Study Of Polymer Nanohybrid Contrast-enhancing Materials

Medical nanotechnology has been developing for decades, and innovative applications are coming to fruition. Nanoparticle formulations, such as micelle and hybrid nanospheres, have been used in biomedical area. Currently, polymer-inorganic hybrid nanospheres have attracted increasing attention because of the synergic properties arising from both the polymeric nanospheres and inorganic nanomaterials. Especially, those that have plasticity and biocompatibility of polymer as well as unique optical, magnetic and electric properties of inorganic materials are greatly useful in diagnosis and therapy disease. Unfortunately, the most construction of hybrid nanospheres reported so far require complicated synthesis processes and may cause environmental toxicity, which arise from either the use of surfactants or the organic solvents. Moreover, photo instability and low magnetic relaxation rate of inorganic nanomaterials limit their applications in biomedicine yield yet. Therefore, inorganic materials with excellent properties and biocompatible polymer become a research hotspot, taking into account that hybrid nanospheres can be prepared in aqueous phase without any aid of organic solvents or surfactants.Our group previously reported "non-solvent aided counter-ion complexation strategies" for preparing stable polyelectrolyte nanospheres through electrostatic interactions. In this thesis, the strategy was extended to study the self-assembly behaviors of polymer-inorganic hybrid nanospheres. We chose biocompatible cationic chitosan and anion ethylenediaminetetraacetic (EDTA) as counterion complex, and enwrapped different inorganic functional nanomaterials to prepare stable hybrid nanospheres based on their characteristics. Their huge potential in biomedical field was explored as well. The detailed work is described as blew:(1) CdSe/ZnS quantum dot-encapsulated chitosan hybrid nanospheres (CS-QD) have been successfully fabricated by utilizing ethanol-aided counterion complexation in aqueous solution. The obtained CS-QD hybrid nanospheres have not only the loading space provided by the chitosan spherical matrix for loading multiply QD but also unique fluorescent properties provided by the encapsulated QDs. Moreover, these hybrid nanospheres possess good biocompatibility and optical stability in physiological environment. It has been demonstrated that CS-QD hybrid nanospheres can be internalized by tumor cells and hence act as labeling agent in cell imaging by optical microscopy. In addition, CS-QD hybrid nanospheres can be used for imaging of tumor in tumor-bearing mice via intratumoral administration and can accumulate at tumor site via the blood circulation based on intravenous injection. Thus, on the one hand, chitosan nanospheres provide the protection in both colloidal and optical stability arising from QDs and offer biocompatibility. On the other hand, the encapsulated QDs light up polymer nanospheres and display the fate of polymer nanospheres in cells and bodies.(2) We used a thermal decomposition approach to synthesize water-soluble superparamagnetic zinc ferrite (ZnFe2O4) nanoparticles. In this approach, tetraethylene glycol (TEG) was utilized as a coordination and stabilization agent, rendering the nanoparticles water-soluble and stable. The formed nanoparticles were characterized by XRD, TEM, EDS, XPS and FTIR technologies. Subsequently, CS-ZnFe2O4 hybrid nanospheres were synthesized via self-assembly of TEG stabilized ZnFe2O4 nanoparticles, CS and EDTA based on simple nonsolvent-aided method. The loading content of ZnFe2O4 nanoparticles is controllable. The obtained hybrid nanospheres exhibited not only the superparamagnetic property provided by pure ZnFe2O4 nanoparticles but also higher r2 relaxivity value than monodisperse ZnFe2O4 nanoparticles, which can be attributed to the high ZnFeCO4 loading content and ZnFe2O4 nanoparticles clustering effect in the core of the nanospheres. Moreover, these hybrid nanospheres possess good biocompatibility and stability, which is in favor of further biological applications.(3) The imaging property of CS-ZnFe2O4 hybrid nanospheres was evaluated as a T2 contrast agent for magnetic resonance imaging (MRI). Meanwhile, the hybrid nanospheres were conjugated with cancer-specific targeting agent cyclic RGD peptide to obtain hybrid nanospheres (RGD-CS-ZnFe2O4) with the tumor-targeting effect. The in vivo MR images demonstrated that both CS-ZnFe2O4 and RGD-CS-ZnFe2O4 hybrid nanospheres had an excellent T2 enhanced contrast ability, while RGD-CS-ZnFe2O4 exhibited a higher MRI sensitivity in the tumor compared CS-ZnFe2O4·In addition, the biodistribution analysis revealed the CS-ZnFe2O4 hybrid nanospheres can accumulate at tumor site via enhanced permeability and retention (EPR) effect in tumor-bearing mice, and RGD-CS-ZnFe2O4 nanospheres showed enhanced accumulation in tumor significantly. Hence, RGD-CS-ZnFe2O4 hybrid nanospheres with tumor-targeting ability can serve as highly efficient T2 contrast probes for cancer diagnosis and treatment.