Assessing the Effect of Photodynamic Therapy on Peripheral Nerve and Cancer Cells Using a Thin Tissue Engineered Collagen Culture Model

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Author Institution: Oxford Universit

Intracellular localisation of mTHPC and effect of photodynamic therapy in cells of the mammalian peripheral nervous system

Fewer nerve-related side effects have been noted after treating head and neck cancer with photodynamic therapy (PDT) compared to conventional cancer therapy. Our aim is to investigate the biological basis for any such nerve-sparing effect. In this study the intracellular localisation and effect on cell viability of the photosensitiser meta-tetrahydroxylphenylchlorin (mTHPC) was investigated in cell culture models using peripheral nerve cells. Primary cells from adult rat dorsal root ganglia (containing both neurons and glia) were used in these experiments. Localisation of mTHPC was detected using fluorescence and confocal microscopy. Levels of mTHPC fluorescence were quantified using digital image analysis. Immunocytochemistry with anti-?-III-tubulin and anti-S100 was used to distinguish neuronal and glial cell populations respectively. A cell-death assay using propidium iodide was used to evaluate neural cell susceptibility to PDT following incubation with mTHPC. The results showed that mTHPC was localised in cytoplasmic regions of neurons and glia, but was not detected in neuronal axons. Necrotic cell death was detected after PDT in these neural cell types. These results suggest that the cells of the peripheral nervous system are susceptible to PDT-mediated necrosis, but that the sparing of nerves observed during clinical PDT may be related to the heterogeneous distribution of mTHPC within neurons

Differences in sensitivity to mTHPC-mediated photodynamic therapy of neurons, glial cells and MCF7 cells in a 3-dimensional cell culture model

The effect of photodynamic therapy (PDT) on the cells of the nervous system is an important consideration in the treatment of tumours that are located within or adjacent to the brain, spinal cord and peripheral nerves. Previous studies have reported the sparing of nerves during PDT using meta-tetrahydroxyphenylchlorin (mTHPC, Foscan®) in patients and in animal models. The aim of this study was to investigate the effects of mTHPC on key nervous system cells using a 3-dimensional cell culture system for the accurate detection of differences in sensitivity

Enhancing protoporphyrin IX-induced photodynamic therapy with a topical iron chelating agent in a normal skin model

PublishedArticle© Under License of Creative Commons Attribution 3.0 LicenseProtoporphyrin IX (PpIX)-induced photodynamic therapy (PDT) is being utilised within dermatological practice as a topical method of localised ablation of non-melanoma skin cancer/precancer. Standardised protocols have been implemented to good effect when the disease remains superficial but improvement is required to widen the application of this light activated drug therapy to treat thicker or acrally located conditions. As innate haem biosynthesis is exploited to accumulate the light sensitive PpIX from a topically applied inert prodrug (aminolaevulinic acid; ALA), this pathway can be further manipulated through the concurrent administration of an iron chelating agent to hyper-accumulate PpIX by temporarily reducing its iron dependent conversion to haem. A topical preparation of ALA was applied to normal rat skin with or without the hydroxypyridinone iron chelator, CP94. Image analysis quantification of tissue fluorescence following excision indicated that ALA plus CP94 produced 29.0% more fluorescence than ALA alone (p < 0.09), peaking at 5 hours. Furthermore, fluorescence spectroscopy of frozen skin samples from each treatment group were characteristic of PpIX (maxima 636 +/- 2 nm), indicating that topical CP94 administration elevated PpIX levels without significantly producing any other fluorescent species. When PDT efficacy was considered post irradiation, a substantial three-fold increase in effect was observed 4 days after treatment when the iron chelator CP94 was co-administered topically with the prodrug (p < 0.07). It has therefore been established that the hydroxypyridinone CP94, is topically active within normal rat skin, effectively chelating iron to elevate PpIX accumulation and thus improve PDT efficacy

Investigating the effect of photodynamic therapy on nerves using tissue engineered culture models

Introduction: Photodynamic therapy (PDT) shows potential as an effective treatment for prostate cancer. Clinical observations indicate that this approach causes fewer nerve damage related side-effects than conventional treatments. The aim here is to investigate the effect of PDT on nerve tissue using engineered 3-dimensional cell culture models. Initial experiments focussed on establishing photosensitiser localisation in neurones and Schwann cells, then developing a model for simulating nerve PDT in culture

The bactericidal activity of glutaraldehyde-impregnated polyurethane

Although glutaraldehyde is known to be bactericidal in solution, its potential use to create novel antibacterial polymers suitable for use in healthcare environments has not been evaluated. Here, novel materials were prepared in which glutaraldehyde was either incorporated into polyurethane using a simple “swell-encapsulation-shrink” method (hereafter referred to as “glutaraldehyde-impregnated polyurethane”), or simply applied to the polymer surface (hereafter referred to as “glutaraldehyde-coated polyurethane”). The antibacterial activity of glutaraldehyde-impregnated and glutaraldehyde-coated polyurethane samples was tested against Escherichia coli and Staphylococcus aureus. Glutaraldehyde-impregnated polyurethane resulted in a 99.9% reduction in the numbers of E. coli within 2 h and a similar reduction of S. aureus within 1 h, whereas only a minimal reduction in bacterial numbers was observed when the biocide was bound to the polymer surface. After 15 days, however, the bactericidal activity of the impregnated material was substantially reduced presumably due to polymerization of glutaraldehyde. Thus, although glutaraldehyde retains antibacterial activity when impregnated into polyurethane, activity is not maintained for extended periods of time. Future work should examine the potential of chemical modification of glutaraldehyde and/or polyurethane to improve the useful lifespan of this novel antibacterial polymer

Conjugatable water-soluble Pt(ii) and Pd(ii) porphyrin complexes: Novel nano- and molecular probes for optical oxygen tension measurement in tissue engineering

Measurement of oxygen tension in compressed collagen sheets was performed using matrix-embedded optical oxygen sensors based on platinum(II) and palladium(II) porphyrins supported on polyacrylamide nanoparticles. Bespoke, fully water-soluble, mono-functionalised Pt(II) and Pd(II) porphyrin complexes designed for conjugation under mild conditions were obtained using microwave-assisted metallation. The new sensors display a linear response (1/τ vs. O₂) to varying oxygen tension over a biologically relevant range (7.0 × 10⁻⁴ to 2.7 × 10⁻¹ mM) in aqueous solutions; a behaviour that is maintained following conjugation to polyacrylamide nanoparticles, and following embedding of the nanosensors in compressed collagen sheets, paving the way to innovative approaches for real-time resolution of oxygen gradients throughout 3D matrices useful for tissue regeneration

Photodynamic therapy: Inception to application in breast cancer.

Photodynamic therapy (PDT) is already being used in the treatment of many cancers. This review examines its components and the new developments in our understanding of its immunological effects as well as pre-clinical and clinical studies, which have investigated its potential use in the treatment of breast cancer