Lanthanide-doped upconversion nanoparticles (UCNPs) are perceived as promising
novel near-infrared (NIR) bioimaging agents characterised by high contrast and high
penetration depth. However, the interactions between charged UCNPs and
mammalian cells have not been thoroughly studied and the corresponding
intracellular uptake pathways remain unclear.
Herein, my research work involved the use of hydrothermal method and ligand
exchange approach to prepare UCNP-PVP, UCNP-PEI, and UCNP-PAA. These
polymer-coated UCNPs demonstrated good water dispersibility, the similar size
distribution as well as similar upconversion luminescence efficiency. However, the
positively charged UCNP-PEI evinced greatly enhanced cellular uptake in
comparison with its neutral or negative counterparts, as revealed by cellular uptake
studies. Meanwhile, it was discovered that cationic UCNP-PEI could be effectively
internalized mainly through the clathrin endocytic machanism. This study is the first
report on the endocytic mechanism of positively charged lanthanide-doped UCNPs.
Furthermore, it allows us to control the UCNP-cell interactions by tuning surface
properties.
Glioblastoma multiforme (GBM) is the most common and malignant form of primary
brain tumors in humans. Small molecule MRI contrast agents are used for GBM
diagnosis and preoperative tumor margin delineation. However, the conventional
gadolinium-based contrast agents have several disadvantages, such as a relatively low
T1 relaxivity, short circulation half lives and the absence of tumor targeting efficiency.
Multimodality imaging probes provide a better solution to clearly delineate the
localization of glioblastoma.
My research work also involved the development of multimodal nanoprobes for
targeted glioblastoma imaging. Two targeted paramagnetic/fluorescence nanoprobes
were designed and synthesized, UCNP-Gd-RGD and AuNP-Dy680-Gd-RGD.
UCNP-Gd-RGD was prepared through PEGylation, Gd3+DOTA conjugation and
RGD labeling of PEI-coated UCNP-based nanoprobe core (UCNP-NH2). It adopted
the cubic NaYF4 phase, had an average size of 36 nm by TEM, and possessed a
relatively intense upconversion luminescence of Er3+ and Tm3+. It also exhibited
improved colloidal stability and reduced cytotoxicity compared with UCNP-NH2, and
a higher T1 relaxivity than Gd3+DOTA. AuNP-Dy680-Gd-RGD was synthesized
through bioconjugation of amine-modified AuNP-based nanoprobe core (AuNPPEG-
NH2) by a NIR dye (Dy680), Gd3+DOTA and RGD peptide. It demonstrated a
size of 3–6 nm by TEM, relatively strong NIR fluorescence centered at 708 nm, longterm
physiological stability, and an enhanced T1 relaxivity compared with
Gd3+DOTA.
Targeting abilities of both UCNP-Gd-RGD and AuNP-Dy680-Gd-RGD towards
overexpressed integrin αvβ3 receptors on U87MG cell surface was confirmed by their
enhanced cellular uptake visualized by confocal microscopy imaging and quantified
by ICP-MS, where their corresponding control nanoprobes were used for comparison.
Furthermore, targeted imaging capabilities of UCNP-Gd-RGD and AuNP-Dy680-Gd-
RGD towards subcutaneous U87MG tumors were verified by in vivo and ex vivo
upconversion fluorescence imaging studies and by in vivo and ex vivo NIR
fluorescence imaging and in vivo MR imaging studies, respectively. These two
synthesized targeted nanoprobes, with surface-bounded cyclic RGD peptide and
numerous T1 contrast enhancing molecules, are applicable in targeted MR imaging
glioblastoma and delineating the tumor boundary. In addition, UCNP-Gd-RGD
favors the upconversion luminescence with NIR-to-visible nature, while AuNPDy680-
Gd-RGD possesses NIR-to-NIR fluorescence, and both lead to their potential
applications in fluorescence-guided surgical resection of gliomas. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/181017 |
| Date | January 2012 |
| Creators | Jin, Jiefu., 金介夫. |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47752579 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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