| Colorectal cancer（CRC）is the third highest incidence of cancer in the world.For patients with advanced CRC,chemotherapy is still the main treatment.However,one of the main reasons for the poor chemotherapy of CRC is the drug resistance of tumor cells.At present,a large number of studies have shown that Fusobacterium nucleatum（Fn）at CRC site can be enriched into the tumor microenvironment to regulate autophagy so as to promote tumor cells to become resistant to chemotherapeutic drugs,resulting in unsatisfactory chemotherapeutic effects.At the same time,the use of traditional chemotherapy drugs alone has shown many shortcomings,such as poor solubility,financially-challenged targeting,toxic side effects and so on.Therefore,by making use of the different characteristics of the microenvironment of normal cells and tumor cells,the design and development of nano-carriers with different stimulus responses is a feasible method for cancer treatment.Based on this,we designed a covalent bond between biodegradable polyaspartic acid derivative（PAsp）and nitric oxide donor,modified azophenyl group with azoreductase response,and co-assembled it with 5-fluorouracil derivative 5-FU-LA,a chemical drug modified by selective antibacterial component,to prepare nano-system5-FU-LA@PSA.The synthesis of polymers and small molecular drugs was characterized by 1H NMR and UV-vis absorption spectra.In addition,the observation of dynamic light scattering（DLS）and scanning electron microscope（SEM）showed that the 5-FU-LA@PSA nanosystem was a spherical structure with a diameter of about200 nm.At the same time,the release of NO from the solution was determined by Griess method,and the azo reductase was used to simulate the drug release by Na2S2O4,which demonstrated the tumor-microenvironment-responsive release characteristics of the nano-system.Through the plate counting method,it is proved that the nano-system has a good growth inhibitory effect on Fn.Finally,the experiments of biocompatibility of L929 and co-culture of three different CRC cells with Fn bacteria show that our nano-system has good biocompatibility and excellent anti-tumor performance.The nanosystem can respond to the tumor hypoxic microenvironment and overexpressed glutathione,and selectively release the therapeutic gas nitric oxide,chemotherapeutic drug 5-fluorouracil and antibacterial agent LA in the tumor area,so as to effectively reverse the drug resistance of colorectal cancer caused by Fusobacterium nucleatum and achieve an efficient combination of gas therapy and chemotherapy.The construction of this responsive nanosystem effectively overcomes the drug resistance to chemotherapy and provides new ideas and methods for overcoming the drug resistance caused by bacteria. |
