Preparation Of PH-responsive Chitosan Anticancer Drug Carriers And Their Application

ObjectiveChitosan?Cts?,a common natural macromolecule polysaccharide,have attracted wide attention as a drug carrier because of its excellent biocompatibility,biodegradability and non-cytotoxicity,etc.With the development of new drug delivery systems,targeting drug delivery system prepared by chitosan are used for sustained release controlled release and targeted release of drugs.It has significant advantages in increasing drug absorption,improving drug bioavailability and reducing drug toxicity and side effects.PI-4 is a synthetic pyrazolium quinoline derivative with strong anticancer properties.Doxorubicin?Dox?,as a common chemotherapeutic drug,has obvious effects in the treatment of various tumors.However,in the clinical treatment of cancer,chemotherapeutic drugs are poor selectivity and have obvious toxic and side effects on normal tissues or organs.In order to improve the effect of drug treatment and reduce toxic and side effects,chitosan was used as the basic material to prepare PI-4 and Doxorubicin nanoparticles with responsive,targeting and sustained release,which provided a theoretical basis for further expanding the research scope of nanocarriers.MethodsThe spherical chitosan microspheres loaded with PI-4?PI-4@Cts MSs?were prepared by hydrothermal reaction using chitosan as carrier material;and Doxorubicin-loaded nanospheres were prepared by ultrasound-assisted precipitation with chitosan as basic material,and functionalized by mesoporous SiO₂ and folic acid to obtain DCSF NSs with pH response,FART and sustained release characteristics.Scanning electron microscopy?SEM?and transmission electron microscopy?TEM?were used to detect the morphology of the particles,Dynamic Light Scattering instrument were used to detect the particle size,and Fourier transform infrared spectroscopy?FTIR?was used to detect the composition of the particles.Under the conditions of pH=7.4 and pH=5.0,the pH-responsive and cytotoxicity of the particles were studied by in vitro release and MTT experiments.Laser confocal scanning microscopy?CLSM?was used to study the endocytosis by tumor cells under different conditions.Results?1?The prepared PI-4@Cts MSs had a smooth surface with an average diameter of about 980 nm and good monodispersity.The prepared Dox@Cts NSs were smooth spheres with good monodispersity and a diameter of about380 nm.The surface of the prepared DCSF NSs was raspberry-like with uniform size,good monodispersity and an average diameter of about 440 nm.?2?PI-4@Cts MSs had a DLC of 31.46 wt%;Dox@Cts NSs and DCSF NSs had DLC of 28.12 wt%and 7.34 wt%,respectively.The swelling solubility of chitosan nanoparticles was confirmed by swelling experiments of PI-4@Cts MSs and Dox@Cts NSs at pH=5.0.?3?Fourier transform infrared spectroscopy?FTIR?showed that the prepared microspheres encapsulated PI-4 successfully.FTIR and UV-vis absorption spectroscopy confirmed that Doxorubicin has been encapsulated in the prepared nanospheres,successfully.?4?In vitro release experiment of PI-4,there was 5.11%of PI-4 released from PI-4@Cts MSs after 9 h of dialysis at pH=7.4,and the release of PI-4 was close to 90.33%at pH=5.0.?5?In the in vitro release experiment of Doxorubicin,the release of Dox@Cts NSs and DCSF NSs was 8.37%and 6.42%after 48 h of dialysis at pH=7.4,respectively.There was 89.00%and 37.43%Doxorubicin released from Dox@Cts NSs and DCSF NSs after 8 h of dialysis at pH=5.0,respectively.After about 48 h,the cumulative doxorubicin release rate from DCSF NSs reached 86.16%.?6?In the MTT experiments of PI-4@Cts MSs under the concentration of PI-4 was 50?g/mL,the cell viability was 88.40%and 18.53%at pH=7.4 and 5.0,respectively.?7?In the MTT experiments under the condition of Doxorubicin concentrate of Dox@Cts NSs and DCSF NSs was 100?g/mL,the cell viability was 81.94%and 93.20%at pH=7.4 and the cell viability was 11.60%and 8.96%at pH=5.0,respectively.Conclusions?1?The preparation method of PI-4@Cts MSs by hydrothermal reaction with chitosan as carrier material was feasible.The preparation method of Dox-loaded nanospheres by ultrasound-assisted precipitation and functiona-lized by mesoporous SiO₂ and folic acid to prepare DCSF NSs is feasible.?2?PI-4@Cts MSs and DCSF NSs both had a good stability at pH=7.4,and they could degrade gradually and release loaded-drug at pH=5.0.Moreover,DCSF NSs had good sustained release effect.?3?The prepared PI-4@Cts MSs and DCSF NSs both had pH-responsive properties in this paper,and could be used as acidity-response drug delivery system.Moreover,DCSF NSs could further improve the efficacy and reduce the toxicity and side effects of drugs through folic acid targeting.Therefore,PI-4@Cts MSs and DCSF NSs had potential applications in effective delivery of anticancer drugs.