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Proceedings Paper

Harnessing cellular differentiation to improve ALA-based photodynamic therapy in an artificial skin model
Author(s): Edward Maytin; Sanjay Anand; Nobuyuki Sato; Judith Mack; Bernhard Ortel
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Paper Abstract

During ALA-based photodynamic therapy (PDT), a pro-drug (aminolevulinic acid; ALA) is taken up by tumor cells and metabolically converted to a photosensitizing intermediate (protoporphyrin IX; PpIX). ALA-based PDT, while an emerging treatment modality, remains suboptimal for most cancers (e.g. squamous cell carcinoma of the skin). Many treatment failures may be largely due to insufficient conversion of ALA to PpIX within cells. We discovered a novel way to increase the conversion of ALA to PpIX, by administering agents that can drive terminal differentiation (i.e., accelerate cellular maturation). Terminally-differentiated epithelial cells show higher levels of intracellular PpIX, apparently via increased levels of a rate-limiting enzyme, coproporphyrinogen oxidase (CPO). To study these mechanisms in a three-dimensional tissue, we developed an organotypic model that mimics true epidermal physiology in a majority of respects. A line of rat epidermal keratinocytes (REKs), when grown in raft cultures, displays all the features of a fully-differentiated epidermis. Addition of ALA to the culture medium results in ALA uptake and PpIX synthesis, with subsequent death of keratinocytes upon exposure to blue light. Using this model, we can manipulate cellular differentiation via three different approaches. (1) Vitamin D, a hormone that enhances keratinocyte differentiation; (2) Hoxb13, a nuclear transcription factor that affects the genetically-controlled differentiation program of stratifying cells (3) Hyaluronan, an abundant extracellular matrix molecule that regulates epidermal differentiation. Because the raft cultures contain only a single cell type (no blood, fibroblasts, etc.) the effects of terminal differentiation upon CPO, PpIX, and keratinocyte cell death can be specifically defined.

Paper Details

Date Published: 8 April 2005
PDF: 12 pages
Proc. SPIE 5689, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XIV, (8 April 2005); doi: 10.1117/12.601940
Show Author Affiliations
Edward Maytin, Cleveland Clinic Foundation (United States)
Wellman Ctr. for Photomedicine, Massachusetts General Hospital (United States)
Sanjay Anand, Cleveland Clinic Foundation (United States)
Nobuyuki Sato, Cleveland Clinic Foundation (United States)
Judith Mack, Cleveland Clinic Foundation (United States)
Bernhard Ortel, Wellman Ctr. for Photomedicine, Massachusetts General Hospital (United States)

Published in SPIE Proceedings Vol. 5689:
Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XIV
David Kessel, Editor(s)

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