Hypoxia In Solid Tumors Research Articles

A glutathione-activatable nanoplatform for enhanced photodynamic therapy with simultaneous hypoxia relief and glutathione depletion

Inspired by unique selectivity and irreversible destruction toward treated tissues or cells, photodynamic therapy (PDT) has gained increasing attention in cancer treatment. However, PDT-induced hypoxia and elevated glutathione (GSH) levels in cancer cells are still great challenges which can significantly reduce treatment outcomes. Herein, we designed a GSH-activatable nitric oxide (NO) generating mannan nanoparticles (NO-mannan), an “All in One” therapy nanoplatform with enhanced reactive oxygen species (ROS) generation through GSH depletion and hypoxia relief. Upon reaching the reductive hypoxic tumor microenvironment, the nanoplatform could undergo a GSH-triggered hydrophobic to hydrophilic transition and simultaneously generate NO gas with vessel-relaxing and GSH scavenging for efficient ROS production. Notably, the NO induced hypoxia relief and redox-responsive cellular antioxidant defense system destruction endowed the NO-mannan with the ability of enhanced photodynamic therapy both in vitro and in vivo. Overall, our work demonstrated a simple strategy to combine the GSH responsive NO-based gas therapy with PDT to greatly improve the PDT efficacy especially for hypoxic solid tumors, which may provide a practical paradigm for effective PDT cancer treatment.

Polymerized human hemoglobin facilitated modulation of tumor oxygenation is dependent on tumor oxygenation status and oxygen affinity of the hemoglobin-based oxygen carrier

Administration of hemoglobin-based oxygen carriers (HBOCs) into the systemic circulation is a potential strategy to relieve solid tumor hypoxia in order to increase the effectiveness of chemotherapeutics. Previous computational analysis indicated that the oxygen (O2) status of the tumor and HBOC O2 affinity may play a role in increased O2 delivery to the tumor. However, no study has experimentally investigated how low- and high-affinity HBOCs would perform in normoxic and hypoxic tumors. In this study, we examined how the HBOC, polymerized human hemoglobin (PolyhHb), in the relaxed (R) or tense (T) quaternary state modulates O2 delivery to hypoxic (FME) and normoxic (LOX) human melanoma xenografts in a murine window chamber model. We examined microcirculatory fluid flow via video shearing optical microscopy, and O2 distributions via phosphorescence quenching microscopy. Additionally, we examined how weekly infusion of a 20% top-load dose of PolyhHb influences growth rate, vascularization, and regional blood flow in the FME and LOX tumor xenografts. Infusion of low-affinity T-state PolyhHb led to increased tissue oxygenation, decreased blood flow, decreased tumor growth, and decreased vascularization in hypoxic tumors. However, infusion of both T-state and R-state PolyhHbs led to worse outcomes in normoxic tumors. Of particular concern was the high-affinity R-state PolyhHb, which led to no improvement in hypoxic tumors and significantly worsened outcomes in normoxic tumors. Taken together, the results of this study indicate that the tumor O2 status is a primary determinant of the potency and outcomes of infused PolyhHb.

Rod-shape inorganic biomimetic mutual-reinforcing MnO2-Au nanozymes for catalysis-enhanced hypoxic tumor therapy

Biomimetic nanozymes possessing natural enzyme-mimetic activities have been extensively applied in nanocatalytic tumor therapy. However, engineering hybrid biomimetic nanozymes to achieve superior nanozyme activity remained to be an intractable challenge in hypoxic tumors. Herein, a rod-like biomimetic hybrid inorganic MnO2-Au nanozymes are developed, where MnO2 and ultrasmall Au nanoparticles (NPs) are successively deposited on the mesoporous silica nanorod to cooperatively improve the O2 content and thermal sensitivity of hypoxic solid tumors guided by multi-modal imaging. Under the catalyzing of MnO2, the intratumoral H2O2 is decomposed to greatly accelerate O2 generation, which could boost the curative effect of radiation therapy (RT) and further enhance the Au-catalyzed glucose oxidation. Mutually, the Au NPs can steadily and efficiently catalyze the oxidation of glucose in harsh tumor microenvironment, thus sensitizing tumor cells to thermal ablation for mild photothermal therapy and further promoting the catalytic efficiency of MnO2 with the self-supplied H2O2/H+. As a result, this mutual-reinforcing cycle can endow the nanoplatform with accelerated O2 generation, thus alleviating hypoxic environment and further boosting RT effect. Furthermore, acute glucose consuming can induce downregulation expression of heat shock protein (HSP), achieving starvation-promoted mild photothermal therapy. This synthesized hybrid nanozymes proves to be a versatile theranostic agent for nanocatalytic cancer therapy.

A Robust and Cost-Effective Luminescent-Based High-Throughput Assay for Fructose-1,6-Bisphosphate Aldolase A.

Hypoxic solid tumors induce the stabilization of hypoxia-inducible factor 1 alpha (HIF1α), which stimulates the expression of many glycolytic enzymes and hypoxia-responsive genes. A high rate of glycolysis supports the energetic and material needs for tumors to grow. Fructose-1,6-bisphosphate aldolase A (ALDOA) is an enzyme in the glycolytic pathway that promotes the expression of HIF1α. Therefore, inhibition of ALDOA activity represents a potential therapeutic approach for a range of cancers by blocking two critical cancer survival mechanisms. Here, we present a luminescence-based strategy to determine ALDOA activity. The assay platform was developed by integrating a previously established ALDOA activity assay with a commercial NAD/NADH detection kit, resulting in a significant (>12-fold) improvement in signal/background (S/B) compared with previous assay platforms. A screening campaign using a mixture-based compound library exhibited excellent statistical parameters of Z' (>0.8) and S/B (~20), confirming its robustness and readiness for high-throughput screening (HTS) application. This assay platform provides a cost-effective method for identifying ALDOA inhibitors using a large-scale HTS campaign.

Hypoxia and cancer related pathology.

Hypoxic environments occur normally at high altitude, or in underground burrows and in deep sea habitats. They also occur pathologically in human ischemia and in hypoxic solid tumors. Hypoxia in various cancer types and its related molecular mechanisms are associated with a poor clinical outcome. This review will discuss how hypoxia can influence two aspects of tumorigenesis, namely the direct, cell-intrinsic oncogenic effects, as well as the indirect effects on tumor progression mediated by an altered tumor microenvironment. We will also discuss recent progress in identifying the functional roles of hypoxia-related factors (HIFs), along with their regulators and downstream target genes, in cancer stem cells and therapy. Importantly, we propose, using convergent evolution schemes to identify novel biomarkers for both hypoxia adaptation and hypoxic solid tumors as an important strategy in the future.

Intelligent Bimetallic Nanoagents as Reactive Oxygen Species Initiator System for Effective Combination Phototherapy.

Phototherapy is a promising oncotherapy method. However, there are various factors greatly restricted phototherapy development, including poor tumor-specific accumulation, the hypoxia in solid tumor, and the systemic phototoxicity of photosensitizer. Herein, a tumor microenvironment (TME)-responsive intelligent bimetallic nanoagents (HSA-Pd-Fe-Ce6 NAs) composed of human serum albumin (HSA), palladium-iron (Pd-Fe) bimetallic particles, and chlorin e6 (Ce6) was designed for effective combination phototherapy. The Pd-Fe part in the HSA-Pd-Fe-Ce6 NAs would react with the endogenous hydrogen peroxide (H2O2) in an acidic ambiance within tumor to generate cytotoxic superoxide anion free radical through the “Fenton-like reaction.” H2O2, coupled with highly toxic singlet oxygen (1O2) caused by the Ce6 component under the irradiation of 660 nm laser, resulted in synergistic cancer therapy effects in hypoxia surroundings. Besides, this nanoagents could result in hyperpyrexia-induced cell apoptosis because of superior absorption performance in near-infrared wavelength window bringing about excellent photothermal conversion efficiency. The cell cytotoxicity results showed that the survival rate after treated by 40 μg mL–1 nanoagents was only 17%, which reveals that the HSA-Pd-Fe-Ce6 NAs had the advantage of efficient and controllable phototherapy. In short, it exhibited excellent hypoxia-resistant combination phototherapy efficacy in vitro. Therefore, the multifunctional nanoagents are powerful and provide a new avenue for effective combination phototherapy.

Photosynthetic Biohybrid Nanoswimmers: Photosynthetic Biohybrid Nanoswimmers System to Alleviate Tumor Hypoxia for FL/PA/MR Imaging‐Guided Enhanced Radio‐Photodynamic Synergetic Therapy (Adv. Funct. Mater. 17/2020)

In article number 1910395, Min Zhou and co-workers utilize a photosynthetic biohybrid nanoswimmer system (PBNs), comprising magnetically engineered Spirulina platensis, for tumor-targeted imaging and therapy. The PBNs can be used as oxygenerators for in situ O2 generation in hypoxic solid tumors through photosynthesis, thus modulating the tumor microenvironment and improving the effectiveness of radiotherapy.

Photosynthetic Biohybrid Nanoswimmers System to Alleviate Tumor Hypoxia for FL/PA/MR Imaging‐Guided Enhanced Radio‐Photodynamic Synergetic Therapy

AbstractBiohybrid microswimmers have recently shown to be able to actively perform in targeted delivery and in vitro biomedical applications. However, more envisioned functionalities of the microswimmers aimed at in vivo treatments are still challenging. A photosynthetic biohybrid nanoswimmers system (PBNs), magnetic engineered bacteria‐Spirulina platensis, is utilized for tumor‐targeted imaging and therapy. The engineered PBNs is fabricated by superparamagnetic magnetite (Fe3O4 NPs) via a dip‐coating process, enabling its tumor targeting ability and magnetic resonance imaging property after intravenous injection. It is found that the PBNs can be used as oxygenerator for in situ O2 generations in hypoxic solid tumors through photosynthesis, modulating the tumor microenvironment (TME), thus improving the effectiveness of radiotherapy (RT). Furthermore, the innate chlorophyll released from the RT‐treated PBNs, as a photosensitizer, can produce cytotoxic reactive oxygen species under laser irradiation to achieve photodynamic therapy. Excellent tumor inhibition can be realized by the combined multimodal therapies. The PBNs also possesses capacities of chlorophyll‐based fluorescence and photoacoustic imaging, which can monitor the tumor therapy and tumor TME environment. These intriguing properties of the PBNs provide a promising microrobotic platform for TME hypoxic modulation and cancer theranostic applications.

Tissue pO2 distributions in xenograft tumors dynamically imaged by Cherenkov-excited phosphorescence during fractionated radiation therapy

Hypoxia in solid tumors is thought to be an important factor in resistance to therapy, but the extreme microscopic heterogeneity of the partial pressures of oxygen (pO2) between the capillaries makes it difficult to characterize the scope of this phenomenon without invasive sampling of oxygen distributions throughout the tissue. Here we develop a non-invasive method to track spatial oxygen distributions in tumors during fractionated radiotherapy, using oxygen-dependent quenching of phosphorescence, oxygen probe Oxyphor PtG4 and the radiotherapy-induced Cherenkov light to excite and image the phosphorescence lifetimes within the tissue. Mice bearing MDA-MB-231 breast cancer and FaDu head neck cancer xenografts show different pO2 responses during each of the 5 fractions (5 Gy per fraction), delivered from a clinical linear accelerator. This study demonstrates subsurface in vivo mapping of tumor pO2 distributions with submillimeter spatial resolution, thus providing a methodology to track response of tumors to fractionated radiotherapy.

Enzyme-Assisted Photodynamic Therapy Based on Nanomaterials.

Photodynamic therapy (PDT) is a noninvasive cancer treatment that requires the copresence of a photosensitizer (PS), oxygen, and light. The efficacy of conventional PDT is usually limited by two factors: delivery of the PS to the tumor and the hypoxic solid tumor environment. To improve the efficacy of PDT, nanomaterial-based, enzyme-assisted PDT (nano-ezPDT), which integrates enzyme-responsive components into nanomedicines, was developed for enhanced PS delivery and oxygen generation. Nano-ezPDT is designed to take full advantage of the catalytic function of locally activated tumor-associated enzymes or smuggled exogeneous enzymes. The enhancement of PS release and accumulation is often controlled by endogenous enzymes upregulated at the tumor sites. Oxygen generation, however, relies mostly on catalase-loaded nanomedicines. In this review, we discuss the associated enzymes, constructs, and types of nanocarriers and highlight the principle and utility of nano-ezPDT for cancer therapy.

Vascular onco-therapies targeting continuous and intermittent intra-tumor hypoxia

Objective: Solid tumors experience intra-tumor hypoxia once they achieve an increase in size. This is due to an imbalance between tumor oxygenation and the metabolic demand of the tumor as well as the development of chaotic microvasculature of the tumor. The hypoxic condition creates several barriers to the delivery of antitumor drugs to the tumor. Intra-tumor hypoxia alters the tumor microenvironment, accelerating the process of tumor angiogenesis, and culminating in the formation of chaotic tumor vasculature. The abnormal and faulty tumor microvasculature alters the interstitial pressure gradients of the tumor which severely impairs delivering drugs to solid tumors. Rectifying this microenvironment is an important avenue of anticancer research. The normalization of tumor vasculature may lead to an excellent anticancer management. Study Selection and Data Source: The present review involves recent studies on anticancer research targeting the hypoxia-signaling cascade in solid tumors. Results and Conclusion: The present review covers the cause of intra-tumor hypoxia, the resulting problems of anticancer drug delivery to the tumor, and contemporary research to overcome the problem of drug delivery to hypoxic solid tumors in humans.

Biomineralization-inspired nanozyme for single-wavelength laser activated photothermal-photodynamic synergistic treatment against hypoxic tumors.

Hypoxia, one of the features of most solid tumors, can severely impede the efficiency of oxygen-dependent treatments such as chemotherapy, radiotherapy and type-II photodynamic therapy. Herein, a catalase-like nanozyme RuO2@BSA (RB) was first prepared through a biomineralization strategy, and a high efficiency near-infrared photosensitizer (IR-808-Br2) was further loaded into the protein shell to generate the safe and versatile RuO2@BSA@IR-808-Br2 (RBIR) for the imaging-guided enhanced phototherapy against hypoxic tumors. RB not only acts like a catalase, but also serves as a photothermal agent that speeds up the oxygen supply under near-infrared irradiation (808 nm). The loaded NIR photosensitizer could immediately convert molecular oxygen (O2) to cytotoxic singlet oxygen (1O2) upon the same laser irradiation. Results indicated that RBIR achieved enhanced therapeutic outcomes with negligible side effects. Features such as a simple synthetic route and imaging-guided and single-wavelength-excited phototherapy make the nanozyme a promising agent for clinical applications.

Natural-Origin Hypocrellin-HSA Assembly for Highly Efficient NIR Light-Responsive Phototheranostics against Hypoxic Tumors.

Tumor hypoxia severely limits the therapeutic efficacy of solid tumors in photodynamic therapy. One strategy is to develop photosensitizers with simultaneously high efficiency in photodynamic (PDT) and photothermal therapies (PTT) in a single natural-origin phototheranostic agent to overcome this problem. However, less attention has been paid to the natural-origin phototheranostic agent with high PDT and PTT efficiencies even though they have negligible side effects and are environmentally sustainable in comparison with many reported phototheranostic agents. In addition, almost all clinical applied photosensitizers are of natural origin so far. Herein, we synthesized a natural product-based hypocrellin derivative (AETHB), with a high singlet oxygen quantum yield of 0.64 as an efficient photosensitizer different from commercially available porphyrin-based photosensitizers. AETHB is further assembled with human serum albumin to construct nanoparticles (HSA-AETHB NPs) with a high photothermal conversion efficiency (more than 50%). As-prepared HSA-AETHB NPs have shown good water solubility and biocompatibility, pH and light stability, wide absorption (400-750 nm), and NIR emission centered at 710 nm. More importantly, HSA-AETHB NPs can be applied for fluorescent/photoacoustic dual-mode imaging and simultaneously highly efficient PDT/PTT in hypoxic solid tumors. Therefore, this natural-origin multifunctional phototheranostic agent is showing very promising for effective, precise, and safe cancer therapy in clinical applications.

Hypoxia in solid tumors: a key promoter of cancer stem cell (CSC) resistance.

Cancer stem cells (CSCs) are highly tumorigenic cell types that reside within specific areas of tumor microenvironment (TME), and are endowed with self-renewal and resistance properties. Here, we aimed to discuss mechanisms involved in hypoxia-derived CSC resistance and targeting for effective cancer therapy. Preferential localization within hypoxic niches would help CSCs develop adaptive mechanisms, mediated through the modification of responses to various stressors and, as a result, show a more aggressive behavior. Hypoxia, in fact, serves as a multi-tasking strategy to nurture CSCs with this adaptive capacity, complexing targeted therapies.

Mitochondria-Targeting Selenophene-Modified BODIPY-Based Photosensitizers for the Treatment of Hypoxic Cancer Cells.

Two red-absorbing, water-soluble and mitochondria (MT)-targeting selenophene-substituted BODIPY-based photosensitizers (PSs) were realized (BOD-Se, BOD-Se-I), and their potential as photodynamic therapy (PDT) agents were evaluated. BOD-Se-I showed higher 1 O2 generation yield thanks to the enhanced heavy-atom effect, and this derivative was further tested in detail in cell culture studies under both normoxic and hypoxic conditions. BOD-Se-I not only effectively functioned under hypoxic conditions, but also showed highly selective photocytotoxicity towards cancer cells. The selectivity is believed to arise from differences in mitochondrial membrane potentials of healthy and cancerous cells. To the best of our knowledge, this marks the first example of a MT-targeted BODIPY PS that functions under hypoxic conditions. Remarkably, thanks to the design strategy, all these properties where realized by a compound that was synthesized in only five steps with 32 % overall yield. Hence, this material holds great promise for the realization of next-generation PDT drugs for the treatment of hypoxic solid tumors.

YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression

Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. Here, we report that genes involved in various human cancers evolved rapidly in Tibetans and six Tibetan domestic mammals compared to reciprocal lowlanders. Furthermore, m6A modified mRNA binding protein YTHDF1, one of evolutionary positively selected genes for high-altitude adaptation is amplified in various cancers, including non-small cell lung cancer (NSCLC). We show that YTHDF1 deficiency inhibits NSCLC cell proliferation and xenograft tumor formation through regulating the translational efficiency of CDK2, CDK4, and cyclin D1, and that YTHDF1 depletion restrains de novo lung adenocarcinomas (ADC) progression. However, we observe that YTHDF1 high expression correlates with better clinical outcome, with its depletion rendering cancerous cells resistant to cisplatin (DDP) treatment. Mechanistic studies identified the Keap1-Nrf2-AKR1C1 axis as the downstream mediator of YTHDF1. Together, these findings highlight the critical role of YTHDF1 in both hypoxia adaptation and pathogenesis of NSCLC.

Ultrasound‐Activated Oxygen and ROS Generation Nanosystem Systematically Modulates Tumor Microenvironment and Sensitizes Sonodynamic Therapy for Hypoxic Solid Tumors

AbstractSonodynamic therapy (SDT) is noninvasive and possesses high body‐penetration depth, showing great potential for the treatment of deep‐seated solid tumors. The efficacy of SDT, however, is limited by widespread hypoxia in solid tumors. Given this, an ultrasound‐activated nanosystem is developed by integrating ferrate(VI) and protoporphyrin IX into biodegradable hollow mesoporous organosilica nanoplatforms, followed by assembling a phase‐change material of lauric acid. The ferrate(VI) effectively reacts with water as well as overexpressed hydrogen peroxide and glutathione (GSH) in tumor cells, leading to tumor‐microenvironment‐independent oxygen production and in situ GSH depletion in tumors. More importantly, significant reactive oxygen species (ROS) overproduction is simultaneously achieved by protoporphyrin‐augmented SDT and intracellular Fenton chemistry. Furthermore, the mild hyperthermia induced by ultrasound can trigger the phase change of lauric acid, achieving ultrasound‐responsive control over the release of oxygen and ROS, and the depletion of GSH. The simultaneous oxygen generation, in situ GSH depletion, and ROS overproduction play a synergetic role in sensitizing SDT toward hypoxic solid tumors, which is verified by the remarkable improvement of hypoxic environments and more significant growth inhibition of SDT against osteosarcoma both in vitro and in vivo, showing promising application in hypoxic solid tumor treatment.

Nanomedicine-Enabled Modulation of Tumor Hypoxic Microenvironment for Enhanced Cancer Therapy.

Hypoxia is a common condition of solid tumors that is mainly caused by enhanced tumor proliferative activity and dysfunctional vasculature. In the treatment of hypoxic human solid tumors, many conventional therapeutic approaches (e.g., oxygen-dependent photodynamic therapy, anticancer drug-based chemotherapy or X-ray induced radiotherapy) become considerably less effective or ineffective. In recent years, various strategies have been explored to deliver or generate oxygen inside solid tumors to overcome tumorous hypoxia and show promising evidence to improve the antitumor efficiency. In this review, the extrinsic regulation of tumor hypoxia via nanomaterial delivery is discussed followed by a summary of the mechanisms through which the modulated tumor hypoxic microenvironment improves therapeutic efficacy. The review concludes with future perspectives, to specifically address the translation of nanomaterial-based therapeutic strategies for clinical applications.

Mitochondria-localized iridium(III) complexes with anthraquinone groups as effective photosensitizers for photodynamic therapy under hypoxia

Photodynamic therapy (PDT) is a potential way for the tumor treatment. However, it notably suffers the limitation of hypoxia in solid tumors. Thus, it is significant to develop effective photosensitizers which can exhibit excellent therapeutic performance under both normoxia and hypoxia. Herein, we reported four ionic iridium(III) complexes ( Ir1 – Ir4 ) with anthraquinone groups which can regulate their excited state energy levels effectively. Among them, the energy gap of Ir1 was between 1.63 and 2.21 eV, which can match well with that of O2, and the HOMO energy of Ir1 is less than −5.51 eV. Compared with Ir2 – Ir4 , the luminescent quantum efficiency of Ir1 was the highest. Particularly, Ir1 can specifically target the mitochondria of the tumor cells. Meanwhile, Ir1 showed high singlet oxygen quantum yields ( Φ Δ) in both solutions and living cells with low cytotoxicity. The results of PDT experiments revealed that Ir1 , as a photosensitizer, exhibited excellent therapeutic effect not only in normoxia but also in hypoxia condition. We believe that this work is meaningful for developing excellent PDT agents based on cyclometalated Ir(III) complexes via rational ligand modification.

Red Blood Cell-Membrane-Coated Poly(Lactic-co-glycolic Acid) Nanoparticles for Enhanced Chemo- and Hypoxia-Activated Therapy.

Herein, a membrane-coated nanocarrier for codelivery of chemotherapeutic agents, curcumin (Cur) and the hypoxia-activated molecule, tirapazamine (TPZ), has been developed. Cur and TPZ were loaded into biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) and finally coated with red blood cell (RBC) membrane by an extrusion process. Characterization of drug-loaded membrane-coated NPs (Cur+TPZ@RB) by dynamic light scattering, TEM and FESEM analyses showed that the NPs were of 105 nm size with a surface charge of -31 mV. Experimental results demonstrated long-term stability, biocompatibility and efficient cellular internalization (primarily through caveolin mediated pathway) of the Cur+TPZ@RB. Antiproliferative studies on 2D monolayer as well as hypoxic 3D multicellular spheroids (MCS) confirmed that the drug-loaded NPs were more potent than free drugs, inducing apoptosis via generation of reactive oxygen species and consequent DNA damage. Furthermore, the reduced cell migration in the scratch assay and down regulations mesenchymal markers as a result of Cur+TPZ@RB treatment suggest the potential of the present system in circumventing hypoxic solid tumors.