Rare Earth Conversion On Luminescent Nanomaterials For Small Animal Imaging Studies

Rare-earth upconversion nanophosphors (UCNPs) have been recognized as a promising new class of biological luminescent labels for fluorescence imaging. However, the major problem with UCNPs arises from the difficulties in obtaining water-soluble UCNPs bearing appropriate surface functional groups. On the other hand, compared with other medical imaging modalities, fluorescence imaging show low penetration depth. In order to combine the advantages of molecular imaging techniques, multifunctional UCNPs are highly required for multi-level molecular imaging from cellular scale to whole body. This thesis is focused on this project and composed of four parts below.1. A Versatile Fabrication of Upconversion Nanophosphors (UCNPs) with Functional-surface Tunable LigandsFor UCNPs to be successfully used as luminescent labels, they must exhibit good aqueous solubility and suitable surface functionality to allow further conjugation with biologically active molecules. Typically, two-step controllable synthetic strategies are usually associated with some intrinsic limitations, such as relatively complicated synthesis processes and post-treatment procedures. We report a general procedure for the one-pot preparation of surface-functionalized UCNPs by a modified polyol route assisted with difunctional ligands containing a carboxyl group. Due to the amino and carboxyl groups pointing outward, both amino-functionlized and carboxyl-functionlized UCNPs were obtained. Moreover, folic acid-functionlized UCNPs have been demonstrated to be effective in targeting folate-receptor overexpressing cancer cell lines.2. Rare-earth Nanocrystals for In Vivo MRI/UCL Dual Modality ImagingTo further improve penetration depth, near infrared (NIR) UCL and magnetic properties were combined into one nanoparticle, and dual-modal bioimaging of whole-body animal were developed. Hydrophilic and carboxylic acid-functionalized Tm3+/Er3+/Yb3+co-doped NaGdF4upconversion nanophosphors (AA-NPs) were synthesized and showed both NIR-to-visible and NIR-to-NIR luminescence under excitation of980nm, and are suitable for cells, tissues and whole-body animals UCL imaging with different penetration depth. Moreover, AA-NPs showed a high relaxivity of5.60s-1·mM-1and were successfully applied as contrast agents for MRI. In vivo imaging indicated that AA-NPs could be dual-modal probes for UCL and MRI imaging.3. Fluorine-18-labeled Gd3+/Yb3+/Er3+Codoped NaYF4Nanophosphors for Multimodality PET/MR/UCL ImagingPositron emission tomography (PET) is an established clinical tool with high detection sensitivity. MRI provides an excellent spatial resolution and depth. Fluorescent imaging is widely used for cell and tissue imaging. To combine the advantages of molecular imaging techniques,18F-Iabeled Gd3+/Yb3+/Er3+co-doped NaYF4nanophosphors (cit-NPs) as PET/MR/UCL multifunctional probes have been fabricated for multifunctional imaging from the cellular scale to whole-body evaluation. Hydrophilic citrate-capped cit-NPs were monodispersed with an average size of22x19nm. The obtained hexagonal cit-NPs show intense UCL emission in the visible region and paramagnetic longitudinal relaxivity (r1=0.405s-1·mM-1). Based on the strong binding between Y3+and F-,18F was labeled on the surface of cit-NPs with high yield (>90%).18F-labeled cit-NPs as a multimodal probe can be used for T1-weighted MR and PET imaging in vivo and UCL imaging of living cells and tissue slides.4. Water-stable NaLuF4-based Upconversion Nanophosphors with Long-term Validity for Multimodal Lymphatic ImagingAmong rare earth elements, lutetium (Lu) has the largest atomic number of the lanthanide ions, so it shows strong X-ray absorption for CT imaging. Moreover, NaLuF4is an excellent host for the fabrication of UCNPs with bright UCL emission. Gd3+,Yb3+,Er3+/Tm3+doped NaLuF4upconversion nanoparticles (Lu-UCNPs) were designed for CT/MRI/UCL multimodal bioimaging. The doping of lanthanide ions (Yb3+and Er3+/Tm3+) endows the Lu-UCNPs with UCL emission. The Gd3+induces magnetic resonance properties. Moreover, NaLuF4-based UCNPs showed excellent X-ray absorption coefficient. Lu-UCNPs have been successfully applied to the trimodal lymphatic imaging on the modal of small animals. Lu-UCNPs are stable in water for more than six months and exhibited low toxicity on living systems.