Colon-specific Drug Delivery Systems Based On Natural Polymers Grafted Graphene Oxide

A major problem associated with colon cancer is liver metastasis.A colon-specific drug delivery system is one way to address this problem after the resection of colorectal cancer.However,traditional drug delivery systems face many challenges,such as an inability to control the release rate,inaccurate targeting,uncontrollable drug release rate,susceptibility to the microenvironment and poor stability.Therefore,the development of new drug delivery system has become a hotspot in this field.Here,we report the development of graphene oxide(GO)-based,sodium alginate(ALG)and sodium carboxymethylcellulose(CMC)functionalized drug delivery system,that is loaded with 5-fluorouracil(5-FU)and methotrexate(MTX)as the anti-cancer drug.Chemical structure and morphology of the as prepared materials were tested.Toxicity and antitumor activity of such drug delivery systems were analysed.First,graphene oxide was synthesized by modified Hummers method.Results showed that thin layer of graphene oxide was prepared,with an interplanar spacing of about 0.866 nm.Sodium alginate was oxidized by sodium periodate and then grafted on graphene oxide by ethylenediamine to obtain sodium alginate modified graphene oxide(ALG-GO).By loading5-fluorouracil(5-FU)on ALG-GO,the 5-FU/ALG-GO drug delivery system was constructed.The chemical structure and morphology of as prepared samples were characterized by Fourier transform infrared spectroscopy(FT-IR),X-ray powder diffraction(XRD),~1HNMR spectroscopy,high resolution transmission electron microscopy(HRTEM)and field emission scanning electron microscopy(FSEM).Drug release properties of 5-FU/ALG-GO were analysed.The results showed that alginate was successfully grafted on graphene oxide;ALG-GO had high entrapment efficiency of 5-FU;5-FU/ALG-GO showed long-term and continuous drug release feature in vitro and in vivo with pH sensitivity.By oral administration,small amount of 5-FU released in the stomach and small intestine,most drugs were transported to the colon,to achieve long-term sustained drug release effect.However,due to the low solubility of 5-FU in water,acid or base solution,the yield of the constructed drug delivery system is too low,thus its preparation is limited.By using the previously prepared ALG-GO as the carrier and MTX as the drug which is easy to dissolve in dilute hydrochloric acid,the MTX/ALG-GO controlled drug delivery system was constructed.The chemical structure and properties of prepared delivery system were characterized by XRD,FT-IR,~1HNMR,TEM,SEM,UV-Vis spectroscopy and high-performance liquid chromatography(HPLC).Drug release properties were also evaluated.The results showed that ALG-GO had high entrapment efficiency of MTX.Due to its high yield,it was suitable for massive preparation.The in vitro and in vivo release experiments showed long-term sustained drug release with pH sensitivity.Drugs can effectively transport to the colon by oral administration.MTX/CMC-GO controlled drug delivery system was constructed by loading MTX with carboxymethyl cellulose grafted graphene(CMC-GO)as carrier.The chemical structure and properties of prepared delivery system were characterized by XRD,FT-IR,~1HNMR,TEM,SEM,UV-Vis spectroscopy and high-performance liquid chromatography(HPLC).Drug release properties were also evaluated.It was found that carboxymethyl cellulose was successfully grafted on graphene oxide.CMC-GO had high entrapment efficiency of MTX and was suitable for mass production because of its high yield.The in vitro and in vivo release experiments showed long-term sustained drug release with pH sensitivity.The toxicity of ALG-GO,CMC-GO,5-FU/ALG-GO,MTX/ALG-GO and MTX/CMC-GO were evaluated.The results demonstrated that both carriers possessed low cytotoxicity.The cytotoxicity and biotoxicity of the drug delivery systems were even lower than the original drug.The as prepared three kinds of drug delivery systems have significant anti-tumor activity and can effectively inhibit liver metastasis.The results provide a scientific basis for the application of controlled drug delivery systems,showing a promising application prospect.