The development and use of nanotechnology towards theranostics (all-in-one disease diagnostics and therapeutic delivery) have been increasing in popularity in recent years, in particular the use of high capacity of nanomaterials to transport both imaging and therapeutic agents into pathological tissues or abnormal cells. In this work, biocompatible mesoporous silica nanoparticles (MSNs) that can be reliably endocytosed by cells are employed in the investigation of novel cancer treatment and magnetic resonance imaging (MRI). One of the principal aims is to develop T<sub>1</sub> contrast nanoparticles not only with extraordinarily high MRI contrast characteristics, but also tunability through surface chemistry and functional protein conjugation. In coupling paramagnetic Gd<sup>3+</sup>-centres to MSNs, one can effectively marry the advantages afforded by increased molecular bulk with those engendered by confined water environment inside the porous network. Specifically, through exclusively biasing paramagnetic Gd<sup>3+</sup>-centres in the internal spaces of nanoparticles, their mobility and interaction with water protons can be altered, significantly, with beneficial changes in molecular tumbling (τ<sub>R</sub>), proton exchange (τ<sub>M</sub>) and water diffusion (τ<sub>D</sub>) within relaxation dynamics. These MRI nanoparticles with internalised Gd<sup>3+</sup>-centres are additionally used in the development of tunable/responsive contrast agents through vectoring protein conjugation. The relaxivity of MSNs can be tailored depending on the separation distances between proteins and nanoparticles; significantly, the simultaneous retention of both high MRI contrast and protein vectoring is achieved by the insertion of long polyethylene glycol (PEG) chain. The image contrast can also be reversibly gated through the competitive displacement of surface proteins by their partner proteins. Specifically, these responsive nanoparticles possess a low contrast resulting from restricted water accessibility when protein moieties are conjugated on the particles, whereas the removal of proteins causes a transition of contrast from a low to high state. The MSNs synthesised in this work are used not only in diagnostic imaging but also in the delivery of therapeutic agents for cancer therapy. The agents can be either physically encapsulated inside the pores or chemically conjugated on the nanoparticles. For the former, their loading and release efficiencies are tunable by the electrostatic interactions with particle surface functional groups; while in the latter case, their retention on nanoparticles, as opposed to being released, plays an important role in the effectiveness of cancer treatment that is achieved by trigging programmed cell death (apoptosis) in this work. This nanoparticle conjugation secures the proteins’ activity by facilitating their bypass of proteolytic degradation. Significantly, specially designed nanoparticles that demonstrate endo/lysosomal escape capability can reliably deliver therapeutic cytochrome c to cell cytosols for the initiation of a caspase cascade within apoptosis with high efficacy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:581279 |
| Date | January 2013 |
| Creators | Huang, Wen-Yen |
| Contributors | Davis, Jason |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:275e12ca-e5a4-4f63-af9e-3c73948f8001 |
Page generated in 0.0017 seconds