Experimental Study On The Construction And Pharmacokinetics Of Quercetin And Paclitaxel Nanoparticles Co-delivery Based On Oleoyl-chitosan In Porous Microspheres For Pulmonary Drug Delivery

Objectives: The purpose of this study was to develope a novel nanoparticles in polymerization into porous microspheres(PMs)loaded with quercetin(QUE)and paclitaxel(PTX)co-delivery based on the synthesis of oleoyl-chitosan(OCS)for pulmonary delivery.In this sustained release drug delivery system,QUE and PTX were used as model drugs,while oleoyl-chitosan(OCS)was used as carrier materials.The physicochemical properties of QUE/OCS-NPs and PTX/OCS-NPs such as morphology,diameter and acute toxicity of inhalation ect.were evaluated.Moreover,study was to establish PMs prepared by spray drying method.The physicochemical characteristics,in vivo pharmacokinetics and biodistribution studies were evaluated.Methods: The OCS with different substitution degree was prepared by OA modified CTS,and substitution degree was determined by Fourier Transform Infrared Spectroscopy.OCS-NPs,QUE/OCS-NPs and PTX/OCS-NPs were produced by the synthesis of oleic acid chitosan.The morphology and size were determined by Transmission electron microscope(TEM).The average diameters and polydispersity index were evaluated by dynamic light scattering(DLS).The interactions between various components and the nanocomplex,crystalline shape were characterized by Fourier Transform Infrared Spectroscopy(FT-IR),Differential Scanning Calorimetry(DSC)and X-ray Diffraction(XRD).The drug loading(DL),encapsulation efficiency(EE)and in vitro release were determined by High performance liquid chromatography(HPLC).PMs were produced by spray drying method.The physicochemical characteristics,in vivo pharmacokinetics and biodistribution studies were evaluated.Results: Most suitable NPs with 11% DS were produced using OCS.The results of TEM demonstrated that the OCS-NPs,QUE/OCS-NPs and PTX/OCS-NPs were spherical in shape,uniform particle size and dispersed uniformly.The diameters of NPs were less than 300 nm,PDI less than 0.300 and zeta potential was about 25 mV.FT-IR showed that OCS and TPP were eletrostatic binding and drugs were encapsulated in NPs.DSC and XRD showed that NPs were amorphous.The drug loading of QUE and PTX were 14.15% and 15.01%,respectively.The encapsulation efficiency of QUE and PTX were 44.60% and 48.80%,respectively.In vitro release study showed that the cumulative release of QUE and PTX from NPs were(52.88%,41.40%)in phosphate buffered saline(PBS,pH 7.4)and the cumulative release of QUE and PTX from NPs were(60.85%,56.21%)in PBS(pH 4.5)within 48 h,which has sustained release effect.Acute toxicity showed that there was no change in the number of white blood cells in the blood,and the content of LDH in the bronchoalveolar lavage fluid was not changed.Tissue HE staining results showed that the drug had no toxicity to the lung and other organs.SEM demonstrated that the PMs were spherical with shrinkage blisters,uniform particle size and dispersed uniformly.The diameter of PMs was about 4 ?m.The average diameter and PDI of PMs were 3373 ?m and 0.456,respectively.The drug loading of QUE and PTX of PMs were 14.79% and 15.36%,respectively.And the encapsulation efficiency was about 90.30% and 92.60%,respectively.The particle size distributions of NPs(redispersibility for PMs)reveal a mean average size of 200 nm.FT-IR displayed that QUE and PTX were encapsulated in PMs.DSC and XRD showed that PMs was amorphous.In vitro release study showed that the release of QUE and PTX from PMs was prolonged in PBS(pH 7.4),and a sustained release of 60.88% and 52.40% within 48 h was observed.The cumulative release of QUE and PTX from PMs was(70.85% and 60.05%)in PBS(pH 4.5)within 48 h.The combination of QUE and PTX exhibits a marked increase in PTX retention in vivo.PMs significantly promoted the pulmonary absorption of PTX and prolonged blood circulation.PMs also showed sustaining release effects.Conclusion: In this study,OCS-NPs,PTX/OCS-NPs,QUE/OCS-NPs and PMs were successfully prepared with good physical and chemical properties.The particles could use as an inhalant sustained release drug delivery system,which have regular spherical shape with a narrow distribution in diameter.They all display good slow-release characteristics at pH 4.5 and 7.4,no toxicity,exert synergistic action in vivo and increase the concentration of drugs in the lungs.Overall,PMs offer a promising pulmonary administration delivery system for the combined pharmacotherapy of hydrophobic anticancer drugs.