Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.631284
Title: Strategies for molecular imaging with inorganic nanoparticles
Author: Williamson, Peter
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2012
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Abstract:
If they are to enter routine clinical application, new radiopharmaceuticals must have rapid and simple labelling procedures, ideally inserting the radionuclide at the last synthetic step with no need for further purification. This thesis describes the development of new targeted strategies for molecular imaging. Targeted nanoparticles have great potential for application as radionuclide molecular imaging agents but are subject to several limitations, including complex radiolabelling procedures, slow pharmacokinetics, low uptake in target tissue, and potential toxicity. We have discussed a targeted nanoparticle system comprising biocompatible materials with intrinsic affinity for readily-prepared radiotracers such as 18F-fluoride and 99mTc-technetium bisphosphonate derivatives. Such a system would offer simple labelling, and signal amplification (each particle can deliver many radionuclides). To overcome slow pharmacokinetics we proposed to exploit pretargeting, whereby the radionuclide-nanoparticle bond can form in vivo. Firstly, a large pretargeting agent (nanoparticle) that has affinity for both its target tissue and radionuclide probe, accumulates at the target site slowly over a period of time. This is followed by a chasing step, where a small radionuclide probe (18F-fluoride and 99mTc-bisphosphonate) distributes rapidly to the pretargeting agent, while untargeted circulating radionuclide probe clears rapidly from the blood pool. The reader is first introduced to the topics of radiopharmaceutical particulates and pretargeting, emphasing the requirement for novel radiopharmaceutical targeting methods. A literature review discussing fluoride affine materials was performed to guide initial screening experiments. We screened many inorganic nanoparticulate materials for binding to 18F-fluoride. Of the materials tested, hydroxyapatite (HA) and Alhydrogel showed the most efficient binding to 18F-fluoride. The 18F-HA interaction was highly stable in serum, while the 18F-Alhydrogel interaction was moderately stable in serum. HA materials were prepared via wet chemical precipitation. The effect of synthesis termperature and post-synthesis treatment was investigated. Stabilisation and functionalisation of HA nanoparticles with various ligands was discussed. Synthesis temperature did not greatly affect particle properties, while calcination and hydrothermal post-synthesis treatments controlled particle morphology and crystallinity. HA particles formed stable colloidal solutions when functionalised with sodium hexametaphosphate (SHMP) and polyethyleneglycol-bisphosphonates (PEG-BP). The bisphosphonate -Alendronate was used to link small molecules such as amino acids and fluorescein isothiocyanate to HA surfaces, for potential targeting applications. Porous hollow silica particles were prepared using a novel templating method, using HA as core material. However, 18F-fluoride showed poor affinity for these materials. A novel bifunctional bisphosphonate chelator, A//A/-bis(quinoylmethyl)pamidronate-amine (BQMPA) was prepared and its potential as a probe for SPECT and fluorescence imaging was investigated. A DOTA like bisphosphonate - BPAMD (a literature compound) - and its novel MCu radiolabelled complex were prepared. The preparation of 99mTc and Re-BQMPA complexes resulted in the formation of multiple products. The Cu-BPAMD complex was identified as a single complex and was kinetically stable in serum over 24 h. Both 99mTc-BQMPA and 64Cu-BPAMD showed high affinity for HA materials. We screened inorganic nanoparticulate materials for binding to 99mTc- and 64Cu-bisphosphonates. We identified that 99mTc(CO)3-DPA-Ale (99mTc labelled dipicolylamine-alendronate) and Cu-BPAMD bind to a wide range of metal oxide materials with high efficiency. HA and Alhydrogel were chosen as lead materials for further in vitro and in vivo investigations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.631284  DOI: Not available
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