Comparing the efficacy of photodynamic and sonodynamic therapy in non-melanoma and melanoma skin cancer
Graphical abstract
Introduction
Photodynamic therapy (PDT) is currently approved as a first line treatment for non-melanoma skin cancer and has been trialled in the treatment of other cancers such as head and neck, oesophageal, bladder and prostate.1, 2 PDT requires the presence of three distinct components before a cytotoxic effect can be observed; (i) a sensitising drug, (ii) light of an appropriate wavelength and (iii) molecular oxygen. The combination of all three components result in the generation of singlet oxygen and other reactive oxygen species (ROS), that when generated in sufficient quantities, result in cell death.3 The attraction of PDT over other cancer therapies is that generation of the cytotoxic species can be controlled by careful positioning of the illumination source. This targeting is further enhanced when treating skin cancer as the sensitiser prodrug aminolevulinic acid (ALA) is converted to the active sensitiser protoporphyrin IX (PpIX) more effectively by cancer cells when compared to non-cancer cells. PpIX is naturally generated during the cellular heme cycle and is meticulously controlled to prevent its natural accumulation.4 This negative feedback system is thought to be modified in cancer tissues due to enzymatic defects that lead to an increase in protoporphyrinogen IX oxidase and/or reduced activity of ferrochelatase.5 Another advantage of PDT is the excellent cosmetic outcome observed post treatment when compared to surgery or topical chemotherapy treatment (i.e., 5-fluorouracil).6, 7 However, the limited penetration of light through mammalian tissue has restricted the use of PDT to the treatment of superficial lesions and reduces its effectiveness in treating more deeply-seated or highly pigmented lesions.8 Indeed, while PDT is routinely used to treat superficial basal cell carcinoma (BCC), it is not indicated for the treatment of malignant melanoma.9 The dark pigmentation associated with melanotic lesions acts as a filter for the light used to activate the majority of conventional sensitizers that absorb in the visible range of the electromagnetic spectrum.10 To compound matters further, melanin has natural anti-oxidant properties thereby acting as a scavenger for ROS generated during PDT.11, 12 The development of near-infrared (NIR) absorbing sensitizers that possess absorption maxima in a region where melanin does not absorb have produced impressive results in treating melanoma, suggesting the anti-oxidant effect of melanin may be overcome when using PDT.13, 14, 15, 16
Sonodynamic therapy (SDT) has recently emerged as an alternative to PDT and uses low intensity ultrasound instead of light to activate the sensitiser. This interaction of the sensitiser with an acoustic field generates ROS that result in cytotoxic effects similar to those observed in PDT.17, 18 The major benefit of using SDT instead of PDT is that ultrasound is clinically approved as a safe and effective imaging modality and unlike light can achieve penetration depths in soft tissue in the region of tens of centimetres.19 Therefore, SDT offers the potential of treating more deeply seated solid tumours than currently possible using PDT.
In this manuscript, we compare the effectiveness of PDT and SDT at treating non-melanoma and melanoma skin cancer in pre-clinical models. Specifically, we determine the effect of ALA mediated PDT/SDT in treating A431 squamous cell carcinoma and Rose Bengal mediated PDT/SDT in treating B16-F10-Luc2 melanoma cells both in vitro and in vivo. The resulting efficacy of these treatments is then discussed.
Section snippets
Materials and reagents
ALA and Rose Bengal were purchased from Aldrich at the highest grade possible. Metvix cream was purchased from Galderma. All other chemicals were purchased from commercial sources at the highest possible purity and used as received. Human epidermoid carcinoma A431 cell line was obtained from ATCC and the B16-F10-Luc2 cell line was purchased from PerkinElmer. SCID and athymic nude mice were obtained from Harlan Laboratories. In these studies all animals were treated humanely and in accordance
Results & discussion
The initial focus of this study was to evaluate the efficacy of ALA mediated SDT as a treatment for non-melanoma skin cancer when compared to conventional ALA mediated PDT treatment. To enable this comparison, A431 squamous cell carcinoma cells were seeded in a 96 well plate and incubated with ALA (1 or 2 μM) for 4 h followed by treatment with either red light (630 nm ± 15 nm) or ultrasound. The cell viability was determined 24 h later using a MTT assay. The results (Fig. 1a) show that both PDT and SDT
Acknowledgements
J.F.C. acknowledges Norbrook Laboratories Ltd for an endowed chair. C.Mc.E. acknowledges the department of employment and learning for a Ph.D. studentship.
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