The integration of hypoxia-activated chemotherapy with photodynamic therapy (PDT) has newly become a potent strategy for tumor treatment. Herein, a reactive oxygen species (ROS)-responsive drug carriers (PS@AQ4N/mPEG- b -PSe NPs) are fabricated based on the amphiphilic selenium-containing methoxy poly(ethylene glycol)-polycarbonate (mPEG- b -PSe), the hydrophobic photosensitizer (PS), and hypoxia-activated prodrug Banoxantrone (AQ4N). The obtained nanoparticles are spherical with an average diameter of 100 nm as characterized by transmission electron microscope (TEM) and dynamic laser scattering (DLS) respectively. The encapsulation efficiency of the PS and AQ4N reaches 92.83% and 51.04% at different conditions, respectively, by UV–vis spectrophotometer. It is found that the drug release is accelerated due to the good ROS responsiveness of mPEG- b -PSe and the cumulative release of AQ4N is up to 89% within 30 h. The cell test demonstrates that the nanoparticles dissociate when triggered by the ROS stimuli in the cancer cells, thus the PS is exposed to more oxygen and the ROS generation efficiency is enhanced accordingly. The consumption of oxygen during PDT leads to the increased tumor hypoxia, and subsequently activates AQ4N into cytotoxic counterpart to inhibit tumor growth. Therefore, the synergistic therapeutic efficacy demonstrates this drug delivery has great potential for antitumor therapy.
Yinglin Zhou,Xinchang Huang,Dezhou Wu,Xiaomei Xie,Hechun Li,Qi Wang,Yan Liao,Huanan Li
High-intensity focused ultrasound (HIFU) represents a game-changing breast-conserving treatment, with its induced immune response playing a crucial role in prognosis. However, the low immunogenicity and immunosuppressive microenvironment of tumors after surgery have prevented HIFU from generating strong antitumor immune responses, resulting in tumor recurrence and metastasis. Herein, we developed CaCO 3 -loaded metal–organic frameworks (MOFs) comprising Mn 2+ , hypoxia-activated prodrug banoxantrone (AQ4N), and stimulator of interferon genes (STING) agonist SR-717 to enhance HIFU-induced antitumor immunotherapy. Upon effective accumulation and drug release within tumor microenvironment (TME), MOFs exploit HIFU-exacerbated hypoxia to activate AQ4N, thereby inducing immunogenic cell death and enhancing tumor immunogenicity. Meanwhile, Mn 2+ enhances the activity of SR-717, synergistically amplifying STING activation and effectively promoting immune cell infiltration. Moreover, CaCO 3 complements immunotherapy by depleting lactate in TME, remodeling the immune microenvironment. As a result, MOFs enhance HIFU postoperative antitumor immune responses, significantly inhibiting tumor recurrence and metastasis. This work provides valuable insights to improve the prognosis of all surgical procedures, including HIFU.
Immunotherapy efficacy has been limited by tumor-associated macrophages (TAMs), which are the most abundant immune regulatory cells infiltrating around tumor tissues. The repolarization of pro-tumor M2 TAMs to anti-tumor M1 TAMs is a very promising immunotherapeutic strategy for cancer therapy. In this manuscript, multifunctional 2D iron-based nanosheets (FeNSs) are synthesized via a simple hydrothermal method for the first time, which not only possess photothermal and photodynamic properties, but also can repolarize TAMs from M2 to M1. After modifying with polyethylene glycol and loading with bioreductive prodrug banoxantrone (AQ4N), abbreviated as AP FeNSs, it can effectively repolarize TAMs from M2 to M1 and deliver AQ4N to tumor microenvironment (TME). Moreover, the repolarized M1 TAMs overexpress inducible nitric oxide synthase, which can convert nontoxic AQ4N to cytotoxic AQ4 under hypoxic TME, enabling immunomodulation-activated chemotherapy. A series of in vitro and in vivo results corroborate that AP FeNSs effectively exert photothermal and photodynamic effects and repolarize M2 TAMs to M1 TAMs, releasing inflammatory factors and activating the chemotherapeutic effect, thereby realizing synergistic tumor therapy.
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