Active Iron‐Drug Nanocomplexes Improve Photodynamic and Photothermal Cancer Therapy by Mitigating Tumor Hypoxia and Counteracting Tumor Heat Resistance

A pH-responsive nanocomplex (PAFH) enhances photodynamic (PDT) and photothermal therapy (PTT) by addressing tumor hypoxia and heat resistance. Under laser irradiation, PAFH releases hypericin for singlet oxygen generation and apigenin to inhibit HSP-90 and alleviate hypoxia. This synergistic approach improves PTT efficiency at mild temperatures and enhances PDT efficacy for precise cancer therapy.

Abstract

Photodynamic therapy (PDT) and photothermal therapy (PTT) offer the advantages of precise temporal and spatial selectivity in cancer treatment, minimizing damage to normal cells while effectively eliminating tumor cells. However, the therapeutic efficacy of phototherapy is always hindered by challenges such as hypoxia and tumor heat resistance. Herein, a pH-responsive metal-drug nanocomplex (denoted as PAFH) comprising hypericin (HYP), apigenin (APG), polyvinylpyrrolidone (PVP), and Fe³⁺ is developed to enhance the therapeutic efficacy of PDT and PTT. The PAFH nanocomplex exhibits photothermal properties under 808 nm laser irradiation, which can disassociate in response to the acidic tumor microenvironment and the temperature increase induced by PTT, thereby eventually triggering the on-site release of APG and HYP. The released APG inhibits the synthesis of heat shock protein HSP-90, facilitating the PAFH-mediated PTT to kill tumor cells at mild temperature. Additionally, APG alleviates hypoxia and then regulates the expression of hypoxia-inducible factor HIF-1