The Application Of Targeted Nanomedicine Towards The Treatment Of Inflammatory Bowel Disease And Colon Cancer

Nowadays,the incidence of inflammatory bowel disease(IBD)is increasing rapidly.With respect to its repeated episodes and low curative rate,IBD has been considered as a serious harm to public health.The common drugs used in clinic treatment of IBD have seriously side effects.Therefore,it is urgent to develop new drug formulations.Curcumin(CUR),extracted from a nature root of plant curcuma langa,has been received increseasing attention as a promising drug for IBD treatment due to its numerous merits,including the limited side effect,antioxidant,anti-inflammatory.Importantly,previous studies demonstrated that CUR is relatively safe to humans.Hence,CUR is gradually being used in IBD treatment.However,the low solubility in aqueous solutions and low bioavailability of CUR restricted its application.Colon cancer is one of the third most common malignant tumors.It has high morbidity and mortality.Therefore,how to effectively cure colon cancer has become a research hotspot all over the world.Chemotherapy,radiotherapy and surgical resection are usually employed in cancer treatment.Among them,chemotherapy has been considered as the most effective therapeutic strategy for colon cancer.Camptothecin(CPT)is a hydrophobic alkaloid which is extracted from the pleasant tree.It has very strong anti-tumor activities against a variety of tumors,including colon cancer,lung cancer and breast cancer.In principle,CPT converts topoisomerase I into a cellular poison by inhibiting the progression of the replication fork,resulting in cell death.Although CPT has a strong preclinical antitumor activity,its clinical application is limited by its low therapeutic efficacy and toxicity to healty tissues.Nanoscale drug delivery system can achive improved solubility of poorly water-soluble drug,sustained drug release and extended the circulation time of drug in the body,as well as enhanced drug accumulate by passive targeting to the disease region.These benefits significantly reduce the side effects of chemotherapeutic drugs.Therefore,nanoscale drug delivery system has been recognized as a potential treatment strategy.In this study,active targeted nanoparticles(NPs)with CUR or CPT were fabricated for the treatment of IBD or colon cancer,respectively.The research contents include the following three sections:In the first section,CUR-loaded poly(lactic acid/glycolic acid)copolymer(PLGA)-based NPs were prepared.Then their surface was further modified by chondroitin sulfate(CS)or carboxymethyl cellulose(CUL),respectively.These NPs were respectively termed as CS-CUR-NPs and CUL-CUR-NPs.Subsequently,their physicochemical characteristics were investigated.The above results showed that their particle size ranged from 281.5 nm to 293.4 nm.These NPs were a slight negative-charged and spherical with regular appearance.X-Ray Diffraction(XRD)results also indicated that CUR was effectively packaged into NPs with amorphous state.Drug release experiments showed that CPT could be released from NPs in a constant manner.Cell experiments further demonstrated that neither of the two NPs had obvious toxic to Raw 264.7 macrophages,and the cellular uptake profiles of CS-CUR–NPs were significantly higher than that of CUL-CUR–NPs.As to the anti-inflammatory effect,CS-CUR-NPs can effectively inhibit the production of proinflammatory cytokines and had much better anti-inflammatory effect compared with CUL-CUR-NPs.Dextran sodium sulfate(DSS)induced IBD mouse model was used in the in vivo animal experiment,the therapeutic effect of CS-CUR-NPs and CUL-CUR-NPs were evaluated in the respect of mice weight,spleen weight,colon length,MPO and H&E staining.The results clearly indicated that CS-CUR-NPs showed much better therapeutic efficacy than CUL-CUR-NPs.The above experiments collectively suggested that the surface functionalization of CS can improve the therapeutic efficacy of CUR-loaded in the treatment of IBD.In the second section,the CPT-loaded PLGA NPs were fabricated using the emulsion solvent evaporation method.Their surface was further modified by CS or CUL,and defined as CS-CPT-NPs and CUL-CPT-NPs,respectively.Physicochemical characterization showed that the particle sizes of these two nanoparticles are 289.6 nm and 287.4 nm,respectively,and the value of polydispersity index(PDI)is much smaller than 0.3.The surface of both NPs was a slight negative charge.In comparison with the CUL-CPT-NPs,CS-CPT-NPs had significant stronger anticancer activity in the in vitro and in vivo experiments.The above experiments indicated that the surface functionalization of CS can achieve the tumor-targeted drug delivery and further improve the therapeutic efficacy of CPT against colon cancer.This may provide an effective approach for the treatment of colon cancer.In the third section,iRGD-functionalized PEGylated CPT-loaded PLGA NPs(iRGD-PEG-NPs)were fabricated with PEG-NPs as a control group.Based on a series of physicochemical characterizations,cell experiments and the anti-cancer effect tests,iRGD-PEG-NPs with desired particle sizes and zeta potentials can effectively promote the cellular uptake efficiency of cells.We further found that iRGD-PEG-NPs significantly induced the apoptosis of colon cancer cells and decreased the expression level of Bcl-2 gene compared with the non-functionalized NPs(PEG-NPs).The results of animal experiments suggested that iRGD-PEG-NPs were more effective in the penetration and accumulation in colon tumor tissues,so it showed much better therapeutic effect on the mouse with colon cancer.The above results suggested that the polymeric NPs modified with iRGD can promote the therapeutic effect of colon cancer.Based on the above three studies,they suggest that the above NPs with surface functionalization of targeting moieties can greatly improve the therapeutic effect of IBD and colon cancer.