Multifunctional Dendrimer-Entrapped Gold Nanoparticles As Dual-Modal Targeting Ct/Mri Contrast Agent For Tumor Diagnosis

Recent advances in nanotechnology have made it possible to prepare multifunctional contrast agents, especially multifunctional multi-modal imaging nanoprobes, for early diagnosis of cancer. Since dual-modal CT/MRI is capable of provide more comprehensive diagnostic information, recently great progresses have been achieved in the development of CT/MRI contrast agents. In addition, in order to improve diagnostic accuracy an ideal contrast agent should contain targeting reagents or ligands inducing specific combining of contrast agent and tumor cells and accumulating on tumor sties to obtain sufficient signal-to-noise ratio. Dendrimer is a novel class of highly branched, synthetic polymer. Its unique properties such as the internal cavity and missive surface functional groups enable it to be used as an ideal platform to simultaneously jntrap contrast agent nanoparticles inside and to conjugate with functional molecules such as targeting ligands on perpheral suface in a nanodevice system. Because of these unique properties, dendrimer have been utilized as versatile templates for dual-modal CT/MR imaging applications.In this work. PEGylated dendrimers were used as platform to entrap CT contrast agent gold nanoparticles (Au NPs) and conjugate with T|MRI contrast agent gadolinium (Gd) and different targeting ligands (FA or RGD) on the perphery for targeting and CT/MR imaging of KB cells overexpressing high-affinity folate receptors or U87MG overexpressing avp_i integrin, respectively. First. The particles Gd-Au DENPs-FA or Gd-Au DENPs-RGD, were synthesized using G5.NH2pie-modified with Gd chelator (DOTA-NHS), polyethylene glycol (PEG) monomethyl ether, and targeting ligands (PEG-FA or PEG-RGD) as templates to entrap gold nanoparticles and chelate Gd(111) ions, followed by acetylation of the remaining dendrimer terminal amines. Second, the properties of the formed NPs including the morphology, size distribution, cytocompatibilit\. hemocompatibility. X-ray attenuation intensity and T1relaxation were characterized. Last,the targeting specificity, in vitro and in vivo CT/MR imaging ability as well as biodistribution of two kinds of formed NPs were evaluated by using tumor model of KB cell lines or U87MG cell lines. respectively.In chapter2and3, FA-conjugated and RGD-conjugated multifunctional dendrimer-based nanoparticles were synthesized, characterized and applied as a dual-modal contrast agents for CT/MR molecular imaging, respectively. The results show that the mean size of Gd-Au DENPs-FA and Gd-Au DENPs-RGD is4.0nm and3.8nm, respectively. They are water soluble and stable. They have a high X-ray attenuation intensity due to the presence of the dual radiodense element of Au and Gd, and display excellent r, relaxivity due to the presence of the chelated Gd(Ⅲ) ions. MTT cytotoxicity assay along with cell morphology observation show that Gd-Au DENPs-FA and Gd-Au DENPs-RGD are non-cytotoxic at the Au concentration as high as35μM or100μM, respectively. CT and T,-weighted MR imaging data show that Gd-Au DENPs-FA and Gd-Au DENPs-RGD are able to specifically target cancer cells overexpressing high-affinity folate receptors or αvβ3integrin in vitro and in vivo, respectively. The biodistribution data of Au NPs in mouse show that Gd-Au DENPs-FA can be cleared from the body after96h. In summary, the results from this study indicate that Gd-Au DENPs-FA and Gd-Au DENPs-RGD could find a potential application in early diagnosis of tumor as non-invasive multimodal molecular imaging contrast agents.