Design And Fabrication Of Multifunctional Nanocarriers And Its Preliminary Application In Both Cancer MR Imaging And Targeted Therapy

Magnetic resonance imaging (MRI) is a painless and safe diagnosticprocedure. The contrast agent is an important part of this technology.Paramagnetic diethylenetriaminepentaacetic acid-Gadolinium (DTPA-Gd) iswell-established contrast agent in clinical use for MRI. However, the clinicallyused low molecular weight contrast agents have serious drawbacks which limittheir further clinical application. In this dissertation, a series of multifunctionalnanocarriers for biomedical applications have been developed by deliberatelycombining the useful functions of cancer MR imaging, targeted therapy,prolonged residence in the blood, and so on. The detailed contents are asfollows:(1) The synthesis of derivatives of the octadecyl-quaternized lysinemodified chitosan (OQLCS). DTPA-Gd, folic acid (FA), polyethylene glycol(PEG) were conjugated to amphiphilic polymer OQLCS. The results showedthat three kinds of OQLCS derivatives can be dissolved in organic solventsother than acetone and aqueous solution, which can also self assemble intomicelles in water due to its amphiphilicity. The OQLCS-DTPA-Gd micelles cansignificantly shorten the longitudinal relaxation time T1. The relaxivity (r1) wassignificantly higher than that of commercial contrast agents DTPA-Gd.(2) The preparation of the polymer liposomes and its preliminaryapplication in MR imaging. The polymer liposomes were synthesized fromOQLCS derivatives and cholesterol. The results show that the prepared polymerliposomes were uniformly dispersed, and have nanometer-sized lipid membranestructure. Compared with the DTPA-Gd, the relaxivity of paramagnetic polymerliposome contrast agent prepared in this experiment was significantly higher.The results of T1-weighted MR images of HeLa cells showed that the folic acidmodified paramagnetic polymer liposomes had better contrast imaging than thatof DTPA-Gd.(3) A multifunctional nanoscale platform was designed forsimultaneous magnetic resonance imaging (MRI) and targeted therapeutics.The DTPA-Gd chelated to the shell layer exhibited significantly higherspin–lattice relaxivity (r1) than that of DTPA-Gd. Meanwhile, the PLGA core serves as a nanocontainer to load and release the hydrophobic drugs. From drugreleased study, the modification of the PLGA core with polymeric liposomeshell could be a useful tool for reducing the drug release rate. Cellular uptake offolate-nanocomplex was found to be higher than that of non-folate-nanocomplex.This work indicates the multifunctional platform with combined characteristicsof MRI and drug delivery may have great potential in cancer chemotherapy anddiagnosis.(4) Preparation of Superparamagnetic iron oxide nanoparticles(SPIONs) and its preliminary application in negative MR imaging. SPIONs(Fe3O4) were synthesized by thermal decomposition. The PEG-OQLCS wasused to coat SPIONs and transfer the magnetic nanoparticles from organicphases to aqueous solutions. The nanoparticles were uniformly dispersedwithout agglomeration. Meanwhile, the relaxation efficiency (r2) of thenanoparticles was163.07mM-1S-1. MRI of the nanoparticles in water confrmedits contrast enhancement effect in T2-weighted sequences.(5) Multifunctional polymeric liposomes-coated Superparamagneticiron oxide nanoparticles as contrast agent for targeted magnetic resonanceimaging of cancer cells. The formed nanoparticles exhibited a narrow range ofsize dispersity and relatively high T2relaxivities. The in vitro tumor celltargeting efficacy of the folate functionalized and PLs-coated SPIONs wasevaluated upon observing cellular uptake of magnetite liposomes by HeLa cells.Meanwhile, The MTT assay explains the negligible cell cytotoxicity of SPIONsand folate-PLs-coated SPIONs.In conclusion, based on polymeric liposome as a kind of modularizedplatform, these multifunctional nanocarriers with combined characteristics ofMRI and drug delivery may have great potential in cancer chemotherapy anddiagnosis.