| Background:Colorectal cancer is one of the malignant tumors with most high incidence,accounting for third of the incidence and mortality of malignant tumors worldwide.Colitis associated colon cancer(CAC)is a special type of colorectal cancer,its occurrence and development are closely related to chronic colonic inflammation.Treatment of C57BL/6 mice with Azoxymethane(AOM)and dextran sulfate sodium salt(DSS)can simulate the pathogenesis of human CAC.Curcumin is extractive from curcuma longa,it has been reported to have extensive pharmacological activities,such as anti-inflammatory,anti-tumor and anti-oxidation.SN38 is the active metabolite of irinotecan(CPT-11),a clinical chemotherapeutic agent.It is reported that the cytotoxicity of SN38 is 1000 times higher than that of CPT-11.However,curcumin and SN38 had poor water solubility and low concentration in the lesion area,which seriously affected the clinical application prospects of these two drugs.Chitosan oligosaccharide is an oligosaccharide which is degraded by chitosan,it has good water solubility and easy to be absorbed and utilized by the organism.Chitosan oligosaccharide is often used as a nanomaterial to transport small molecule drugs,which can greatly improve the solubility and bioavailability of drugs,increase the drug concentration and retention in the focus,and improve the curative effect.It deserves to be further discussed that the utility of chitosan oligosaccharide combined with curcumin and SN38 in CAC mice models,and its improvement in efficacy and side effects.Purpose:To evaluate the prevention and treatment effects of nanodrugs,chitosan oligosaccharide-curcumin and chitosan oligosaccharide-SN3 8,in CAC mice models,and compare them with the traditional drugs,curcumin and CPT-11.To observe the general conditions and side efifects of mice during the treatment of nanodrugs,and investigate the synergistic effect of curcumin and SN38 on the treatment of CAC.Methods:The chitosan oligosaccharides were chemically combined with curcumin and SN38 respectively to produce nanodrugs.The CAC mice models were induced by treating C57BL/6 mice with AOM/DSS.Then,chitosan oligosaccharide-curcumin and chitosan oligosaccharide-SN38 were separately or jointly used in different stages of the mice CAC,and the curcumin oil solution and CPT-11 were used as control.The efficacy of nanodrugs was evaluated and compared by observing the mice survival rate,body weight and tumor phenotype statistics.In vitro study,the mouse macrophage line RAW264.7 was treated with curcumin and SN38,and the expression of inflammatory cytokines of RAW264.7 in different treatment conditions was detected by real-time polymerase chain reaction(qRT-PCR).Results:We first evaluated the preventive effect of drugs on CAC.Nanodrug chitosan oligosaccharide-curcumin was used in the chronic inflammation stage of CAC mice models,and the mice survival rate was 15.62%higher than that of the control group(100%vs 84.38%,P<0.05).The number and the sum length of the longest diameters of the colorectal tumors in mice were statistically analyzed after anatomy.The average number of tumors in the chitosan oligosaccharide-curcumin group was 4.50 ± 2.32,which was less than that of the CAC control group(6.81 ± 2.71,P<0.05)and the traditional drug curcumin oil solution group(6.82 ± 2.86,P<0.05).The average sum length of the longest diameters of tumors in the chitosan oligosaccharide-curcumin group was 11.67 ± 4.42 mm,which was less than that of the CAC control group(20.00± 7.88 mm,P<0.01)and the curcumin oil solution group(18.41 ± 6.60 mm,P<0.01).Then,we evaluated the therapeutic effects of nanodrugs on CAC and its side effects during treatment.After DSS withdrawal,the body weight of the two groups of mice treated with chitosan oligosaccharide-SN38 had gradually recovered,and the weight changes of these two groups of mice were 107.67 ± 1.94%and 108.10 ± 2.21%on the 26th day of the treatment,which was approximately equal to that of the control group(107.45 ± 1.03%),while the body weight of the CPT-11 group of mice did not recover(101.71 ± 2.11%,P<0.05).The number and the sum length of the longest diameters of the colorectal tumors in mice were statistically analyzed after anatomy.The average number of tumors in the chitosan oligosaccharide-SN38 group was 2.83 ± 1.47,which was less than that of the CPT-11 group(4.17 ± 1.59,P<0.05).The average sum length of the longest diameters of tumors in the chitosan oligosaccharide-SN38 group was 6.00 ± 2.11 mm,which was less than that of the CPT-11 group(12.42 ± 5.48 mm,P<0.01).The combination of chitosan oligosaccharide-curcumin and chitosan oligosaccharide-SN38 was used in different stages of mice CAC,which could further improve the prevention and treatment efficacy of nanodrugs.The average number of tumors in the two drugs combined group was 1.75 ± 0.87,which was less than that of the single use of chitosan oligosaccharide-curcumin group(4.50 ± 2.32,P<0.01)and the single use of chitosan oligosaccharide-SN38 group(2.83 ± 1.47,P<0.05).The average sum length of the longest diameters of tumors in the two drugs combined group was 3.46 ± 1.92 mm,which was less than that of the single use of chitosan oligosaccharide-curcumin group(11.67 ± 4.42 mm,P<0.001)and the single use of chitosan oligosaccharide-SN38 group(6.00 ±2.11 mm,P<0.01).Chitosan oligosaccharide was labeled with infrared fluorescent dye Cyanine5.5 amine(Cy5.5),which was given to CAC mice by once gavage.Then mice was observed in the near infrared deep fluorescence imaging system,nanodrugs was obviously distributed in the digestive tract of mice,other organs had less intake of drugs,and specific drug concentration could be seen in colorectal tumor sites.Furthermore,curcumin could reduce the expression of inflammatory cytokines IL-1?,IL-6,IFN-? and iNOS in RAW264.7 cells and inhibit the transformation of macrophages into M1 type in vitro.The combination usage of curcumin and SN38 could reverse the increase of inflammatory cytokines IL-1?,iNOS,TNF-? and CXCL11 induced by SN38 treatment.Conclusion:Chitosan oligosaccharide-curcumin and chitosan oligosaccharide-SN38 had better prevention and treatment efficacy than traditional drugs,as well as lighter side effects and better security and tolerability.Moreover,the synergistic effect of curcumin and SN38 on CAC treatment was further confirmed in vitro.The research and application of nanodrugs provide a reliable strategy for improving the efficacy of inflammatory bowel diseases(IBDs)and CAC. |
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