A hypoxia-leveraged near-IR theranostic nanomedicine enables imaging-guided tumor diagnosis and photothermal therapy

Theranostic nanomedicine has emerged as a promising approach that integrates both therapy and diagnostics into a single nanoplatform in revolutionizing cancer treatment. Taking advantage of the near-IR fluorescence emission and photothermal conversion effects of heptamethine cyanine dyes, we have developed a near-IR theranostic nanomedicine (Cy7-NO₂NM) based on a fluorescent photosensitizer (Cy7-NO₂) with a high photothermal conversion efficiency (η = 31.4 %) upon near-IR light irradiation, attaining synergistic tumor diagnosis and photothermal therapy. In the presence of overexpressed nitroreductase in hypoxic tumor tissues and cells, Cy7-NO₂ is reduced and converted into a nonfluorescent counterpart containing the same fluorophore (Cy7-NH₂), which thereby can be leveraged to sense tumor hypoxia. The sensitive optical behaviors of Cy7-NO₂ in response to the tumor microenvironment enable the nanomedicine to differentiate tumor lesions of different sizes, achieving size-dependent tumor diagnosis. Meanwhile, the resulting Cy7-NH₂ is a photothermal agent too, as nearly efficient as Cy7-NO₂ in photothermal conversion. Therefore, before and after responding to the tumor hypoxia to expose the tumor lesions, the nanomedicine exerts uninterrupted phototherapeutic effects on cancerous tissues and cells under near-IR light irradiation. This study provides a simple but effective theranostic strategy to develop single-molecule nanomedicine for synergistic imaging-guided tumor diagnosis and phototheranostics.

Statement of significance

• A new single-molecule theranostic nanomedicine strategy integrating near-IR fluorescence imaging-guided tumor diagnosis and photothermal therapy was developed and evaluated in vitro and in vivo.

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  The synergistic diagnostic and therapeutic functions of the nanomedicine rely on a hypoxia-sensitive fluorescent photosensitizer, which exhibits sensitive optical responses toward the hypoxic environment of tumor tissues, enabling the nanomedicine to differentiate tumor lesions of different sizes and thus achieving size-dependent tumor diagnosis.
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  The photosensitizer has a high photothermal conversion efficiency upon near-IR light irradiation and thus can serve as a photothermal therapeutic agent for cancer treatment. Before and after detecting tumors, the nanomedicine retains its photothermal efficiency and keeps exerting photothermal effects on tumor lesions uninterruptedly.
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  Our research provides a simple but effective theranostic strategy to develop single-molecule nanomedicine for synergistic imaging-guided tumor diagnosis and phototheranostics.