Preclinical Evaluation of an Integrin α(v)β(6)-Targeted Photodynamic Therapy.

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作者:Zhang Hua, Ganguly Tanushree, Harris Rebecca, Davis Ryan A, Hausner Sven H, Kovacs Luciana, Sutcliffe Julie L
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 α(v)β(6). The integrin α(v)β(6) 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 α(v)β(6) targeting peptide (ABM-5G) was conjugated onto a water-soluble PS (IRDye700DX, IR700) in solution phase, and the resulting PS-α(v)β(6)-targeted-peptide conjugate (IR700-ABM-5G, 1) demonstrated excellent photochemical and photophysical properties, including high extinction coefficient and singlet oxygen productivity similar to the nontargeted PS (free IR700). In vitro, 1 showed α(v)β(6)-selective binding to and internalization into DX3puroβ6 (α(v)β(6)+) cells vs DX3puro (α(v)β(6)-) cells, and α(v)β(6)-selective phototoxicity with EC(50)s of 1.6 nM for DX3puroβ6 cells and ≥ 250 nM for DX3puro cells. In mice bearing paired DX3puroβ6 (α(v)β(6)+) and DX3puro (α(v)β(6)-) tumor xenografts, the fluorescence intensity of 1 in DX3puroβ6 (α(v)β(6)+) tumors was 2.5- to 7-fold higher than that of the other tissues (including DX3puro (α(v)β(6)-) tumors, p < 0.0001), except for the kidneys and stomach. A single treatment of 1 (1.4 nmol per mouse) combined with near-infrared light exposure significantly suppressed the growth of DX3puroβ6 (α(v)β(6)+) tumors (198 ± 112 mm(3) vs 714 ± 251 mm(3) for saline control, p < 0.0001, on day 37 post treatment). In summary, PDT treatment with 1 demonstrated α(v)β(6)-selective therapeutic efficacy both in vitro and in vivo and is a promising targeted therapy for the treatment of a range of α(v)β(6)-expressing cancers.

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