Hyaluronic Acid Oligosaccharide Modified MOF Loaded With Oxaliplatin As Drug Delivery System For Colorectal Cancer Therapy

Background:Oxaliplatin（Oxa）is the first-line chemotherapy drug for the treatment of colorectal cancer.However,due to the lack of selectivity and the existence of chemotherapy resistance,the therapeutic effect of oxaliplatin is not ideal.Hyaluronic acid oligosaccharide（oHA）can target colorectal cancer and reverse chemotherapy resistance.Therefore,the development of targeted drug delivery system is a good strategy to improve the therapeutic effect of colorectal cancer.Objective:Taking advantage of Zeolitic imidazolate frameform-8（ZIF-8）with its high drug loading,good biocompatibility,and p H-responsive drug release,combined with the targeting and reversal of chemotherapy resistance of hyaluronic acid oligosaccharide,to synthesize a novel targeted drug delivery system,oHA@ZIF-8@Oxa nanoparticles,and evaluate its therapeutic effect on colorectal cancer in vitro and in vivo.Methods:1.Using ZIF-8 as a drug carrier,oxaliplatin was loaded by physical encapsulation method to form ZIF-8@Oxa.Then,the carboxy and hydroxyl groups of hyaluronic acid oligosaccharide were used to create electrostatic interaction and coordination bond with the metal center Zn²⁺of ZIF-8,and the hyaluronic acid oligosaccharide was modified to the surface of ZIF-8@Oxa,forming a nano-drug delivery system oHA@ZIF-8@Oxa;2.The system was extensively characterized from the aspects of morphology,particle size,Zeta potential,nitrogen adsorption-desorption test,X-ray diffraction analysis（XRD）,Fourier transform infrared spectroscopy（FTIR）,etc.,which proved the loading of oxaliplatin and the modification of hyaluronic acid oligosaccharide.3.The stability of the drug loading system in vitro was detected,and the biocompatibility of the carrier material ZIF-8 was detected by CCK-8 assay.4.The drug loading and encapsulation efficiency of oxaliplatin in oHA@ZIF-8@Oxa system was detected by high performance liquid chromatography,and the linking amount of oHA was detected by carbazole sulfate chromogenic method.5.To simulate the p H values of normal tissues and tumor microenvironment,perform oHA@ZIF-8@Oxa p H-responsive drug release assay in vitro;6.The effect of oHA@ZIF-8@Oxa on the proliferation and apoptosis of colorectal cancer cell line RKO was detected by CCK-8 assay and flow cytometry.7.The RKO tumor-bearing mouse model was established,the growth of tumor volume and weight change of mice were observed after injection,and the tumor inhibition rate was calculated.After stripping the tumor,HE staining was performed to observe the tissue necrosis,and the anti-colorectal cancer effect of oHA@ZIF-8@Oxa in vivo was evaluated.Results:1.The characterization results showed that the carrier ZIF-8 with a specific surface area of 1510.36 m²/g and a good pore size distribution was successfully synthesized,and oxaliplatin was successfully loaded into ZIF-8,and hyaluronic acid oligosaccharide was successfully modified on the surface of ZIF-8.Scanning electron microscopy（SEM）and Transmission electron microscopy（TEM）images showed that the drug loading system had uniform morphology and uniform dispersion.The particle size was121.6±5.0 nm,which was in accordance with the nanoscale properties.The Zeta potential was-6.7±2.1 m V,and the particle had good stability in vitro.2.The drug loading of oxaliplatin in oHA@ZIF-8@Oxa system was 11.82%,and the encapsulation efficiency was 90.8%.The amount of hyaluronic acid oligosaccharide modified in 1 mg oHA@ZIF-8@Oxa was 0.0297±0.096 mg,and the modification efficiency was 90%.3.The p H-responsive drug release experiment showed that the release of oxaliplatin in p H 7.4 was not significant within 24 h,and the release amount was only25.49%.In contrast,the release rate and cumulative release amount of oxaliplatin in p H5.5 were significantly increased,and the release amount of oxaliplatin in 24 h reached68.58%.After 168 h,the cumulative release of oxaliplatin at p H 5.5 was 81.79%,while it was only 33.21%at p H 7.4.4.In vitro cytotoxicity results showed that oHA@ZIF-8@Oxa had a stronger killing effect on colorectal cancer cells than oxaliplatin alone（cell survival rate 24.55%vs 54.24%,p<0.001;Apoptosis rate:29.31%vs 16.42%,p<0.001）.5.In vivo experiments showed that the oHA@ZIF-8@Oxa group had the highest tumor inhibition rate,but the weight loss was not obvious.HE showed that oHA@ZIF-8@ox A-induced apoptosis and necrosis of tumor cells were the most obvious.Conclusions:The oHA@ZIF-8@Oxa drug delivery system significantly enhances the anti-colorectal cancer effect of oxaliplatin in vitro and in vivo,which provides a more promising drug delivery system for the treatment of colorectal cancer and has clinical translational value.