Differential Diagnosis and Precision Therapy of Two Typical Malignant Cutaneous Tumors Leveraging Their Tumor Microenvironment: A Photomedicine Strategy

Abstract

Elevated hydrogen peroxide (H₂O₂) in biological tissues is generally recognized to be relevant to the carcinogenesis process that regulates the proliferative activity of cancer cells and the transformation of malignant features. Inspired by this observation, it can be hypothesized that imaging H₂O₂ in the tumor microenvironment (TME) could help diagnose tumor types and malignancy, and even guide precise therapy. Thus, in this study, a noninvasive photomedicine strategy is demonstrated that leverages the different levels of H₂O₂ in the TME, and two representative skin cancers, malignant melanoma (MM, clinically higher incidence of metastasis and recurrence) and cutaneous squamous cell carcinoma (cSCC, relatively less dangerous), are differentially diagnosed. The working probe used here is one we previously developed, namely, intelligent H₂O₂ responsive ABTS-loaded HRP@Gd nanoprobes (iHRANPs). In this study, iHRANPs have advantages over ratiometric imaging due to their bimodal imaging elements, in which the inherent magnetic resonance imaging (MR) mode can be used as the internal imaging reference and the H₂O₂ responsive photoacoustic (PA) imaging modality can be used for differential diagnosis. Results showed that after intravenous injection of iHRANPs, the tumor signals on both MM and cSCC are obviously enhanced without significant difference under the MR modality. However, under the PA modality, MM and cSCC can be easily distinguished with obvious variations in signal enhancement. Particularly, guided by PA imaging, photothermal therapy (PTT) can be precisely applied on MM, and a strong antitumor effect was achieved owing to the excessive H₂O₂ in the TME of MM. Furthermore, exogenous H₂O₂ was injected into cSCC to remedy H₂O₂ deficiency in the TME of cSCC, and an evident therapeutic efficacy on cSCC can also be realized. This study demonstrated that MM can be differentially diagnosed from cSCC by noninvasive imaging of H₂O₂ in the TME with iHRANPs; meanwhile, it further enabled imaging-guided precision PTT ablation, even for those unsatisfactory tumor types (cSCC) through exogenously delivering H₂O₂.

Keywords: cutaneous squamous cell carcinoma; differential diagnosis; hydrogen peroxide; malignant melanoma; photomedicine.