Construction Of A Nanodrug For Antibacterial And Combined Chemotherapy And Its Application In The Treatment Of Fusobacterium Nucleatum-induced Drug-resistant Colorectal Cancer

Colorectal cancer(CRC)is considered to be a major disease affecting human health and quality of life,and its incidence ranks third among all cancers.Chemotherapy is still the main treatment for most CRC patients.However,single drug therapy,such as 5-fluorouracil(5-FU)or oxaliplatin(OxPt),has some disadvantages,such as high dose,rapid metabolism in vivo,strong side effects and so on.Even the combination of 5-fluorouracil and oxaliplatin(FOLFOX)can not improve the above problems of chemotherapeutic drugs in treatment.At the same time,Fusobacterium nucleatum(Fn),which exists widely in CRC,can cause significant resistance of CRC to 5-FU and OxPt.In addition,the existence of Fn can induce autophagy of tumor cells,thus protect tumor cells and reduce the damage caused by chemotherapeutic drugs,which increases the difficulty of treatment of CRC.Therefore,it is necessary to design an integrated drug delivery system with both antibacterial and anti-tumor to reverse drug resistance and enhance the therapeutic effect.Based on this,we introduced long-chain fatty acid lauric acid(LA),which can selectively eliminate Fn,as an antibacterial agent to reverse the drug resistance of CRC induced by Fn.In this strategy,hyperbranched poly glycidyl ether(Pg)was used as the skeleton,LA and OxPt were grafted onto Pg by esterification to form a polymer Pg-Pt-LA which could be self-assembled in water,and then 5-FU-LA,a derivative of5-FU,was coated to form a nano-micelle 5-FU-LA@PPL loaded with 5-FU and OxPt.Dynamic light scattering(DLS)and scanning electron microscopy(SEM)showed that the average diameter of the nano-micelle was about 219 nm,which could be enriched in the tumor site through enhanced permeation and retention effect(EPR)to reduce the toxicity and side effects of the drug.The results of ICP-MS and ultra-micro ultraviolet spectrophotometer showed that the nano-micelle had high drug loading and stable drug release behavior.The antibacterial experiment in vitro showed that the nano-drug could selectively eliminate Fn,but had almost no killing effect on Escherichia coli(E.coli)and Clostridium butyricum(C.butyricum).In vitro experiments showed that the nano-micelles could effectively reduce the survival rate of CRC cells and successfully reverse the CRC drug resistance induced by Fn.In addition,the AO staining results of HCT116 cells showed that the nano-drug could inhibit autophagy of CRC cells and enhance the therapeutic effect of CRC.Finally,in vivo experiments in mice further confirmed that 5-FU-LA@PPL nano-micelles have good biosafety,significant anti-tumor activity,and can effectively reverse the drug resistance caused by Fn.The above experimental results prove that we have successfully prepared a combined drug delivery system with both antibacterial and anti-tumor,and this strategy of combining antibacterial molecules and chemotherapy to reduce the drug resistance of cancer cells has great potential in the treatment of bacteria-related drug-resistant tumors.