Cancer immune escape,
metastasis, recurrence, and multidrug resistance are all associated with
hypoxia in the tumor microenvironment (TME). We synthesized a CuPPaCC conjugate for
reactive oxygen species (ROS)-mediated
cancer therapy. CuPPaCC continuously produced cytotoxic ROS and
oxygen through a photo-chemocycloreaction, alleviated
hypoxia, and inhibited the expression of a
hypoxia-inducing factor (HIF-1α). CuPPaCC was synthesized from
pyromania phyllophyllic
acid a (PPa),
cystine (CC), and
copper ions, and its structure was characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The ability of CuPPaCC to produce ROS and
oxygen after
photodynamic therapy (
PDT) in vitro and in vivo was investigated. The ability of CuPPaCC to consume
glutathione was investigated. CuPPaCC toxicity (light and dark) in CT26 cells was analyzed by MTT and live/dead cell staining. The anticancer effect of CuPPaCC in vivo was investigated in CT26 Balb/c mice. When stimulated by the TME, CuPPaCC released Cu2+ and PPaCC, and the
singlet oxygen yield increased from 34 to 56.5%. The dual ROS-generating mechanism via a Fenton-like reaction/photoreaction and dual
glutathione depletion via Cu2+/CC multiplied the antitumor efficacy of CuPPaCC. The photo-chemocycloreaction continued to produce
oxygen and maintained high ROS levels even after
PDT, significantly alleviating
hypoxia in the TME and downregulating the expression of HIF-1α. CuPPaCC thus showed excellent antitumor activity in vitro and in vivo. These results showed that the strategy could be effective in improving the antitumor efficacy of CuPPaCC and could be used as a synergistic regimen for
cancer therapy.