Hypoxia In Solid Tumors Research Articles

Cascade-Enhanced Catalytic Nanocomposite with Glutathione Depletion and Respiration Inhibition for Effective Starving-Chemodynamic Therapy Against Hypoxic Tumor.

Although chemodynamic therapy (CDT) has attracted enormous attention in anti-tumor studies for converting endogenous hydrogen peroxide (H2O2) into toxic hydroxyl radicals (•OH) by Fenton-type reaction, the treating effects of using CDT alone is still unsatisfying. Recently, glucose oxidase (GOx) was reported to be co-delivered with Fenton agent for synergistic starvation therapy (ST) and CDT. However, the overexpressed glutathione (GSH) and hypoxia in tumor microenvironment (TME) restrict the therapeutic efficacy of ST/CDT. In this work, a novel nanoplatform composed of GOx plus Fenton agent (Cu2+) encapsulated core and metformin (MET)-loaded manganese dioxide nanosheets (MNSs) shell was prepared and further functionalized by arginine-glycine-aspartate (RGD). With the RGD-mediated affinity with cancer cells, the nanocomposite (GOx-CuCaP@MNSs-MET@PEG-RGD, GCMMR) could accomplish targeting delivery and TME-activated release of cargos. The intracellular GSH was depleted by MnO2/Cu2+ and abundant H2O2 was generated along with the GOx-induced glucose deprivation, which process was further enhanced by MET-mediated hypoxia relief via inhibiting mitochondria-associated respiration. Subsequently generated •OH from Cu+-mediated Fenton-like reaction exerts severe intracellular oxidative stress and cause apoptosis. Moreover, significant inhibition of tumor growth was detected in a subcutaneous xenograft model of osteosarcoma (OS) after GCMMR treatment. The excellent therapeutic efficacy and biosafety of the nanoplatform were confirmed both in vitro and in vivo. Collectively, this study provides an appealing strategy with catalytic cascade enhancement on targeted ST/CDT for cancer treatment, especially for hypoxic solid tumors.

Carbonic Anhydrase IX (CAIX) Expressing Hypoxic Micro-environment Hampers CD8+ Immune Cell Infiltrate in Breast Carcinoma.

Hypoxia and necrosis are common features of invasive cancer. The dynamic upregulation of carbonic anhydrase IX (CAIX), triggered by hypoxia-inducible factor 1 (HIF-1) is 1 of the mechanisms supporting cellular adaptation to hypoxia in solid tumors, including breast carcinoma. CAIX activity results in extracellular acidosis and in a profound reorganization of the tumor micro-environment, influencing biological behavior and prognosis. The main focus of our study was to evaluate the mass and distribution of the immune infiltrate, more specifically of CD8+ effector T-cells, in relation with tumoral CAIX expression. Formalin-fixed and paraffin-embedded breast carcinoma sections were analyzed following double immunohistochemical staining for CAIX and CD8. Scanned digital slides were evaluated for both labelings, and CD8-related signal was determined within and outside CAIX-positive tumor areas using the HistoQuant (3DHistech) image analysis software. Statistical analysis was performed using GraphPad Prism software. Of the 34 breast carcinomas, 18 tested partially positive for CAIX. The remaining 16 cases were used as the CAIX-negative control group. Necrotic foci were generally associated with CAIX overexpression, and tumors exhibiting signs of necrosis had a significantly higher rate of relative CAIX expression compared with samples without necrosis (11.47±5.505 vs. without necrosis 3.765±3.5 P-value=0.0216). On the other hand, no statistically significant difference was found when comparing relative CD8+ lymphocyte counts in cases with necrosis as opposed to those where necrosis was absent (134.7±55.7 vs. 97.70±57.25; P value=0.1579). No difference in gross CD8+ T-lymphocyte infiltrate could be measured between CAIX positive and negative samples (98.48±37.32 vs. 95.99±50 P value=0.5928). However, in CAIX-expressing tumors a statistical correlation between the CD8+ T-lymphocyte infiltrate and the extent of CAIX-positive areas was observed. Within the same tumor, CD8+ T-lymphocyte counts showed a significant difference betweeen CAIX+ and CAIX- areas (13.06±9.4 vs. 135.6±62.2 P value <0.0001). Our measurements demonstrate for the first time that tumor areas with CAIX expression potentially hamper CD8+ T-lymphocyte infiltration in breast carcinoma. The hypoxia-driven adaptive micro-environment likely interferes with the specific response to biological and immune therapies requiring intact effector T-cell response.

Three gamma annihilation using radioiodine-124 for PET hypoxia imaging: Pilot study

Hypoxic solid tumours have a poor prognosis and little curability when treated with radiation therapy. Consequently, evaluation of oxygen levels in solid tumours is required to increase the proportion of patients who experience treatment success. The three gamma annihilation of radioiodine −124 (124I) during positron emission tomography (PET) can be used to diagnose hypoxia in solid tumours. 124I is the focus of this study, which intends to evaluate its role in detecting hypoxia in samples with various oxygen concentrations. At King Faisal Specialist Hospital and Research Center (KFSH&RC) in Saudi Arabia, a system was set up to monitor the yield of the three gamma using High Purity Germanium (HPGe) radiation detectors. These detectors, operating under the same conditions as one another, were used to record the triple coincidence. 5.0 mL of water was treated with oxygen and nitrogen gases to produce oxygenated and deoxygenated samples. In measuring the relative three gamma to two gamma yield, the peak to valley and peak to peak methods were compared. The three gamma coincidence was increased by 23% in deoxygenated sample compared to oxygenated one. The results of this study illustrated that the three gamma detection was increased in deoxygenated samples (hypoxia).

Picomolar fluorescent probes for compound affinity determination to carbonic anhydrase IX expressed in live cancer cells

Numerous human cancers, especially hypoxic solid tumors, express carbonic anhydrase IX (CAIX), a transmembrane protein with its catalytic domain located in the extracellular space. CAIX acidifies the tumor microenvironment, promotes metastases and invasiveness, and is therefore considered a promising anticancer target. We have designed a series of high affinity and high selectivity fluorescein-labeled compounds targeting CAIX to visualize and quantify CAIX expression in cancer cells. The competitive binding model enabled the determination of common CA inhibitors’ dissociation constants for CAIX expressed in exponentially growing cancer cells. All tested sulfonamide compounds bound the proliferating cells with similar affinity as to recombinantly purified CAIX. The probes are applicable for the design of selective drug-like compounds for CAIX and the competition strategy could be applied to other drug targets.

A Microneedle Patch with Self-Oxygenation and Glutathione Depletion for Repeatable Photodynamic Therapy.

Photodynamic therapy (PDT) has attained extensive attention as a noninvasive tumor treatment modality. However, the hypoxia in solid tumors, skin phototoxicity of "always on" photosensitizers (PSs), and abundant supply of glutathione (GSH) in cancer cells severely hampered the clinical applications of PDT. Herein, a self-oxygenation nanoplatform (denoted as CZCH) with GSH depletion ability was encapsulated into the hyaluronic acid microneedle patch (MN-CZCH) to simultaneously improve the biosafety and therapeutic efficacy of PDT. The Cu2+-doped porous zeolitic imidazolate framework incorporated with catalase (CAT) is capable of efficiently loading PS 2-(1-hexyloxyethyl)-2-divinylpyropheophorbic-a (HPPH). The CZCH intermingled MN patch (MN-CZCH) could effectively penetrate the stratum corneum, topically transport HPPH to the target tumor site, achieve a long tumor retention time, and enhance the efficacy of PDT via the simultaneously synergistic effect of CAT-catalyzed self-supplying O2 and Cu2+-mediated GSH depletion. Using traceable fluorescence (FL) imaging of the released HPPH from CZCH, the FL imaging-guided repeatable PDT can be achieved for enhanced antitumor efficacy. As a result, the MN-CZCH patch exhibited excellent therapeutic efficacy against melanoma with minimal toxicity, which has promising potential for cancer theranostics.

Targeted co-delivery of a photosensitizer and an antisense oligonucleotide based on an activatable hyaluronic acid nanosystem with endogenous oxygen generation for enhanced photodynamic therapy of hypoxic tumors

Photodynamic therapy (PDT) is a promising cancer treatment modality with advantages of minimal invasiveness, repeatable therapy, and mild systemic toxicity. However, the limited bioavailability of photosensitizer (PS), tumor hypoxia, and the presence of antiapoptotic proteins in cancer cells, has hampered the efficiency of PDT. To address these limitations, herein, we developed a hyaluronic acid (HA) based nanosystem (HA-Ce6-Hemin@DNA-Protamine NPs, HCH@DP) loaded with chlorin e6 (Ce6, as PS), hemin (as mimetic catalase) and antisense oligonucleotide (ASO) of B-cell lymphoma 2 (Bcl-2) anti-apoptosis protein via a simple electrostatic self-assembly method for enhanced PDT of hypoxic solid tumors. The HCH@DP can target deliver the PS and ASO to tumor cells via cancer cell overexpressed HA receptors (i.e., CD44 or RHAMM). The Ce6 was released from HA-ss-Ce6 (HSC conjugates) after the reaction of cleavable disulfide bond with glutathione (GSH), which recovered the fluorescence and phototoxicity of Ce6 upon laser irradiation. Meanwhile, the catalase-mimicking hemin (degradation of HA-eda-hemin by hyaluronidase) decomposed the tumor overdressed endogenous H2O2 to oxygen, which relieved tumor hypoxia and further overcome hypoxia-associated resistance of PDT. Furthermore, the inhibition of Bcl-2 expression by Bcl-2 ASO also greatly improved the cellular sensitivity to PDT. Both in vitro and in vivo results showed the tumor cell targeting ability, hypoxia relief and significantly enhanced antitumor PDT efficacy of HCH@DP for hypoxic tumor cells upon laser irradiation. Thus, by improving the target delivery of PS and ASO, relieving tumor hypoxia, and down-regulation of anti-apoptotic proteins, this HCH@DP nanosystem achieved enhanced PDT efficiency against hypoxic tumors. In general, our work provided a promising strategy to increase the utilization of key components (PS and oxygen) of PDT and the cell sensitivity to PDT by targeting co-delivery PS and oligonucleotides to tumor cells via a biocompatible HA based carrier, thereby achieving efficiently PDT treatment of hypoxic solid tumors with potential translation possibility. Statement of significanceThe efficiency of PDT against solid tumor is severely restricted by the limited bioavailability of photosensitizer, tumor hypoxia, and the presence of antiapoptotic proteins in cancer cells. Herein, we have developed an activatable hyaluronic acid (HA) based nanosystem (HA-Ce6-Hemin@DNA-Protamine NPs, HCH@DP) via a simple electrostatic self-assembly method for PDT treatment of hypoxic solid tumors. The HCH@DP enabled to target co-delivery of photosensitizer and antisense oligonucleotide to tumor cells, overcoming tumor hypoxia through in situ oxygen production and improving cellular sensitivity by efficiently reducing anti-apoptosis effect of cancer cells for synergistically enhancing PDT efficiency. This work suggests a promising strategy to develop small molecule drug and oligonucleotides co-delivery nanoplatforms for efficiently PDT treatment of hypoxic solid tumor.

A synergistic therapy strategy for hypoxic solid tumor therapy

Photodynamic therapy (PDT) has been considered an effective treatment for various types of cancers. However, hypoxic microenvironment within the solid tumor is averse to oxygen-involved PDT, resulting in low therapeutic efficacy. This Preview highlights a recent study regarding a synergistic therapy that combines PDT and chemotherapy, in which hypoxic solid tumor diagnosis imaging and therapy can be achieved. Photodynamic therapy (PDT) has been considered an effective treatment for various types of cancers. However, hypoxic microenvironment within the solid tumor is averse to oxygen-involved PDT, resulting in low therapeutic efficacy. This Preview highlights a recent study regarding a synergistic therapy that combines PDT and chemotherapy, in which hypoxic solid tumor diagnosis imaging and therapy can be achieved. Engineering a theranostic platform for synergistic hypoxia-responsive photodynamic therapy and chemotherapyXiong et al.MatterMarch 11, 2022In BriefA molecular theranostic (DHQ-Cl-Azo) integrating hypoxia-responsive photodynamic therapy and chemotherapy, as well as NIR fluorescence surveillance, was reported. The agent serves as a novel heavy-atom-free photosensitizer via intersystem crossing. Thus, PDT could be operated in the normoxic tumor cells on the surface of solid tumors, and hypoxia-activatable chemotherapy was triggered in the hypoxic center of solid tumors. Through dual-mode therapies in different regions of a solid tumor with DHQ-Cl-Azo, good treatment efficacies for solid tumors have been achieved. Full-Text PDF

Tumor homing-penetrating and nanoenzyme-augmented 2D phototheranostics against hypoxic solid tumors

Tumor microenvironment (TME)-oriented nanomedicine emerges as an efficient routine to greatly improve the efficiency of cancer treatment. The typical feature of hypoxia in TME remains as the main obstacle of many therapeutics like photodynamic therapy. Herein, a specific two-dimensional (2D) phototheranostics (GO-MnO2@tLyP-1/Ce6, denoted as GMtC) with the function of oxygen self-producing and tumor barrier-breaking was detailed by integrating the nanoenzyme MnO2 colloids, tumor homing-penetrating peptide tLyP-1 and photosensitizer chlorin e6 (Ce6) to tackle the hypoxic tumors. GMtC was capable to accumulate into the inner of murine mammary 4T1 tumor spheroids (and the depth could be as far as 90 µm) and to relieve the hypoxia state by catalytic decomposition of endogenous H2O2 to oxygen, which subsequently enhanced the yield of cytotoxic singlet oxygen under laser irradiation. In vivo dual-modal imaging of magnetic resonance and biofluorescence demonstrated the targeted accumulation and distribution of GMtC in tumor regions, thus facilitating the tumor hypoxia alleviation. Notably, GMtC achieved the highest photodynamic anticancer efficiency against 4T1 tumors without obvious systemic toxicity compared with the non-penetrating and no oxygen-generating counterparts. This study suggests the great promise of GMtC as an endogenous TME-responsive and exogenous laser-triggered theranostic platform against the solid hypoxic tumors. Statement of significanceThe hostile tumor hypoxia not only induces the tumor angiogenesis, invasiveness and irreversible metastasis, but also inherently impairs the efficiency of many therapeutic modalities like photodynamic therapy (PDT). Though numerous hypoxia-alleviating strategies based on nanomedicine have been proposed, little attention is paid to the hypoxia-specific transportation barriers. This study develops a type of 2D phototheranostics GMtC against hypoxic solid tumors by integrating the function of tumor homing-penetrating and in situ oxygen-generating. GMtC displays outstanding performance in tumor deep penetration to hypoxia center and generating abundant oxygen in responsive to tumor microenvironment, thus exerting the highest efficiency of PDT against 4T1 mammary tumor. GMtC can be a potent theranostics to treat the solid hypoxic tumors.

Surface-engineered chlorella alleviated hypoxic tumor microenvironment for enhanced chemotherapy and immunotherapy of first-line drugs

A large number of chemotherapeutic and immunotherapeutic agents have been shown to be less effective when exposed to a hypoxic solid tumor. The tumor hypoxia microenvironment contributes to multidrug resistance and immunosuppression, and current delivery of oxygen or enzyme to alleviate hypoxic microenvironment is often limited by the oxygen supplying capacity of material-based carriers and short window of oxygen production. Herein, macrophage membrane coated chlorella (M-Chl) is constructed for targeted delivery to the solid tumor and sustainable oxygen production via photosynthesis, which provides a new general strategy to overcome tumor hypoxia and improve chemotherapy and immunotherapy. The camouflaged strategy via macrophage membrane coating enhances tumor accumulation and retention of Chl due to the inflammatory homing effects of macrophage membrane, which contributes to long term oxygen production for at least 6 days with one dose of Chl, resulting in efficient downregulation of tumor HIF-1α. In vivo antitumor therapy in mice shows that M-Chl enhances the chemotherapeutic efficacy of doxorubicin via inhibiting hypoxia-mediated overexpression of drug efflux proteins, and also improves the poor immunotherapeutic performance of T cell activation agent, anti-CTLA-4 antibody, via downregulating hypoxia-mediated immunosuppressive proteins. Thus, M-Chl may serve as an important adjuvant for enhancing the therapeutic efficacy of clinical antitumor drugs against solid tumors.

A Porous Bimetallic Au@Pt Core-Shell Oxygen Generator to Enhance Hypoxia-Dampened Tumor Chemotherapy Synergized with NIR-II Photothermal Therapy.

The characteristic hypoxia of solid tumors and inadequate oxygen supply become a key causation of the resistance to chemotherapy in cancer treatment. Herein, a bimetallic oxygen nanogenerator, i.e., porous Au@Pt core-shell nanostructures, is particularly developed to reduce the multidrug resistance by oxygenating the tumor along with synergistic chemo-photothermal therapy for efficient tumor eradication. The porous platinum (Pt) shell was able to catalyze oxygen generation from endogenous hydrogen peroxide in the tumor, reducing the exocytosis of doxorubicin (DOX) via suppressed expression of hypoxia-inducible factor-1α, multidrug resistance gene 1, and P-glycoprotein. The strong absorbance of Au@Pt nanostructures in NIR window II enabled NIR-II photothermal therapy. Further incorporation of DOX into the mesopores of Au@Pt nanostructures with the assistance of phase change materials (PCM) led to the formulation of Au@Pt-DOX-PCM-PEG nanotherapeutics for NIR-II-activated chemotherapy. This work presents an efficient H2O2-driven oxygenerator for enhanced hypoxia-dampened chemotherapy and NIR-II photothermal therapy.

A NTR and O2 programmed responsive photogenic radicals for efficient hypoxia cancer therapy

Stimulus responsive photodynamic therapy has attracted much attention. Although many methods have been proposed to alleviate the impact of hypoxia on photodynamic therapy (PDT), hypoxia is still one of the biggest obstacles to the efficient photodynamic treatment of tumors. Herein, a novel kind of nitroreductase (NTR) and O2 programmed responsive photosensitizer Eos-NO2 was developed to achieve precise and efficient PDT of hypoxia tumor. Specifically, the PDT “off” state Eos-NO2 was activated by the overexpressed NTR in tumor region to form PDT “on” state Eos. Then, the produced Eos in hypoxia could further generate the active free radicals and singlet oxygen for the efficient treatment of hypoxic tumors owing to photo-induced free radical process. Both in vitro and in vivo results confirm that such a NTR and O2 programmed responsive photosensitizer Eos-NO2 shows high specificity and selectivity for hypoxic solid tumor, presenting good prospects in the clinical cancer phototherapy.

Dual-Mode Tumor Imaging Using Probes That Are Responsive to Hypoxia-Induced Pathological Conditions.

Hypoxia in solid tumors is associated with poor prognosis, increased aggressiveness, and strong resistance to therapeutics, making accurate monitoring of hypoxia important. Several imaging modalities have been used to study hypoxia, but each modality has inherent limitations. The use of a second modality can compensate for the limitations and validate the results of any single imaging modality. In this review, we describe dual-mode imaging systems for the detection of hypoxia that have been reported since the start of the 21st century. First, we provide a brief overview of the hallmarks of hypoxia used for imaging and the imaging modalities used to detect hypoxia, including optical imaging, ultrasound imaging, photoacoustic imaging, single-photon emission tomography, X-ray computed tomography, positron emission tomography, Cerenkov radiation energy transfer imaging, magnetic resonance imaging, electron paramagnetic resonance imaging, magnetic particle imaging, and surface-enhanced Raman spectroscopy, and mass spectrometric imaging. These overviews are followed by examples of hypoxia-relevant imaging using a mixture of probes for complementary single-mode imaging techniques. Then, we describe dual-mode molecular switches that are responsive in multiple imaging modalities to at least one hypoxia-induced pathological change. Finally, we offer future perspectives toward dual-mode imaging of hypoxia and hypoxia-induced pathophysiological changes in tumor microenvironments.

Dual-action nanoplatform with a synergetic strategy to promote oxygen accumulation for enhanced photodynamic therapy against hypoxic tumors

With the development of redox-related therapy modalities in cancer therapy, photodynamic therapy (PDT) has gradually become the most widely used type in the clinic. However, the hypoxic tumor microenvironment restricted the curative effect of PDT. Here, a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy was designed to alleviate tumor hypoxia on the basis of PDT. Specifically, the oxygen producer MnO2, oxygen consumption inhibitor atovaquone (ATO) and photosensitizer hypericin (HY) were loaded in SHRN. MnO2 reacted with excess H2O2 in the tumor microenvironment to increase oxygen generation, while ATO inhibited electron transfer in the aerobic respiratory chain to decrease oxygen consumption. Then, HY utilized this sufficient oxygen to produce ROS under irradiation to enhance the PDT effect. In vitro and in vivo assays confirmed that SHRN exhibits powerful and overall antitumor PDT effects. This formulation may provide an alternative strategy for the development of PDT effects in hypoxic tumor microenvironments. Statement of significanceWe constructed a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy to alleviate tumor hypoxia on the basis of photodynamic therapy (PDT). This work uniquely aimed at not only increased O2 generation in hypoxic tumor microenvironment but also reduced O2 consumption. Moreover, we designed a nanodrug delivery system to enhance the tumor permeability of SHRN. In vitro and in vivo assays all confirmed that SHRN exhibited powerful and overall antitumor effects. This formulation may provide an alternative strategy for the development of the PDT effect in hypoxic solid tumor.

Triggered azobenzene-based prodrugs and drug delivery systems.

Azobenzene-based molecules show unique trans-cis isomerization upon ultraviolet light irradiation, which induce the change of polarity, crystallinity, stability, and binding affinity with pharmacological target. Moreover, azobenzene is the substrate of azoreductase that is often overexpressed in many pathological sites, e.g. hypoxic solid tumor. Therefore, azobenzene can be a multifunctional molecule in material science, pharmaceutical science and biomedicine because of its sensitivity to light, hypoxia and certain enzymes, hence showing potential application in site-specific smart therapy. Herein we focus on the employment of azobenzene and its derivatives for engineering triggered prodrugs and drug delivery systems, and provide an overview of photoswitchable azo-based prodrugs, the associated problems regarding the reversible isomerization and tissue penetration of ultraviolet (UV) light, as well as the potential solutions. We also present the advance of azo-bearing delivery vehicles wherein azobenzene acts as the linker, capping agent, and building block, and discuss the corresponding mechanisms for controlled cargo release, endocytosis enhancement and sensitization of free radical cancer therapy.

An osmium-peroxo complex for photoactive therapy of hypoxic tumors

The limited therapeutic effect on hypoxic and refractory solid tumors has hindered the practical application of photodynamic therapy. Herein, we report our investigation of an osmium-peroxo complex (Os2), which is inactive in the dark, but can release a peroxo ligand O2•− upon light irradiation even in the absence of oxygen, and is transformed into a cytotoxic osmium complex (Os1). Os1 is cytotoxic in the presence or absence of irradiation in hypoxic tumors, behaving as a chemotherapeutic drug. At the same time, the light-activated Os2 induces photocatalytic oxidation of endogenous 1,4-dihydronicotinamide adenine dinucleotide in living cancer cells, leading to ferroptosis, which is mediated by glutathione degradation, lipid peroxide accumulation and down-regulation of glutathione peroxidase 4. In vivo studies have confirmed that the Os2 can effectively inhibit the growth of solid hypoxic tumors in mice. A promising strategy is proposed for the treatment of hypoxic tumors with metal-based drugs.

Improving the Therapeutic Efficiency of Hypoxic-Activated Prodrugs by Enhancing Hypoxia in Solid Tumors.

The low sensitivity of hypoxic regions in solid tumors to radiotherapy and chemotherapy remains a major obstacle to cancer treatment. By taking advantage of hypoxic-activated prodrugs, tirapazamine (TPZ), generating cytotoxic reductive products and the glucose oxidase (GOx)-based glucose oxidation reaction, we designed a nanodrug-loading system that combined TPZ-induced chemotherapy with GOx-mediated cancer-orchestrated starvation therapy and cancer oxidation therapy. In this work, we first prepared mesoporous silica (MSN) loaded with TPZ. Then, in order to prevent the leakage of TPZ in advance, the surface was coated with a layer of carMOF formed by Fe3+ and carbenicillin (car), and GOx was adsorbed on the outermost layer to form the final nanosystem MSN-TPZ@carMOF-GOx (MT@c-G). GOx could effectively consume oxygen and catalyzed glucose into gluconic acid and hydrogen peroxide. First, the generated gluconic acid lowered the pH of tumor tissues, promoted the decomposition of carMOF, and released TPZ. Second, oxygen consumption could improve the degree of hypoxia in tumor tissues, so that enhanced the activity of TPZ. Furthermore, GOx could generate cancer-orchestrated starvation/oxidation therapy. Therefore, our study provided a new strategy that TPZ combined with GOx achieved starvation/oxidation/chemotherapy for enhancing anticancer effects in hypoxic regions.

Cascade-activatable NO release based on GSH-detonated "nanobomb" for multi-pathways cancer therapy.

Therapeutic approaches of combining conventional photodynamic therapy (PDT) with other adjuvant treatments to sensitize PDT represent an appealing strategy. Herein, a novel synergetic “nanobomb” strategy based on glutathione (GSH)-responsive biodegradation was proposed to effectively destroy tumors expeditiously and accurately. This “nanobomb” was rationally constructed via the simultaneous encapsulation of methylene blue (MB) and l-arginine (L-Arg) into polyethylene glycol (PEG) modified mesoporous organosilicon nanoparticles (MON). The resulting L-Arg/MB@MP initially exhibited prolonged blood circulation, improved bioavailability, and enhanced tumor accumulation in mice after tail vein injection according to the pharmacokinetic investigations, before the nanoparticles were entirely excreted. Under laser irradiation, L-Arg/MB@MP produced remarkable reactive oxygen species (ROS) directly for PDT therapy, while a portion of ROS may oxidize L-Arg to generate nitric oxide (NO) not only for gas therapy (GT) but also serve as a biological messenger to regulate vasodilation to alleviate the tumor hypoxia. Subsequently, the rapidly released NO was further oxidized to reactive nitrogen species, which together with ROS promote immunogenic cell death by inducing G2/M cell-cycle arrest and apoptosis in cancer cells, and eventually resulting in enhanced anti-tumor immune responses. Moreover, the GSH depletion in tumor tissues induced by L-Arg/MB@MP biodegradation can cooperate with GT to amplify the therapeutic effect of PDT. These results demonstrate that this “nanobomb” provides new ideas for clinical translation to treat tumor patients in terms of synergistic PDT-GT nanotherapy in hypoxic-solid tumors.

A benzoindole-based fluorescent probe for nitroreductase imaging in living cells under hypoxia conditions

Nitroreductase (NTR) plays a vital part in the activation of drugs and the biodegradation of nitroaromatic compounds. With the enhanced expression level of NTR in hypoxic solid tumors, it has been widely used as one of the biomarkers to evaluate the degree of tumor hypoxia. In this work, we reported a benzoindole-based fluorescent probe NFP-NTR for nitroreductase detection. NFP-NTR can react with NTR specifically to cleave the p-nitrobenzyl ether bond when nicotinamide adenine dinucleotide (NADH) is present, showing significant fluorescence augment characteristics. Encouragingly, NFP-NTR exhibited excellent selectivity and satisfactory sensitivity, with a detection limit of 17 ng/mL. In addition, this probe has been successfully used to image live Hela cells under hypoxic conditions with low cytotoxicity, indicating that probe NFP-NTR has great potential to further elucidate more biological applications of NTR.

Rational design of a meso phosphate-substituted pyronin as a type I photosensitizer for photodynamic therapy.

Type I photodynamic therapy (PDT) with less oxygen consumption shows great potential to overcome the malignant hypoxia in solid tumors. Herein, a novel meso phosphate-substituted pyronin PY-P and its nanoparticles (PY-P NPs) were prepared as an efficient type I organic photosensitizer. The in vivo data prove that PY-P NPs have outstanding low dark toxicity but high photocytotoxicity under hypoxia (<1% O2).

A tailored and red-emissive type I photosensitizer to potentiate photodynamic immunotherapy.

Photodynamic immunotherapy (PDIT) has emerged as a technique which shows great potential in eradicating malignant tumors due to its advantages of simultaneously damaging primary tumors and inhibiting tumor metastasis and recurrence. However, the hypoxic microenvironment of tumor tissue and immune escape are two major challenges that PDIT faces. Hence, a well-designed water-soluble type I photosensitizer (TbT-TPP) based on a "D-A" strategy is reported for imaging-guided PDIT. The enhanced dihedral angle, prolonged conjugation length, strong electron withdrawing effect, and electron-rich condition endow TbT-TPP with a superior type I ROS generation ability and aggregation-induced red emission, which is demonstrated by comparision with the control molecule. We demonstrate that in hypoxic tissue, TbT-TPP can light up tumors and further efficiently kill them, triggering immunogenic cell death by generating type I ROS, which sequentially promotes the maturation of dendritic cells and enhances the T-cell response to tumor cells. Combined with immune adjuvant R837, TbT-TPP based-PDIT achieves the complete elimination of solid tumors and inhibition of tumor metastasis of living mice. This work provides a potential theranostic material and new insights into the improvement of PDIT against hypoxic tumors.