Hypoxic niches attract and sequester tumor-associated macrophages and cytotoxic T cells and reprogram them for immunosuppression.

Glioblastoma (GBM), a highly lethal brain cancer, is notorious for immunosuppression, but the mechanisms remain unclear. Here, we documented a temporospatial patterning of tumor-associated myeloid cells (TAMs) corresponding to vascular changes during GBM progression. As tumor vessels transitioned from the initial dense regular network to later scant and engorged vasculature, TAMs shifted away from perivascular regions and trafficked to vascular-poor areas. This process was heavily influenced by the immunocompetence state of the host. Utilizing a sensitive fluorescent UnaG reporter to track tumor hypoxia, coupled with single-cell transcriptomics, we revealed that hypoxic niches attracted and sequestered TAMs and cytotoxic T lymphocytes (CTLs), where they were reprogrammed toward an immunosuppressive state. Mechanistically, we identified chemokine CCL8 and cytokine IL-1ß as two hypoxic-niche factors critical for TAM trafficking and co-evolution of hypoxic zones into pseudopalisading patterns. Therefore, perturbation of TAM patterning in hypoxic zones may improve tumor control.

Tumor hypoxia and radiotherapy: A major driver of resistance even for novel radiotherapy modalities.

Hypoxia in solid tumors is an important predictor of poor clinical outcome to radiotherapy. Both physicochemical and biological processes contribute to a reduced sensitivity of hypoxic tumor cells to ionizing radiation and hypoxia-related treatment resistances. A conventional low-dose fractionated radiotherapy regimen exploits iterative reoxygenation in between the individual fractions, nevertheless tumor hypoxia still remains a major hurdle for successful treatment outcome. The technological advances achieved in image guidance and highly conformal dose delivery make it nowadays possible to prescribe larger doses to the tumor as part of single high-dose or hypofractionated radiotherapy, while keeping an acceptable level of normal tissue complication in the co-irradiated organs at risk. However, we insufficiently understand the impact of tumor hypoxia to single high-doses of RT and hypofractionated RT. So-called FLASH radiotherapy, which delivers ionizing radiation at ultrahigh dose rates (> 40 Gy/sec), has recently emerged as an important breakthrough in the radiotherapy field to reduce normal tissue toxicity compared to irradiation at conventional dose rates (few Gy/min). Not surprisingly, oxygen consumption and tumor hypoxia also seem to play an intriguing role for FLASH radiotherapy. Here we will discuss the role of tumor hypoxia for radiotherapy in general and in the context of novel radiotherapy treatment approaches.

In Situ Formed Microalgae-Integrated Living Hydrogel for Enhanced Tumor Starvation Therapy and Immunotherapy through Photosynthetic Oxygenation.

The effectiveness of various cancer therapies for solid tumors is substantially limited by the highly hypoxic tumor microenvironment (TME). Here, a microalgae-integrated living hydrogel (ACG gel) is developed to concurrently enhance hypoxia-constrained tumor starvation therapy and immunotherapy. The ACG gel is formed in situ following intratumoral injection of a biohybrid fluid composed of alginate, Chlorella sorokiniana, and glucose oxidase, facilitated by the crossing-linking between divalent ions within tumors and alginate. The microalgae Chlorella sorokiniana embedded in ACG gel generate abundant oxygen through photosynthesis, enhancing glucose oxidase-catalyzed glucose consumption and shifting the TME from immunosuppressive to immunopermissive status, thus reducing the tumor cell energy supply and boosting antitumor immunity. In murine 4T1 tumor models, the ACG gel significantly suppresses tumor growth and effectively prevents postoperative tumor recurrence. This study, leveraging microalgae as natural oxygenerators, provides a versatile and universal strategy for the development of oxygen-dependent tumor therapies.

Resveratrol suppresses liver cancer progression by downregulating AKR1C3: targeting HCC with HSA nanomaterial as a carrier to enhance therapeutic efficacy.

The enzyme AKR1C3 plays a crucial role in hormone and drug metabolism and is associated with abnormal expression in liver cancer, leading to tumor progression and poor prognosis. Nanoparticles modified with HSA can modulate the tumor microenvironment by enhancing photodynamic therapy to induce apoptosis in tumor cells and alleviate hypoxia. Therefore, exploring the potential regulatory mechanisms of resveratrol on AKR1C3 through the construction of HSA-RSV NPs carriers holds significant theoretical and clinical implications for the treatment of liver cancer. The aim of this study is to investigate the targeted regulation of AKR1C3 expression through the loading of resveratrol (RSV) on nanomaterials HSA-RSV NPs (Nanoparticles) in order to alleviate tumor hypoxia and inhibit the progression of hepatocellular carcinoma (HCC), and to explore its molecular mechanism. PubChem database and PharmMapper server were used to screen the target genes of RSV. HCC-related differentially expressed genes (DEGs) were analyzed through the GEO dataset, and relevant genes were retrieved from the GeneCards database, resulting in the intersection of the three to obtain candidate DEGs. GO and KEGG enrichment analyses were performed on the candidate DEGs to analyze the potential cellular functions and molecular signaling pathways affected by the main target genes. The cytohubba plugin was used to screen the top 10 target genes ranked by Degree and further intersected the results of LASSO and Random Forest (RF) to obtain hub genes. The expression analysis of hub genes and the prediction of malignant tumor prognosis were conducted. Furthermore, a pharmacophore model was constructed using PharmMapper. Molecular docking simulations were performed using AutoDockTools 1.5.6 software, and ROC curve analysis was performed to determine the core target. In vitro cell experiments were carried out by selecting appropriate HCC cell lines, treating HCC cells with different concentrations of RSV, or silencing or overexpressing AKR1C3 using lentivirus. CCK-8, clone formation, flow cytometry, scratch experiment, and Transwell were used to measure cancer cell viability, proliferation, migration, invasion, and apoptosis, respectively. Cellular oxygen consumption rate was analyzed using the Seahorse XF24 analyzer. HSA-RSV NPs were prepared, and their characterization and cytotoxicity were evaluated. The biological functional changes of HCC cells after treatment were detected. An HCC subcutaneous xenograft model was established in mice using HepG2 cell lines. HSA-RSV NPs were injected via the tail vein, with a control group set, to observe changes in tumor growth, tumor targeting of NPs, and biological safety. TUNEL, Ki67, and APC-hypoxia probe staining were performed on excised tumor tissue to detect tumor cell proliferation, apoptosis, and hypoxia. Lentivirus was used to silence or overexpress AKR1C3 simultaneously with the injection of HSA-RSV NPs via the tail vein to assess the impact of AKR1C3 on the regulation of HSA-RSV NPs in HCC progression. Bioinformatics analysis revealed that AKR1C3 is an important target gene involved in the regulation of HCC by RSV, which is associated with the prognosis of HCC patients and upregulated in expression. In vitro cell experiments showed that RSV significantly inhibits the respiratory metabolism of HCC cells, suppressing their proliferation, migration, and invasion and promoting apoptosis. Silencing AKR1C3 further enhances the toxicity of RSV towards HCC cells. The characterization and cytotoxicity experiments of nanomaterials demonstrated the successful construction of HSA-RSV NPs, which exhibited stronger inhibitory effects on HCC cells. In vivo, animal experiments further confirmed that targeted downregulation of AKR1C3 by HSA-RSV NPs suppresses the progression of HCC and tumor hypoxia while exhibiting tumor targeting and biological safety. Targeted downregulation of AKR1C3 by HSA-RSV NPs can alleviate HCC tumor hypoxia and inhibit the progression of HCC.

Improved Photodynamic Therapy Based on Glutaminase Blockage via Tumor Membrane Coated CB-839/IR-780 Nanoparticles.

Photodynamic therapy (PDT) has promising applications. However, the lethal function of reactive oxygen species (ROS) produced during PDT is typically limited. This restriction is induced by oxygen shortage in the tumor microenvironment due to tumor cell hypermetabolism and reductive chemicals overexpression in tumor tissues. Glutamine (Gln) metabolism is crucial for malignancy development and is closely associated with redox. Herein, a novel nanoparticle (NP) named IRCB@M is constructed to boost PDT through dual effects. This NP simultaneously blocks aerobic respiration and inhibits cellular reduced substances by blocking the Gln metabolic pathway. Within the nanocomplex, a photosensitizer (IR-780) and a glutaminase inhibitor (CB-839) are self-assembled and then encapsulated by cancer cell membranes for homologous targeting. The Gln metabolism intervention relieves hypoxia and decreases the levels of nicotinamide adenine dinucleotide phosphate (NADPH) as well as reduced glutathione (GSH) in vitro and in vivo, which are the dual amplification effects on the IR-780-mediated lethal PDT. The antitumor effects against gastric cancer are ultimately evoked in vivo, thus offering a novel concept for enhancing PDT and other ROS-dependent therapeutic approaches.

Oxygen-Evolving Radiotherapy-Radiodynamic Therapy Synergized with NO Gas Therapy by Cerium-Based Rare-Earth Metal-Porphyrin Framework.

The efficacy of traditional radiotherapy (RT) has been severely limited by its significant side effects, as well as tumor hypoxia. Here, the nanoscale cerium (Ce)-based metaloxo clusters (Ce(IV)6)-porphyrin (meso-tetra (4-carboxyphenyl) porphyrin, TCPP) framework loaded with L-arginine (LA) (denoted as LA@Ce(IV)6-TCPP) is developed to serve as a multifarious radio enhancer to heighten X-ray absorption and energy transfer accompanied by O2/NO generation for hypoxia-improved RT-radiodynamic therapy (RDT) and gas therapy. Within tumor cells, LA@Ce(IV)6-TCPP will first react with endogenous H2O2 and inducible NO synthase (iNOS) to produce O2 and NO to respectively increase the oxygen supply and reduce oxygen consumption, thus alleviating tumor hypoxia. Then upon X-ray irradiation, LA@Ce(IV)6-TCPP can significantly enhance hydroxyl radical (•OH) generation from Ce(IV)6 metaloxo clusters for RT and synchronously facilitate singlet oxygen (1O2) generation from adjacently-coordinated TCPP for RDT. Moreover, both the •OH and 1O2 can further react with NO to generate more toxic peroxynitrite anions (ONOO-) to inhibit tumor growth for gas therapy. Benefitting from the alleviation of tumor hypoxia and intensified RT-RDT synergized with gas therapy, LA@Ce(IV)6-TCPP elicited superior anticancer outcomes. This work provides an effective RT strategy by using low doses of X-rays to intensify tumor suppression yet reduce systemic toxicity.

A Contrast-Enhanced Tri-Modal MRI Technique for High-Performance Hypoxia Imaging of Breast Cancer.

Personalized radiotherapy strategies enabled by the construction of hypoxia-guided biological target volumes (BTVs) can overcome hypoxia-induced radioresistance by delivering high-dose radiotherapy to targeted hypoxic areas of the tumor. However, the construction of hypoxia-guided BTVs is difficult owing to lack of precise visualization of hypoxic areas. This study synthesizes a hypoxia-responsive T1, T2, T2 mapping tri-modal MRI molecular nanoprobe (SPION@ND) and provides precise imaging of hypoxic tumor areas by utilizing the advantageous features of tri-modal magnetic resonance imaging (MRI). SPION@ND exhibits hypoxia-triggered dispersion-aggregation structural transformation. Dispersed SPION@ND can be used for routine clinical BTV construction using T1-contrast MRI. Conversely, aggregated SPION@ND can be used for tumor hypoxia imaging assessment using T2-contrast MRI. Moreover, by introducing T2 mapping, this work designs a novel method (adjustable threshold-based hypoxia assessment) for the precise assessment of tumor hypoxia confidence area and hypoxia level. Eventually this work successfully obtains hypoxia tumor target and accurates hypoxia tumor target, and achieves a one-stop hypoxia-guided BTV construction. Compared to the positron emission tomography-based hypoxia assessment, SPION@ND provides a new method that allows safe and convenient imaging of hypoxic tumor areas in clinical settings.

Size-Switchable Ru Nanoaggregates for Enhancing Phototherapy: Hyaluronidase-Triggered Disassembly to Alleviate Deep Tumor Hypoxia.

Hypoxia is a critical factor for restricting photodynamic therapy (PDT) of tumor, and it becomes increasingly severe with increasing tissue depth. Thus, the relief of deep tumor hypoxia is extremely important to improve the PDT efficacy. Herein, tumor microenvironment (TME)-responsive size-switchable hyaluronic acid-hybridized Ru nanoaggregates (HA@Ru NAs) were developed via screening reaction temperature to alleviate deep tumor hypoxia for improving the tumor-specific PDT by the artful integration multiple bioactivated chemical reactions in situ and receptor-mediated targeting (RMT). In this nanosystem, Ru NPs not only enabled HA@Ru NAs to have near infrared (NIR)-mediated photothermal/photodynamic functions, but also could catalyze endogenous H2O2 to produce O2 in situ. More importantly, hyaluronidase (HAase) overexpressed in the TME could trigger disassembly of HA@Ru NAs via the hydrolysis of HA, offering the smart size switch capability from 60 to 15 nm for enhancing tumor penetration. Moreover, the RMT characteristics of HA ensured that HA@Ru NAs could specially enter CD44-overexpressed tumor cells, enhancing tumor-specific precision of phototherapy. Taken together these distinguishing characteristics, smart HA@Ru NAs successfully realized the relief of deep tumor hypoxia to improve the tumor-specific PDT.

Metal-Organic Framework PCN-224 Combined Cobalt Oxide Nanoparticles for Hypoxia Relief and Synergistic Photodynamic/Chemodynamic Therapy.

Photodynamic therapy (PDT) and chemodynamic therapy (CDT) are promising tumor treatments mediated by reactive oxygen species (ROS), which have the advantages of being minimally invasive. However, the hypoxia of tumor microenvironment and poor target ability often reduce the therapeutic effect. Here we propose a tumor targeted nanoplatform PCN-224@Co3O4-HA for enhanced PDT and synergistic CDT, constructed by hyaluronate-modified Co3O4 nanoparticles decorated metal-organic framework PCN-224. Co3O4 can catalyze the decomposition of highly expressed H2O2 in tumor cells to produce oxygen and alleviate the problem of hypoxia. It can also produce hydroxyl radicals according to the Fenton-like reaction for chemical dynamic therapy, significantly improving the therapeutic effect. The cell survival experiment showed that after in vitro treatment, 4T1 and MCF-7 cancer cells died in a large area under the anaerobic state, while the survival ability of normal cell L02 was nearly unchanged. This result effectively indicated that PCN-224@Co3O4-HA could effectively relieve tumor hypoxia and improve the effect of PDT and synergistic CDT. Cell uptake experiments showed that PCN-224@Co3O4-HA had good targeting properties and could effectively aggregate in tumor cells. In vivo experiments on mice, PCN-224@Co3O4-HA presented reliable biosafety performance, and can cooperate with PDT and CDT therapy to prevent the growth of tumor.

Reactive Reductive Species Participating Photodynamic Therapy for Cancer Treatment.

Although the development of oxidative photodynamic therapy (O-PDT) based on reactive oxygen species (ROS) has led to great progress in cancer treatment, tumor hypoxia, cellular adaptation and intrinsic antioxidant defenses are still obstacles at this stage. Fortunately, with the discovery and development of reactive reductive species (RRS) in the PDT process, reductive PDT (R-PDT) is receiving increasing research interest. R-PDT with oxygen-independence is an effective reduction therapy that promises excellent therapeutic efficacy in extremely hypoxic or even anaerobic environments. In the concept, we introduce representative strategies to boost the type-I photosensitizing pathway, and then focus on the most recent R-PDT involving hydrogen radical (H⋅) and the single electron transfer (SET) process.

PDGFRß-Antagonistic Affibody-Mediated Tumor-Targeted Tumor Necrosis Factor-Alpha for Enhanced Radiotherapy in Lung Cancer.

The morbidity and mortality of lung cancer are still the highest among all malignant tumors. Radiotherapy plays an important role in clinical treatment of lung cancer. However, the effect of radiotherapy is not ideal due to the radiation resistance of tumor tissues. Abnormalities in tumor vascular structure and function affect blood perfusion, and oxygen transport is impeded, making tumor microenvironment hypoxic. Tumor hypoxia is the major cause of radiotherapy resistance. By promoting tumor vessel normalization and enhancing vascular transport function, tumor hypoxia can be relieved to reduce radiotherapy resistance and increase tumor radiotherapy sensitivity. In our previous study, a pericytes-targeted tumor necrosis factor alpha (named Z-TNFα) was first constructed and produced by genetically fusing the platelet-derived growth factor receptor ß (PDGFRß)-antagonistic affibody (ZPDGFRß) to the TNFα, and the Z-TNFα induced normalization of tumor vessels and improved the delivery of doxorubicin, enhancing tumor chemotherapy. In this study, the tumor vessel normalization effect of Z-TNFα in lung cancer was further clarified. Moreover, the tumor hypoxia improvement and radiosensitizing effect of Z-TNFα were emphatically explored in vivo. Inspiringly, Z-TNFα specifically accumulated in Lewis lung carcinoma (LLC) tumor graft and relieved tumor hypoxia as well as inhibited HIF-1α expression. As expected, Z-TNFα significantly increased the effect of radiotherapy in mice bearing LLC tumor graft. In conclusion, these results demonstrated that Z-TNFα is also a promising radiosensitizer for lung cancer radiotherapy.

Recent advances in hypoxia-activated compounds for cancer diagnosis and treatment.

Hypoxia, as a prevalent feature of solid tumors, is correlated with tumorigenesis, proliferation, and invasion, playing an important role in mediating the drug resistance and affecting the cancer treatment outcomes. Due to the distinct oxygen levels between tumor and normal tissues, hypoxia-targeted therapy has attracted significant attention. The hypoxia-activated compounds mainly depend on reducible organic groups including azo, nitro, N-oxides, quinones and azide as well as some redox-active metal complex that are selectively converted into active species by the increased reduction potential under tumor hypoxia. In this review, we briefly summarized our current understanding on hypoxia-activated compounds with a particular highlight on the recently developed prodrugs and fluorescent probes for tumor treatment and diagnosis. We have also discussed the challenges and perspectives of small molecule-based hypoxia-activatable prodrug for future development.

Assessment of tumor hypoxia in spontaneous canine tumors after treatment with OMX, a novel H-NOX oxygen carrier, with [18F]FMISO PET/CT.

BACKGROUND: Hypoxia is a detrimental factor in solid tumors, leading to aggressiveness and therapy resistance. OMX, a tunable oxygen carrier from the heme nitric oxide/oxygen-binding (H-NOX) protein family, has the potential to reduce tumor hypoxia. [18F]Fluoromisonidazole ([18F]FMISO) positron emission tomography (PET) is the most widely used and investigated method for non-invasive imaging of tumor hypoxia. In this study, we used [18F]FMISO PET/CT (computed tomography) to assess the effect of OMX on tumor hypoxia in spontaneous canine tumors. RESULTS: Thirteen canine patients with various tumors (n = 14) were randomly divided into blocks of two, with the treatment groups alternating between receiving intratumoral (IT) OMX injection (OMX IT group) and intravenous (IV) OMX injection (OMX IV group). Tumors were regarded as hypoxic if maximum tumor-to-muscle ratio (TMRmax) was greater than 1.4. In addition, hypoxic volume (HV) was defined as the region with tumor-to-muscle ratio greater than 1.4 on [18F]FMISO PET images. Hypoxia was detected in 6/7 tumors in the OMX IT group and 5/7 tumors in the OMX IV injection group. Although there was no significant difference in baseline hypoxia between the OMX IT and IV groups, the two groups showed different responses to OMX. In the OMX IV group, hypoxic tumors (n = 5) exhibited significant reductions in tumor hypoxia, as indicated by decreased TMRmax and HV in [18F]FMISO PET imaging after treatment. In contrast, hypoxic tumors in the OMX IT group (n = 6) displayed a significant increase in [18F]FMISO uptake and variable changes in TMRmax and HV. CONCLUSIONS: [18F]FMISO PET/CT imaging presents a promising non-invasive procedure for monitoring tumor hypoxia and assessing the efficacy of hypoxia-modulating therapies in canine patients. OMX has shown promising outcomes in reducing tumor hypoxia, especially when administered intravenously, as evident from reductions in both TMRmax and HV in [18F]FMISO PET imaging.

Sonodynamic and sonomechanical effect on cellular stemness and extracellular physicochemical environment to potentiate chemotherapy.

BACKGROUND: Hypoxia-activated prodrug (HAP) is a promising candidate for highly tumor-specific chemotherapy. However, the oxygenation heterogeneity and dense extracellular matrix (ECM) of tumor, as well as the potential resistance to chemotherapy, have severely impeded the resulting overall efficacy of HAP. RESULTS: A HAP potentiating strategy is proposed based on ultrasound responsive nanodroplets (PTP@PLGA), which is composed of protoporphyrin (PpIX), perfluoropropane (PFP) and a typical HAP, tirapazamine (TPZ). The intense vaporization of PFP upon ultrasound irradiation can magnify the sonomechanical effect, which loosens the ECM to promote the penetration of TPZ into the deep hypoxic region. Meanwhile, the PpIX enabled sonodynamic effect can further reduce the oxygen level, thus activating the TPZ in the relatively normoxic region as well. Surprisingly, abovementioned ultrasound effect also results in the downregulation of the stemness of cancer cells, which is highly associated with drug-refractoriness. CONCLUSIONS: This work manifests an ideal example of ultrasound-based nanotechnology for potentiating HAP and also reveals the potential acoustic effect of intervening cancer stem-like cells.

NF-κB in the Radiation Response of A549 Non-Small Cell Lung Cancer Cells to X-rays and Carbon Ions under Hypoxia.

Cellular hypoxia, detectable in up to 80% of non-small cell lung carcinoma (NSCLC) tumors, is a known cause of radioresistance. High linear energy transfer (LET) particle radiation might be effective in the treatment of hypoxic solid tumors, including NSCLC. Cellular hypoxia can activate nuclear factor κB (NF-κB), which can modulate radioresistance by influencing cancer cell survival. The effect of high-LET radiation on NF-κB activation in hypoxic NSCLC cells is unclear. Therefore, we compared the effect of low (X-rays)- and high (12C)-LET radiation on NF-κB responsive genes' upregulation, as well as its target cytokines' synthesis in normoxic and hypoxic A549 NSCLC cells. The cells were incubated under normoxia (20% O2) or hypoxia (1% O2) for 48 h, followed by irradiation with 8 Gy X-rays or 12C ions, maintaining the oxygen conditions until fixation or lysis. Regulation of NF-κB responsive genes was evaluated by mRNA sequencing. Secretion of NF-κB target cytokines, IL-6 and IL-8, was quantified by ELISA. A greater fold change increase in expression of NF-κB target genes in A549 cells following exposure to 12C ions compared to X-rays was observed, regardless of oxygenation status. These genes regulate cell migration, cell cycle, and cell survival. A greater number of NF-κB target genes was activated under hypoxia, regardless of irradiation status. These genes regulate cell migration, survival, proliferation, and inflammation. X-ray exposure under hypoxia additionally upregulated NF-κB target genes modulating immunosurveillance and epithelial-mesenchymal transition (EMT). Increased IL-6 and IL-8 secretion under hypoxia confirmed NF-κB-mediated expression of pro-inflammatory genes. Therefore, radiotherapy, particularly with X-rays, may increase tumor invasiveness in surviving hypoxic A549 cells.

Exploring Geometrical, Electronic and Spectroscopic Properties of 2-Nitroimidazole-Based Radiopharmaceuticals via Computational Chemistry Methods.

Tumor hypoxia plays an important role in the clinical management and treatment planning of various cancers. The use of 2-nitroimidazole-based radiopharmaceuticals has been the most successful for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging probes, offering noninvasive means to assess tumor hypoxia. In this study we performed detailed computational investigations of the most used compounds for PET imaging, focusing on those derived from 2-nitroimidazole: fluoromisonidazole (FMISO), fluoroazomycin arabinoside (FAZA), fluoroetanidazole (FETA), fluoroerythronitroimidazole (FETNIM) and 2-(2-nitroimidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5). Conformational analysis, structural parameters, vibrational IR and Raman properties (within both harmonic and anharmonic approximations), as well as the NMR shielding tensors and spin-spin coupling constants were obtained by density functional theory (DFT) calculations and then correlated with experimental findings, where available. Furthermore, time-dependent DFT computations reveal insight into the excited states of the compounds. Our results predict a significant change in the conformational landscape of most of the investigated compounds when transitioning from the gas phase to aqueous solution. According to computational data, the 2-nitroimidazole moiety determines to a large extent the spectroscopic properties of its derivatives. Due to the limited structural information available in the current literature for the investigated compounds, the findings presented herein deepen the current understanding of the electronic structures of these five radiopharmaceuticals.

Inducing Immunogenic Cancer Cell Death through Oxygen-Economized Photodynamic Therapy with Nitric Oxide-Releasing Photosensitizers.

Photodynamic therapy (PDT) utilizes reactive oxygen species (ROS) for eradication of cancer cells. Its effectiveness is governed by the oxygen content, which is scarce in the hypoxic tumor microenvironment. We report herein two zinc(II) phthalocyanines substituted with two or four nitric oxide (NO)-releasing moieties, namely ZnPc-2NO and ZnPc-4NO, which can suppress the mitochondrial respiration, thereby sparing more intracellular oxygen for PDT. Using HT29 human colorectal adenocarcinoma cells and A549 human lung carcinoma cells, we have demonstrated that both conjugates release NO upon interaction with the intracellular glutathione, which can reduce the cellular oxygen consumption rate and adenosine triphosphate generation and alter the mitochondrial membrane potential. They can also relieve the hypoxic status of cancer cells and decrease the expression of hypoxia-inducible factor protein HIF-1α. Upon light irradiation, both conjugates can generate ROS and induce cytotoxicity even under a hypoxic condition, overcoming the oxygen-dependent nature of PDT. Interestingly, the photodynamic action of ZnPc-2NO elicits the release of damage-associated molecular patterns, inducing the maturation of dendritic cells and triggering an antitumor immune response. The immunogenic cell death caused by this oxygen-economized PDT has been demonstrated through a series of in vitro and in vivo experiments.

Carbonic anhydrase IX: A tumor acidification switch in heterogeneity and chemokine regulation.

The primary physiological process of respiration produces carbon dioxide (CO2) that reacts with water molecules which subsequently liberates bicarbonate (HCO-3) and protons. Carbonic anhydrases (CAs) are the primary catalyst involved in this conversion. More than 16 isoforms of human CAs show organ or subcellular specific activity. Dysregulation of each CA is associated with multiple pathologies. Out of these members, the overexpression of membrane-bound carbonic anhydrase IX (CAIX) is associated explicitly with hypoxic tumors or various solid cancers. CAIX helps tumors deal with higher CO2 by sequestering it with bicarbonate ions and helping cancer cells to grow in a comparatively hypoxic or acidic environment, thus acting as a pH adaptation switch. CAIX-mediated adaptations in cancer cells include angiogenesis, metabolic alterations, tumor heterogeneity, drug resistance, and regulation of cancer-specific chemokines. This review comprehensively collects and describe the cancer-specific expression mechanism and role of CAIX in cancer growth, progression, heterogeneity, and its structural insight to develop future combinatorial targeted cancer therapies.

Hypoxia-induced CXC chemokine ligand 14 expression drives protumorigenic effects through activation of insulin-like growth factor-1 receptor signaling in glioblastoma.

Hypoxic tumor microenvironment (HTM) promotes a more aggressive and malignant state in glioblastoma. However, little is known about the role and mechanism of CXC chemokine ligand 14 (CXCL14) in HTM-mediated glioblastoma progression. In this study, we report that CXCL14 expression correlated with poor outcomes, tumor grade, and hypoxia-inducible factor (HIF) expression in patients with glioblastoma. CXCL14 was upregulated in tumor cells within the hypoxic areas of glioblastoma. Hypoxia induced HIF-dependent expression of CXCL14, which promoted glioblastoma tumorigenicity and invasiveness in vitro and in vivo. Moreover, CXCL14 gain-of-function in glioblastoma cells activated insulin-like growth factor-1 receptor (IGF-1R) signal transduction to regulate the growth, invasiveness, and neurosphere formation of glioblastoma. Finally, systemic delivery of CXCL14 siRNA nanoparticles (NPs) with polysorbate 80 coating significantly suppressed tumor growth in vivo and extended the survival time in patient-derived glioblastoma xenografts. Together, these findings suggest that HIF-dependent CXCL14 expression contributes to HTM-promoted glioblastoma tumorigenicity and invasiveness through activation of the IGF-1R signaling pathway. CXCL14 siRNA NPs as an oligonucleotide drug can inhibit glioblastoma progression and constitute a translational path for the clinical treatment of glioblastoma patients.

Research Progress in Oxygen Carrier Design and Application.

Ischemia or hypoxia can lead to pathological changes in the metabolism and function of tissues and then lead to various diseases. Timely and effective blood resuscitation or improvement of hypoxia is very important for the treatment of diseases. However, there is a need to develop stable, nontoxic, and immunologically inert oxygen carriers due to limitations such as blood shortages, different blood types, and the risk of transmitting infections. With the development of various technologies, oxygen carriers based on hemoglobin and perfluorocarbon have been widely studied in recent years. This paper reviews the development and application of hemoglobin and perfluorocarbon oxygen carriers. The design of oxygen carriers was analyzed, and their application as blood substitutes or oxygen carriers in various hypoxic diseases was discussed. Finally, the characteristics and future research of ideal oxygen carriers were prospected to provide reference for follow-up research.