Research On The Preparation And Targeting Of Gefitinib Nanoparticles With Chitosan And Protamine As Delivery Materials

ObjectiveGefitinib is a new medicine for lung cancer,targeting non-small cells.It is an inhibitor of tyrosine kinase which is normally found in epithelium tumor.Gefitinib can block the messages transfer between tumor cells,and thus inhibit the growth,transfer and vessel formation of tumor.Nowadays,in domestic market,gefitinib are sold as tablets,which have poor oral absorption,lower bioavailability and stronger side-effects in digestive system.Also,it may lose clinical therapeutic effects by being digested to a low active substance.Nanoparticle,as a nano-scale drug delivery system,has high membrane permeability.It can pass through tumor vessels to aggregate around tumor tissue,and protect drug from digesting.In this experiment,gefitinib nanoparticles were prepared with non-toxic,non-stimulating chitosan and protamine as the delivery materials.Chitosan and protamine have high biocompatibility and biodegradability,and thus they can improve the distribution of gefitinib in the plasma.They are also good targeting agents,which improves bioavailability and decrease the side-effects.MethodsBased on the literatures and preliminary experimental results of chitosan as the delivery material,we used ion gelation method to prepare nanoparticles.Chitosan and protamine were used as the drug delivery materials and analytical method in vitro was established.We used encapsulating efficiency and loading capacity as the quality control,and the central composite design-response surface methodology to optimize this method.We evaluated the quality of the nanoparticle prepared from the optimal preparation method,for its appearance,morphology,size distribution,surface charge,stability and release property in vitro.Based on literature,we establish the High Performance Liquid Chromatography(HPLC)method to detect gefitinib in plasma and tissues of mice.We used gefitinib solution as the control,to study gefitinib nanoparticle distribution in mice tissues.We measured the concentration of gefitinib in tissues and plasma;calculated the corresponding pharmacokinetic parameters;and study the targeting of gefitinib nanoparticles.ResultsThis study established the analytical method for measuring gefitinib in vitro based on the methodological requirements.We used central composite design-response surface methodology and found the optimal formulation:gefitinib 1 mg/m L,chitosan 3.5 mg/m L,and protamine 1 mg/m L.Verification of the optimal formulation shows that the mathematical model has good predictive effects.Quality evaluation shows that the nanoparticles have structural integrity and have uniform sizes.They are spherical or spherical-like particles with the average diameter of 169 nm,and can form stable blue opalescence colloidal solution.Their zeta potential is +23.7 m V,and have a good sustained-release effect and high cumulative drug release rate at p H=5.8.They can be stably stored at 4?.This paper established HPLC method to measure the gefitinib distribution in mice.Results show that compared with oral gefitinib solution,gefitinib nanoparticles have a high distribution in liver,spleen,and lung in which the concentration is the best.ConclusionsPrepartion for gefitinib nanoparticles is simple and well-defined.Nanoparticles from optimal preparation methods are spherical or spherical-like particles with uniform sizes.They have positive charge on the surface and good control for releasing drugs.Results from tissue distribution of gefitinib show that,compared with oral gefitinib solution,gefitinib nanoparticles are good controlled-release formulations and show good targeting to lung.Thus they can improve the distribution of gefitinib in vivo.