Preclinical Evaluation of an Integrin αβ-Targeted Photodynamic Therapy.

Photodynamic therapy (PDT) is a minimally invasive treatment in which an external light source activates an injected photosensitizer (PS) to generate reactive oxygen species, causing localized cell death. Although the first PDT received FDA approval in 1995, clinical adoption has been limited, in part due to the limited tumor selectivity of PSs. The goal of this study was to develop a PS with improved tumor selectivity by incorporating a targeting peptide that selectively binds to the integrin αβ. The integrin αβ is an epithelial-specific cell-surface receptor that is overexpressed in several cancer types, with expression level often linked to poor overall survival. The integrin αβ targeting peptide (ABM-5G) was conjugated onto a water-soluble PS (IRDye700DX, IR700) in solution phase, and the resulting PS-αβ-targeted-peptide conjugate (IR700-ABM-5G, ) demonstrated excellent photochemical and photophysical properties, including high extinction coefficient and singlet oxygen productivity similar to the nontargeted PS (free IR700). showed αβ-selective binding to and internalization into DX3puroβ6 (αβ+) cells vs DX3puro (αβ-) cells, and αβ-selective phototoxicity with ECs of 1.6 nM for DX3puroβ6 cells and ≥ 250 nM for DX3puro cells. In mice bearing paired DX3puroβ6 (αβ+) and DX3puro (αβ-) tumor xenografts, the fluorescence intensity of in DX3puroβ6 (αβ+) tumors was 2.5- to 7-fold higher than that of the other tissues (including DX3puro (αβ-) tumors, < 0.0001), except for the kidneys and stomach. A single treatment of (1.4 nmol per mouse) combined with near-infrared light exposure significantly suppressed the growth of DX3puroβ6 (αβ+) tumors (198 ± 112 mm vs 714 ± 251 mm for saline control, < 0.0001, on day 37 post treatment). In summary, PDT treatment with demonstrated αβ-selective therapeutic efficacy both and and is a promising targeted therapy for the treatment of a range of αβ-expressing cancers.