.[11] Hunt, C. A., MacGregor, R. D., Siegel, R. A. Engineering targeted in vivo drugdelivery. I. The physiological and physicochemical principles governing opportunities and limitations[J]. Pharmaceutical Research, 1986, 3 (6): 333-344.[12] Bolot, G., David, M., Taki, T., etc. Analysis of glycosphingolipids of human head and neck carcinomas with comparison to normal tissue[J]. IUBMB Life, 1998, 46 (1):125-135.[13] Geisow, M. J., Evans, W. H. pH in the endosome: measurements during pinocytosis and receptor-mediated endocytosis[J]. Experimental Cell Research, 1984, 150 (1): 36-46.[14] Gillies, R. J., Raghunand, N., Garcia-Martin, M. L., etc. pH imaging[J]. IEEE Engineering in Medicine and Biology Magazine, 2004, 23 (5): 57-64.[15] Mellman, I., Fuchs, R., Helenius, A. Acidification of the endocytic and exocytic pathways[J]. Annual Review of Biochemistry, 1986, 55 (1): 663-700.[16] Tannock, I. F., Rotin, D. Acid pH in tumors and its potential for therapeutic exploitation[J]. Cancer Resarch, 1989, 49 (16): 4373-4384.[17] Dautry-Varsat, A., Ciechanover, A., Lodish, H. F. pH and the recycling of transferrin during receptor-mediated endocytosis[J]. Proceedings of the National Academy of Sciences of the United States of America, 1983, 80 (8): 2258-2262.[18] Liu, D., et al.Self-assembled nanoscale coordination polymers with trigger release properties for effective anticancer therapy.Nat Commun 2014.5: 4182.[19] Frasconi, M., et al.Photoexpulsion of surface-grafted ruthenium complexes and subsequent release of cytotoxic cargos to cancer cells from mesoporous silica nanoparticles.J Am Chem Soc 2013.135(31): 11603-11613.[20] Ruiz-Sanchez, P., et al. Vitamin B(1)(2) as a carrier for targeted platinum delivery: in vitro cytotoxicity and mechanistic studies.J Biol Inorg Chem 2011.16(1): 33-44.
3. 设计方案和技术路线
1、 查阅文献，了解联合给药的优势与创新性2、筛选联合载药模型药物，了解阿霉素的性质和抗肿瘤作用，发现其临床应用上的缺陷，结合姜黄素在抗肿瘤方面的应用，将两药进行联合，从而达到联合用药的目的3、制备联合载药纳米粒，,通过初步考察阿霉素和姜黄素的理化性质，研究实现载药纳米粒的最终制备方法4、肿瘤细胞的选择与培养5、模型药物单一给药细胞毒性的研究：通过阿霉素和姜黄素的单一给药，来了解单一药物的毒性研究，从而印证联合给药的合理性6、协同抑瘤效果研究：基于单一给药的毒性研究，进行药物联合给药的实验，对比单一给药的实验结果，从而确认联合给药的抑瘤效果
4. 工作计划
2022/01/04~2022/01/15完成了文献查阅，初步了解了联合载药，筛选了模型药物2022/01/16~2022/01/31筛选了载体材料，制备了联合载药纳米粒2022/02/18~2022/03/10确定了协同抑瘤效果研究的方案
5. 难点与创新点
针对临床化疗存在的问题，引出联合载药。
利用铜，来实现药物的共传递。
由于肿瘤的酸性，铜的存在可以实现pH响应，在肿瘤部位释放。
