Near infrared light-mediated upconversion nanocrystals for precisely theranostic applications

• Main Author: Ai, Xiangzhao
• Other Authors: Xing Bengang
• Format: Theses and Dissertations
• Language: English
• Published: 2018
• Subjects: DRNTU::Science::Biological sciences::Biochemistry
• Online Access: http://hdl.handle.net/10356/74379
• Institution: Nanyang Technological University

In recent decades, precision theranostics are greatly demanded to efficiently treat various human diseases in clinics. However, it’s still challenging to accumulate the specific therapeutic agents in the targeted pathological regions and simultaneously avoid the harmful side effects to healthy tissues in human body. As a promising and powerful tool in living system, the light-mediated therapeutic strategy can precisely activate the imaging probes and reagents remotely at targeted areas based on its non-invasive properties and greatly spatiotemporal resolution in vivo. Despite the initial success, the established approaches for light-mediated treatment mainly focus on short-wavelength light, which is limited by several unavoidable disadvantages including serious phototoxicity, undesired absorption/scattering and low penetration depth in tissues. Thus, a long-wavelength near-infrared (NIR) light-triggered strategy at “optical window” (700-1000 nm) is highly demanded in the last decades which displays negligible photo-damage, excellent penetration depth and minimized auto-fluorescence for precisely phototherapeutic applications in clinics. As an amazing candidate in nanomedicine, NIR light-mediated lanthanide-doped upconversion nanocrystals (UCNs) have attracted considerable attention in the basis of its impressive optical properties in the NIR windows to convert NIR light excitation into UV or visible light emission through non-linear multiphoton processes. Therefore, UCNs have been considered as effective theranostic agents in living studies benefiting from their promising characteristics including excellent tissue penetration depth, tunable multicolor emission, long lifetime, high photostability, and excellent biocompatibility. In this dissertation, we fabricated some smart UCNs-based nanoplatforms to further advance their theranostic applications in vitro and in vivo, as shown in following parts. Firstly, tumor-specific cathepsin protease-triggered method was developed to cross-link dual peptide-functionalized-UCNs in tumor cells. Upon the formation of covalent bonds between 2-cyanobenzothiazole (CBT) and exposed cysteine residual between different UCNs, the photoactivation of Pt(IV) prodrug was enhanced and the increased reactive oxygen species (ROS) generation in the process of cell death was detected by a sensitive fluorescent dye in real time. Therefore, this UCNs nanoplatform could lead to increased antitumor efficacy and was capable of evaluating therapeutic response in an early stage. Secondly, we presented another novel microenvironment-sensitive strategy for localization of peptide-premodified UCNs within tumor areas both in vitro and in vivo. Upon tumor-specific cathepsin protease reactions, the cleavage of peptides induces covalent cross-linking between the exposed cysteine and 2-cyanobenzothiazole on neighboring particles, thus triggering the accumulation of UCNs into tumor site. Such enzyme-triggered cross-linking of UCNs leads to enhanced upconversion emission upon 808 nm laser irradiation, and in turn amplifies the singlet oxygen generation from the photosensitizers attached on UCNs. More importantly, this design enables remarkable tumor inhibition through either intratumoral UCNs injection or intravenous injection of nanoparticles modified with the targeting ligands. The presented strategy may provide a multimodality solution for effective molecular sensing and site-specific tumor treatment. Thirdly, we introduced a novel strategy to achieve site-specific covalent linkage of UCNs on the cell membrane through metabolic glycan biosynthesis and copper-free click cyclization. Upon NIR light irradiation (808 nm), the strong blue emission (~ 480 nm) could effectively activate a photosensitive ion channel, channelrhodopsins-2, and remotely manipulate the cation influx in living cells and zebrafish. This unique strategy could provide valuable insights about the remote and precise regulation of membrane-associated activities in living conditions. In summary, these proposed NIR light-mediated approaches in this dissertation provided a prospective future for the precision theranostics in nanomedicine based on the promising physical properties of UCNs. We believe the present works will lead to inspiring innovations in this research field and will be developed continuously to benefit human health in the future.