Study Of Novel Cyclodextrin Complexes Targeting Intestinal Oligopeptide Transporter

Objective: Doxorubicin is an anthracycline antitumor drug that has been widely used in clinical antitumor therapy.However,due to its poor water solubility and membrane permeability,it is mostly administered by injection in clinic.Therefore,changing the dosing method of adriamycin has become the research direction in recent years.In this study,doxorubicin was wrapped in the cavity of cyclodextrin by the formation of cyclodextrin inclusion complex,and L-type valine was modified onto β-cyclodextrin to synthesize new cyclodextrin derivatives by using the specific recognition of intestinal oligopeptide transporter 1(PepT1).To improve the water solubility of β-cyclodextrin and make it a specific transport substrate for PepT1,thereby improving the water solubility,membrane permeability and stability of doxorubicin and enabling it to be absorbed through the small intestine,thereby improving its bioavailability for oral absorption.Methods: In this paper,L-valine was modified to β-cyclodextrin by chemical synthesis,and a new cyclodextrin derivative L-val-β-CD was synthesized.The optimal synthesis route was screened,and its chemical structure was confirmed and characterized.The optimal inclusion ratio of doxorubicin to L-Val-β-CD was explored to prepare the inclusion complex of doxorubicin,and its inclusion rate and drug loading were calculated.The inclusion complex molecules were characterized by nuclear magnetic resonance spectroscopy,infrared spectroscopy,differential scanning calorimetry,X-ray diffraction and other methods,and their stability was investigated by high temperature test and high humidity test.The solubility of doxorubicin inclusion complexes was determined,and the release of doxorubicin in vitro was investigated under different pH conditions.The release location of doxorubicin in gastrointestinal tract was analyzed.Results: L-Val-β-CD was synthesized successfully,and a simple and easy synthesis route with relatively high yield was selected.The chemical structures of the new cyclodextrin derivatives were confirmed by hydrogen NMR and mass spectrometry.By calculating the encapsulation rate and drug loading of the inclusion complexes obtained from different feeding ratios,it was determined that when the feeding ratio was 1:1,the inclusion ratio of the inclusion complexes was the best,and the encapsulation rate and drug loading were 73.6% and 24.3%,respectively.The inclusion complex molecules were characterized by nuclear magnetic resonance spectroscopy,infrared spectroscopy,differential scanning calorimetry,X-ray diffraction and other methods to determine the formation of the inclusion complex,rather than chemical reaction or formation of a simple physical mixture.High temperature test and high humidity test showed that the stability of adriamycin inclusion complex was significantly improved than that of naked drug.The solubility test showed that the water solubility of adriamycin inclusion complex increased by 2400 times.At pH 1.2,4.5,6.8,7.4 and 8.0,the cumulative release of doxorubicin L-val-β-CD inclusion complex was 26.8%,55.9%,75.3%,69.1% and53.9%,respectively.The data showed that the cumulative release of doxorubicin L-val-β-Cd inclusion complex was the highest at pH 6.8 in small intestine.Conclusions: A novel cyclodextrin inclusion complex delivery system specifically recognized by PepT1 was successfully constructed,and DOX@L-Val-β-CD inclusion complex was prepared using adriamycin as the model drug.The inclusion complex can significantly improve the water solubility and stability of adriamycin,and has a higher cumulative release in the small intestine pH environment.Adriamycin can be transported to the circulatory system through the small intestine to play a drug effect.