Abstract
Treatment using light-activated photosensitizers (photodynamic therapy, PDT) has shown limited efficacy in pigmented melanoma, mainly due to the poor penetration of light in this tissue. Here, an optical clearing agent (OCA) was applied topically to a cutaneous melanoma model in mice shortly before PDT to increase the effective treatment depth by reducing the light scattering. This was used together with cellular and vascular-PDT, or a combination of both. The effect on tumor growth was measured by longitudinal ultrasound/photoacoustic imaging in vivo and by immunohistology after sacrifice. In a separate dorsal window chamber tumor model, angiographic optical coherence tomography (OCT) generated 3D tissue microvascular images, enabling direct in vivo assessment of treatment response. The optical clearing had minimal therapeutic effect on the in control, non-pigmented cutaneous melanomas but a statistically significant effect (p < 0.05) in pigmented lesions for both single- and dual-photosensitizer treatment regimes. The latter enabled full-depth eradication of tumor tissue, demonstrated by the absence of S100 and Ki67 immunostaining. These studies are the first to demonstrate complete melanoma response to PDT in an immunocompromised model in vivo, with quantitative assessment of tumor volume and thickness, confirmed by (immuno) histological analyses, and with non-pigmented melanomas used as controls to clarify the critical role of melanin in the PDT response. The results indicate the potential of OCA-enhanced PDT for the treatment of pigmented lesions, including melanoma.
Highlights
Melanoma arises from the melanocytes and is highly invasive and metastatic
Photodynamic therapy (PDT) the vascular network was re-established, and tumor growth continued until day 7
PDT using conventional photosensitizers has not resulted in clinically useful responses in cutaneous melanomas, which are usually heavily pigmented
Summary
According to the American Cancer Society, melanoma rates have been rising for the last 30 years and are expected to increase by 2% in 2020 [1], with about 100,350 new melanoma cases and 6850 deaths in the USA alone. Surgical resection is the standard first-line treatment for primary melanoma, often combined with chemotherapy, radiation therapy and, more recently, immunotherapy such as with the use of anti-PD1 monoclonal antibodies [2,3]. Most melanomas (≈96%) are highly pigmented [5], which negatively impacts light-based treatments. Photodynamic therapy (PDT), using light-activated compounds (photosensitizers) to produce reactive cytotoxic species such as singlet oxygen, is already established for non-melanoma skin cancer, basal cell carcinoma in which it has >90% cure rate in non-nodular lesions [6]
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