The noninvasive nature of photodynamic therapy (PDT) enables the preservation of organ function in cancer patients. However, PDT is impeded by hypoxia in the tumor microenvironment (TME) caused by high intracellular oxygen (O 2 ) consumption and distorted tumor blood vessels. Therefore, increasing oxygen generation in the TME would be a promising methodology for enhancing PDT. Herein, we proposed a concept of ferroptosis-promoted PDT based on the biochemical characteristics of cellular ferroptosis, which improved the PDT efficacy significantly by producing reactive oxygen species (ROS) and supplying O 2 sustainably through the Fenton reaction. In contrast to traditional strategies that increase O 2 based on decomposition of limited concentration of hydrogen peroxide (H 2 O 2 ), our methodology could maintain the concentration of H 2 O 2 and O 2 through the Fenton reaction. Methods : For its association with sensitivity to ferroptosis, solute carrier family 7 member 11 (SLC7A11) expression was characterized by bioinformatics analysis and immunohistochemistry of oral tongue squamous cell carcinoma (OTSCC) specimens. Afterwards, the photosensitizer chlorin e6 (Ce6) and the ferroptosis inducer erastin were self-assembled into a novel supramolecular Ce6-erastin nanodrug through hydrogen bonding and π-π stacking. Then, the obtained Ce6-erastin was extensively characterized and its anti-tumor efficacy towards OTSCC was evaluated both in vitro and in vivo . Results : SLC7A11 expression is found to be upregulated in OTSCC, which is a potential target for ferroptosis-mediated OTSCC treatment. Ce6-erastin nanoparticles exhibited low cytotoxicity to normal tissues. More significantly, The over-accumulated intracellular ROS, increased O 2 concentration and inhibited SLC7A11 expression lead to enhanced toxicity to CAL-27 cells and satisfactory antitumor effects to xenograft tumour mouse model upon irradiation. Conclusion : Our ferroptosis promoted PDT approach markedly enhances anticancer actions by relieving hypoxia and promoting ROS production, thereby our work provides a new approach for overcoming hypoxia-associated resistance of PDT in cancer treatment.
The high solution costs and non-uniqueness difficulties in the boundary element method (BEM) based on the conventional boundary integral equation (CBIE) formulation are two main weaknesses in the BEM for solving exterior acoustic wave problems. To tackle these two weaknesses, an adaptive fast multipole boundary element method (FMBEM) based on the Burton-Miller formulation for 3-D acoustics is presented in this paper. In this adaptive FMBEM, the Burton-Miller formulation using a linear combination of the CBIE and hypersingular BIE (HBIE) is applied to overcome the non-uniqueness difficulties. The iterative solver generalized minimal residual (GMRES) and fast multipole method (FMM) are adopted to improve the overall computational efficiency. This adaptive FMBEM for acoustics is an extension of the adaptive FMBEM for 3-D potential problems developed by the authors recently. Several examples on large-scale acoustic radiation and scattering problems are presented in this paper which show that the developed adaptive FMBEM can be several times faster than the non-adaptive FMBEM while maintaining the accuracies of the BEM.
Recent years have witnessed significant progress in the field of two-photon-activated photodynamic therapy (2P-PDT). However, the traditional photosensitizer (PS)-based 2P-PDT remains a critical challenge in clinics due to its low two-photon absorption (2PA) cross sections. Here, we propose that the therapeutic activity of current PSs can be enhanced through a combination of two-photon excited fluorescence resonance energy transfer (FRET) strategy and photothermal effect of near-infrared (NIR) light. A core-shell unimolecular micelle with a large two-photon-absorbing conjugated polymer core and thermoresponsive shell was constructed as a high two-photon light-harvesting material. After PSs were grafted onto the surface of a unimolecular micelle, the FRET process from the conjugated core to PSs could be readily switched "on" to kill cancer by the collapsed thermoresponsive shell due to the photothermal effect of NIR light. Such NIR-triggered FRET leads to an enhanced 2PA activity of the traditional PSs and, in turn, amplifies their cytotoxic singlet oxygen generation. Eventually, both in vitro and in vivo PDT efficiencies treated with the thermoresponsive micelles were dramatically enhanced under NIR light irradiation, as compared to pure PSs excited by traditional visible light. Such a facile and simple methodology for the enhancement of the photodynamic antitumor effect holds great promises for cancer therapy with further development.
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