A theranostic endoperoxide agent with targeted singlet oxygen release and concomitant fluorescence signals

To circumvent the lingering limitations of photodynamic therapy, we developed a novel naphthalene-derived endoperoxide through structural optimization of 1,4-dimethylnaphthalene. Strategic introduction of an amide group at the 2-position enabled precise modulation of steric and electronic properties, resulting in prolonged 1O2 release half-life (t1/2 = 8.6 h) compared to simpler derivatives. This temporal control is likely to result in more 1O2 release in tumor tissues, significantly enhancing the therapeutic effect. Our studies reveal that thermal cycloreversion drives 1O2 generation from these compounds, achieving potent cytotoxicity in cancer cell cultures (IC50 = 11.6 µM). In vivo evaluation using a murine 4T1 breast cancer model demonstrated marked tumor suppression following intraperitoneal administration, with no observable systemic toxicity at the therapeutic doses. To enable real-time evaluation of therapeutic efficacy, we designed a modular system combining a naphthalimide fluorescent group with an H2O2-responsive phenylboronic ester. This construct capitalizes on the pathological overproduction of H2O2, a well-established biomarker of tumor progression. When exposed to elevated H2O2 levels in cancer cells, the phenylboronic ester undergoes specific cleavage to generate hydroxyl groups. This structural transformation triggers a blue-to-green fluorescence emission change, providing direct visual confirmation of therapeutic activation within the tumor microenvironment.