Hyperbaric Oxygen Activates Enzyme-Driven Cascade Reactions for Cooperative Cancer Therapy and Cancer Stem Cells Elimination.

Tumor starvation induced by intratumor glucose depletion emerges as a promising strategy for anticancer therapy. However, its antitumor potencies are severely compromised by intrinsic tumor hypoxia, low delivery efficiencies, and undesired off-target toxicity. Herein, a multifunctional cascade bioreactor (HCG), based on the self-assembly of pH-responsive hydroxyethyl starch prodrugs, copper ions, and glucose oxidase (GOD), is engineered, empowered by hyperbaric oxygen (HBO) for efficient cooperative therapy against aggressive breast cancers. Once internalized by tumor cells, HCG undergoes disassembly and releases cargoes in response to acidic tumor microenvironment. Subsequently, HBO activates GOD-catalyzed oxidation of glucose to H2 O2 and gluconic acid by ameliorating tumor hypoxia, fueling copper-catalyzed •OH generation and pH-responsive drug release. Meanwhile, HBO degrades dense tumor extracellular matrix, promoting tumor accumulation and penetration of HCG. Moreover, along with the consumption of glucose and the redox reaction of copper ions, the antioxidant capacity of tumor cells is markedly reduced, collectively boosting oxidative stress. As a result, the combination of HCG and HBO can not only remarkably suppress the growth of orthotopic breast tumors but also restrain pulmonary metastases by inhibiting cancer stem cells. Considering the clinical accessibility of HBO, this combined strategy holds significant translational potentials for GOD-based therapies.

A two-pronged strategy to alleviate tumor hypoxia and potentiate photodynamic therapy by mild hyperthermia.

The application of photodynamic therapy (PDT) is limited by tumor hypoxia. To overcome hypoxia, catalase-like nanozymes are often used to catalyze endogenous H2O2 enriched in tumor tissues to O2. Nonetheless, the catalase activity may not be optimal at body temperature and the O2 supply may not meet the rapid O2 consumption of PDT. Herein, we provide a two-pronged strategy to alleviate tumor hypoxia based on hollow mesoporous Prussian blue nanoparticles (HMPB NPs). HMPB NPs can efficiently load the photosensitizer chlorin e6 (Ce6) and exhibit photothermal capability and temperature-dependent catalase activity. Under 808 nm laser irradiation, the photothermal effect of HMPB NPs elevated the catalase activity of HMPB NPs for O2 production. Furthermore, mild hyperthermia reduced cancer associated fibroblasts (CAFs) and induced extracellular matrix (ECM) degradation. The reduction of CAFs and the ECM decreased the solid stress of tumor tissues and normalized the tumor vasculature, which was beneficial for the external supplementation of O2 to tumors. Thereafter, under 606 nm laser irradiation, Ce6-mediated PDT generated excessive reactive oxygen species (ROS) that induced tumor cell apoptosis and achieved a high tumor inhibition rate of 92.2% in 4T1 breast tumors. Our work indicated that the alleviation of tumor hypoxia from both internal and external pathways significantly enhanced Ce6-mediated PDT against breast cancers.

Hyperbaric Oxygen Boosts PD-1 Antibody Delivery and T Cell Infiltration for Augmented Immune Responses Against Solid Tumors.

Aberrant mechanical properties and immunosuppression are the two key factors that limit the antitumor efficacy of T cell immune checkpoint blockade inhibitors, e.g., programmed cell death-1 antibody (PD-1 Ab), against solid tumors in the clinic. This study leverages hyperbaric oxygen (HBO) for the first time to address these two issues and reports the PD-1-Ab-mediated immune responses against various stroma-rich solid malignancies. The results demonstrate that HBO promoted PD-1 Ab delivery and T cells infiltration into tumor parenchyma by depleting the extracellular matrix's main components, such as collagen and fibronectin. Furthermore, HBO disrupts hypoxia-mediated immunosuppression and helps PD-1 Ab trigger robust cytotoxic T lymphocytes and long-lasting immunological memory to inhibit tumor relapses. Such enhanced immune responses are effective in solid tumors from rodents and the cancer cells from hepatocellular carcinoma patients. The results illustrate that HBO bolsters antitumor efficacy of PD-1 Ab, and the HBO-PD-1 Ab combination is a promising stroma-rich solid tumors' treatment in the clinic.

Rational Design of Conjugated Small Molecules for Superior Photothermal Theranostics in the NIR-II Biowindow.

Extensive recent progress has been made on the design and applications of organic photothermal agents for biomedical applications because of their excellent biocompatibility comparing with inorganic materials. One major hurdle for the further development and applications of organic photothermal agents is the rarity of high-performance materials in the second near-infrared (NIR-II) window, which allows deep tissue penetration and causes minimized side effects. Up till now, there have been few reported NIR-II-active photothermal agents and their photothermal conversion efficiencies are relatively low. Herein, optical absorption of π-conjugated small molecules from the first NIR window to the NIR-II window is precisely regulated by molecular surgery of substituting an individual atom. With this technique, the first demonstration of a conjugated oligomer (IR-SS) with an absorption peak beyond 1000 nm is presented, and its nanoparticle achieves a record-high photothermal conversion efficiency of 77% under 1064 nm excitation. The nanoparticles show a good photoacoustic response, photothermal therapeutic efficacy, and biocompatibility in vitro and in vivo. This work develops a strategy to boost the light-harvesting efficiency in the NIR-II window for cancer theranostics, offering an important step forward in advancing the design and application of NIR-II photothermal agents.

Bis-diketopyrrolopyrrole conjugated polymer nanoparticles as photothermic nanoagonist for specific and synergistic glioblastoma therapy.

Development of high-performance photoactive agents with tumor-specific capability for effective nanotherapeutics has received much attention in the past decades. Herein, we report a nanotherapeutic based on bis-diketopyrrolopyrrole (BDPP) conjugated polymer nanoparticles (PBDPP NPs) with remarkable near-infrared (NIR) absorption at 808 nm and high photothermal energy conversion efficiency up to 60%. In particular, precise glioblastoma-specific capability and killing ability for glioblastoma cells were effectively achieved in vitro by treating with only PBDPP NPs to induce cell apoptosis or by interaction with PBDPP NPs under NIR laser irradiation to trigger cell necrosis. Impressively, a half-maximal inhibitory concentration as low as of ∼0.15 µg mL-1 was achieved, and the magnitude is 5 to 4.4 × 104-fold lower than those of reported agents. In vivo experiment with mice further shows that the PBDPP NPs show good efficacy of photothermal therapy and complete tumor elimination using a record-low dosage of 0.35 mg mL-1 under 808 nm irradiation of low power (0.5 W cm-2). This study thus demonstrates a promising strategy of low-dose, high-efficacy polymer-based nanoagonist for specific phototherapy of glioblastoma.