Heat shock protein 90-targeted photodynamic therapy enables treatment of subcutaneous and visceral tumors

Heat shock protein 90 (Hsp90) is highly expressed in cancer cells. Kaneko et al show that targeting Hsp90 on the cancer cell surface with a photosensitizer tethered to an Hsp90 small molecule inhibitor improves the efficacy of photodynamic therapy in various human breast cancer xenografts, suggesting a therapeutic avenue for human disease. 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.