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Studies On Preparation And Biological Effects In Vitro Of Magnetic Fibroin/Chitosan Complex Microspheres As Vehicles For The Targeted Delivery Of 5-Fluorouracil

Posted on:2004-09-03Degree:DoctorType:Dissertation
Country:ChinaCandidate:L P LiuFull Text:PDF
GTID:1104360095956602Subject:Biomedical engineering
Abstract/Summary:PDF Full Text Request
Magnetic targeted drugs delivery system consists of polymer carrier, drug and magnetic nanoparaticles. It could be selectively localized to the target-site of tumor by external magnetic field and then the drug would be delivered to cell and sub-cell of tumor tissues. Magnetic microspheres agent loaded antitumor drug is suggested as an efficient method of obtaining high local drug concentration and may reduce many undesirable toxic side effects from unrestricted systemic circulation.The aim of the thesis is that biodegradable silk fibroin modified by blending with chitosan as vehicle are prepared target microspheres formulation with a high loading efficiency for the cytotoxic drug 5-fluorouracil (5-Fu) and magnetic nanoparticles. The interrelationships are studied between phy-chemical preparation parameters and technical indexes of microspheres. It is studied that the kinetic release model of 5-Fu from fibroin/chitosan microspheres, influential factors to microspheres localized sites by external magnetic field and its antitumor activities to tumors, respectively. Some achieved progresses have been obtained as follows: (1)With a chemical coprecipitation and ultrasonic technology, ferric/ferrous ion salt dispersed in polyethylene glycol-4000(a dispersant agent), and then ammonia water added to pH 10~11 of solutions, magnetic nanoparticles were obtained. Measuring results of scanning tunnel microscope showed that the particles were round with a size range of (25±10nm). Its saturation magnetization was 36.2×103A/s and it belongs to superparamagnetism of ferrofluid. The magnetic nanoparticles exhibited excellent stability, strong magnetic response and well affinity with hydrophilic polymer.(2) The Modified fibroin membranes were studied some characters to be found such as there was a strong hydrogen bond and good compatibility between fibroin and chitosan molecules, and its isoelectric point at pH=5.35, but that of fibroin film was around pH 4.5. It was also found that its mechanical properties were much higher than those of fibroin or chitosan film. Its tensile strength and breaking elongation were greatly enhanced with increasing the chitosan content and showed maximum values of 71.4~72.7MPa and 2.96~3.82% respectively at containing chitosan 40~60%. Its coefficient of permeability to 5-fluorouracil was decreased initially and then increased slowly from pH 5 to 9 of solutions with the minimum located at pH=7.(3) The first order derivative spectrophotometry method for the determination of5-Fu content in magnetic fibroin/chitosan blended microspheres was established. Blended magnetic microspheres were digested with HAc and NaOH respectively to release entrapped 5-Fu. The absorption value of amplitude at the wavelength of 280nm in 10%HAc and at 299nm in 0.1 mol/l NaOH was used. The interference of fibroin and chitosan could be ignored. Its regression equations were ,(in HAc) and (in NaOH) respectively. The average recovery was 101.83±0.68% and RSD was 0.67%. This method is simple, rapid and well reproducible.(4) A novel W/O emulsion/polymer cross-linking technique was used to prepare magnetic fibroin/chitosan microspheres containing 5-Fu (5-Fu-MFCMs). An orthogonal experimental design and statistical analysis methods were employed to simultaneously optimize and evaluate a variety of formulation factors on a number of response variables. OD value was the overall desirability of multiple response variables, such as mean diameter and dispersity efficiency, drug loading and loading efficiency, magnetic response and 50% release time etc. Second-order polynomial and linear equations were fitted to the data, and the regression equations and their correlation coefficients R>0.9 were obtained. The statistical optimization procedures indicated the sequence of the factors of significantly influence to OD(P<0.05)was below:Crosslinking time>Stirring rate>FB/CS concentration>5-Fu /magnet /FB-CS ratio>Emulsifier concentration>Cross-linker concentration.Most of these factors above were posit...
Keywords/Search Tags:hydrophilic magnetic nanoparticles, silk fibroin films modified by blending with chitosan, magnetic fibroin/chitosan complex microspheres loaded 5-Fu, release drug in vitro, magnetic target-site, cytotoxicity
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