Abstract
Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); however, the accumulation of existing PS is not tumor-exclusive. We developed a tumor-localizing strategy for PDT, exploiting the high expression of heat shock protein 90 (Hsp90) in cancer cells to retain high concentrations of PS by tethering a small molecule Hsp90 inhibitor to a PS (verteporfin, VP) to create an Hsp90-targeted PS (HS201). HS201 accumulates to a greater extent than VP in breast cancer cells both in vitro and in vivo, resulting in increased treatment efficacy of HS201-PDT in various human breast cancer xenografts regardless of molecular and clinical subtypes. The therapeutic index achieved with Hsp90-targeted PDT would permit treatment not only of localized tumors, but also more diffusely infiltrating processes such as inflammatory breast cancer.
Highlights
Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared light onto a lesion of interest after systemic administration of a photosensitizer (PS); the accumulation of existing PS is not tumor-exclusive
Enable PDT for visceral or diffuse superficial tumors, we developed a strategy for selective tumor targeting of the PS by exploiting molecular signaling unique to cancer, heat shock protein 90 (Hsp90)
We recently demonstrated an Hsp[90] small molecule inhibitor could be tethered to a near infrared probe (HS131), and would accumulate in all molecular subtypes of breast cancer (BC) in vitro and in vivo[20]
Summary
Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); the accumulation of existing PS is not tumor-exclusive. Photodynamic therapy (PDT) of cancer involves administering a photoactive compound that when taken up by tissues and exposed to specific wavelengths of light, leads to conversion of oxygen to reactive oxygen species, resulting in direct cytotoxic effects on tumor cells, occlusion of the tumor vasculature, and inflammatory and adaptive immune responses[1,2,3,4]. Therapeutic ablation of tumor is achieved by the targeted delivery of light to the PS, PS within the non-tumor tissue will be activated when exposed to environmental light, resulting in phototoxicity. Treatment of deeper tumors with VP-PDT depends on the percutaneous delivery of laser fibers into tumors and laser illumination from inside the tumors, rather than the selective uptake of the PS into the tumor tissue
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