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Title: Targeted nano-systems for improving the selectivity of photodynamic therapy
Author: Bovis, M. J.
ISNI:       0000 0004 5357 2053
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Introduction: Photodynamic therapy (PDT) is a minimally invasive treatment that requires a light-activated drug, known as a photosensitiser (PS), light of a specific wavelength and oxygen. 5,10,15,20-meta-tetra(hydroxyphenyl)chlorin (m-THPC) is one of the most potent PS’s currently available for use in PDT, however, its undesirable accumulation in healthy tissues has prompted research to improve its uptake and selectivity into tumour tissue for the treatment of certain malignant diseases, whilst reducing adverse skin photosensitivity. In this investigation, a range of nanocarriers, eliciting a host of different properties, were developed to achieve more efficient delivery of m-THPC in vivo. These included liposomes, organically modified silica (ORMOSIL) nanoparticles (NPs) and polymeric NPs, which were additionally surface modified with a biocompatible polymer (PEG) coating to improve blood circulation times and the bioavailability of m-THPC. Further to this, studies investigating the conjugation of ligands, over-expressed on many cancers, to the NP surface aimed to increase active m-THPC-delivery via targeted nanocarriers. The overall objective of this study was to compare the pharmacokinetics of m-THPC delivery between the nanocarrier formulations and standard Foscan®, in normal rat and tumour-bearing animal models, to ultimately improve the efficacy of PDT. Materials & Methods: The biodistribution of m-THPC in its standard formulation (Foscan) compared to its incorporation in untargeted and targeted pegylated NPs was assessed through quantitative chemical extraction methods and pharmacokinetic analysis. A range of tissue samples were collected over different time periods following i.v. administration of NPs (m-THPC dose equivalent) in both healthy and tumour-bearing murine models. Confocal and fluorescence microscopy techniques were employed for in vitro uptake studies and to examine ex vivo tissue localisation of encapsulated m-THPC. Finally PDT and skin photosensitivity studies were carried out in vivo to assess the efficacy of treatment to tumours and skin through histological analysis. Results & Conclusion: Pharmacokinetic data typically indicated an increase in blood plasma t1/2 of pegylated NPs in comparison to non-pegylated NPs or Foscan alone, indicative of the stealth properties conferred by the PEG corona. Peak accumulation of m-THPC in tumour tissue occurred between 6-24 h via passive uptake with untargeted NPs, attributed to the enhanced permeability and retention (EPR) effect. A significant improvement in tumour uptake, by a factor of three, was observed using pegylated liposomes compared to Foscan alone. Active targeting of NPs demonstrated a positive uptake into cells, unfortunately this did not translate to an improvement in m-THPC biodistribution or PDT results using in vivo models. Encouragingly anti-tumour PDT effects were observed with all NPs compared to Foscan, but treatment was most effective with untargeted pegylated liposomes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available