Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug.

Alison Curnow,Alexis Perry,Mark Wood

doi:10.1016/j.pdpdt.2018.12.005

Alison Curnow, Alexis Perry + Show 1 more

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https://doi.org/10.1016/j.pdpdt.2018.12.005

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Abstract

Photodynamic therapy (PDT) is a light activated drug therapy that can be used to treat a number of cancers and precancers. It is particularly useful in its topical form in dermatology but improvement of efficacy is required to widen its application. An ester between aminolaevulinic acid (ALA) and CP94 was synthesised (AP2-18) and experimentally evaluated to determine whether protoporphyrin IX (PpIX)-induced PDT effectiveness could be improved. A biological evaluation of AP2-18 was conducted in cultured human primary cells with both PpIX fluorescence and cell viability (as determined via the neutral red assay) being assessed in comparison to the PpIX prodrugs normally utilised in clinical practice (aminolaevulinic acid (ALA) or its methyl ester (MAL)) either administered alone or with the comparator iron chelator, CP94. No significant dark toxicity was observed in human lung fibroblasts but AP2-18 significantly increased PpIX accumulation above and beyond that achieved with ALA or MAL administration +/- CP94 in both human dermal fibroblasts and epithelial squamous carcinoma cells. On light exposure, the combined hydroxypyridinone iron chelating ALA prodrug AP2-18 generated significantly greater cytotoxicity than any of the other treatment parameters investigated when the lowest concentration (250 μM) was employed. Newly synthesised AP2-18 is therefore concluded to be an efficacious prodrug for PpIX-induced PDT in these dermatologically relevant human cells, achieving enhanced effects at lower concentrations than currently possible with existing pharmaceuticals.

Highlights

Non-melanoma skin cancer (NMSC) is the most common form of cancer worldwide [1] and its causation is predominantly associated with excessive solar ultraviolet radiation exposure [2]
These were tested alongside equimolar concentrations of aminolaevulinic acid (ALA) and CP94 and methyl aminolevulinate (MAL), with all test compounds being investigated in both human dermal fibroblasts (84BR; Fig. 2) and human epithelial squamous cell carcinoma cells (A431; Fig. 3)
AP218 was found to significantly increase protoporphyrin IX (PpIX) accumulation in both dermatological cell types, above and beyond that achieved with ALA or MAL administration either alone or in combination with the comparator iron chelating agent, CP94

Summary

Introduction

Non-melanoma skin cancer (NMSC) is the most common form of cancer worldwide [1] and its causation is predominantly associated with excessive solar ultraviolet radiation exposure [2]. Traditional treatment of NMSC commonly includes surgical excision, topical 5-fluorouracil or cryotherapy [4,5,6,7] These conventional therapies are not always associated with excellent cosmesis [4,5,6,7] and their appropriateness can be limited, depending on the location, size and number of NMSC lesions to be treated [7,8,9]. Methods: An ester between aminolaevulinic acid (ALA) and CP94 was synthesised (AP2-18) and experimentally evaluated to determine whether protoporphyrin IX (PpIX)-induced PDT effectiveness could be improved. Conclusions: Newly synthesised AP2-18 is concluded to be an efficacious prodrug for PpIX-induced PDT in these dermatologically relevant human cells, achieving enhanced effects at lower concentrations than currently possible with existing pharmaceuticals

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