Hypoxic Tumor Environment Research Articles

A simple hydrogen peroxide-activatable Bodipy for tumor imaging and type I/II photodynamic therapy.

Tumor microenvironment-activatable photosensitizers have gained significant attention for cancer theranostics. Considering the hypoxic environment of solid tumors, activatable phototheranostic agents with type I PDT are desired to obtain improved cancer treatment efficiency. Herein, we report a simple, effective and multifunctional Bodipy photosensitizer for tumor imaging and type I/II photodynamic therapy. The photosensitizer featuring a methylphenylboronic acid pinacol ester group at the meso-position of Bodipy specifically responds to tumor-abundant H2O2. Its photophysical properties were characterized using steady-state and time-resolved transient optical spectroscopies. The fluorescence (ΦF = 0.09%) and singlet oxygen efficacy (ΦΔ = 10.2%) of the Bodipy units were suppressed in the caged dyads but significantly enhanced (ΦF = 0.72%, ΦΔ = 20.3%) upon H2O2 activation. Fluorescence emission spectroscopy and continuous wave electron paramagnetic resonance (EPR) spectroscopy confirmed that the Bodipy photosensitizer generates reactive oxygen species (ROS) via both electron transfer-mediated type I and energy transfer-mediated type II mechanisms. In vitro experiments demonstrated rapid internalization into tumor cells, enhanced brightness stimulated by tumor microenvironments, and tumor cell death (phototoxicity, IC50 = 0.5 μM). In vivo fluorescence imaging indicated preferential accumulation of this Bodipy photosensitizer in tumor sites, followed by decaging by tumor-abundant H2O2, further elevating the signal-to-background ratio (SBR) of imaging. Besides outstanding performance in tumor imaging, a prominent inhibition of tumor growth was observed. Given its simple molecular skeleton, this Bodipy photosensitizer is a competitive candidate for cancer theranostics.

Hypoxia and Singlet Oxygen Dual-Responsive Micelles for Photodynamic and Chemotherapy Therapy Featured with Enhanced Cellular Uptake and Triggered Cargo Delivery.

Combination therapy provides better outcomes than a single therapy and becomes an efficient strategy for cancer treatment. In this study, we designed a hypoxia- and singlet oxygen-responsive polymeric micelles which contain azo and nitroimidazole groups for enhanced cellular uptake, repaid cargo release, and codelivery of photosensitizer Ce6 and hypoxia-activated prodrug tirapazamine TPZ (DHM-Ce6@TPZ), which could be used for combining Ce6-mediated photodynamic therapy (PDT) and PDT-activated chemotherapy to enhance the therapy effect of cancer. The hypoxia- and singlet oxygen-responsive polymeric micelles DHM-Ce6@TPZ were prepared by film hydration method. The morphology, physicochemical properties, stimuli responsiveness, in vitro singlet oxygen production, cellular uptake, and cell viability were evaluated. In addition, the in vivo therapeutic effects of the micelles were verified using a tumor xenograft mice model. The resulting dual-responsive micelles not only increased the concentration of intracellular photosensitizer and TPZ, but also facilitated photosensitizer and TPZ release for enhanced integration of photodynamic and chemotherapy therapy. As a photosensitizer, Ce6 induced PDT by generating toxic singlet reactive oxygen species (ROS), resulting in a hypoxic tumor environment to activate the prodrug TPZ to achieve efficient chemotherapy, thereby evoking a synergistic photodynamic and chemotherapy therapeutic effect. The cascade synergistic therapeutic effect of DHM-Ce6@TPZ was effectively evaluated both in vitro and in vivo to inhibit tumor growth in a breast cancer mice model. The designed multifunctional micellar nano platform could be a convenient and powerful vehicle for the efficient co-delivery of photosensitizers and chemical drugs for enhanced synergistic photodynamic and chemotherapy therapeutic effect of cancer.

Azo-based hypoxic-activated 6-diazo-5-oxo-L-norleucine (DON) prodrug combined with vascular disrupting agent nanoparticles for tumor-selective glutamine metabolism blockade

Glutamine antagonists, such as 6-diazo-5-oxo-L-norleucine (DON), have demonstrated remarkable anti-tumor effects by blocking tumor glutamine metabolism, but their use is frequently causing toxicity. Despite the existence of multiple glutamine antagonist prodrug designs, a tumor-selective prodrug has yet to be developed. Herein, a novel prodrug of DON, Azo-DON, has been developed, which remains stable and inactive in normal tissues with sufficient oxygen levels, while can be selectively reduced to DON by highly expressed azo-reductase in hypoxic tumor environments. This leads to blockade of glutamine metabolism in cancer cells and promotes cell death without affecting T cell proliferation. In a high-hypoxic H22 hepatoma cancer model, Azo-DON showed a 1.8-fold enhancement in glutamine blockade compared to the control group, resulting in a tumor suppression rate (TSR) of 84.2% in vivo with no significant weight loss. In a low-hypoxic CT26 colon cancer model, when combined with vascular disrupting agent nanoparticles (CBP) to induce a hypoxic environment, Azo-DON exhibited a 4.6-fold enhancement in glutamine blockade over the control group, resulted in a remarkable TSR of 96.6% in vivo. This innovative approach represents a promising strategy for the application of broad-spectrum metabolic inhibitors in the field of precision cancer treatment.

Metal-Organic Framework-Mediated Synergistic Hypoxia-Activated Chemo-Immunotherapy Induced by High Intensity Focused Ultrasound for Enhanced Cancer Theranostics.

High intensity focused ultrasound (HIFU) has attracted considerable attention as a noninvasive, efficient, and economic therapeutic modality for solid tumors. However, HIFU surgery has its intrinsic limitation in completely ablating tumors, leading to residual tumor tissue. Furthermore, the severely hypoxic environment ensuring after surgery can exacerbate the unrestricted proliferation and metabolism of residual tumor cells, leading to tumor recurrence and metastasis. To address these limitations, a versatile HIFU-specific metal-organic framework nanosystem (called ADMOFs) is developed by coordinating hypoxia-activated prodrug AQ4N, Mn2+, and DOX based on the postoperative response to changes in the tumor microenvironment. ADMOFs loaded with AQ4N/Mn2+ exhibited remarkable tumor-targeting behavior in vivo and enhanced photoacoustic/magnetic resonance imaging effects, enabling more accurate guidance for HIFU surgery. After surgery, the ADMOFs exploited the severely hypoxic tumor environment induced by HIFU, overcoming hypoxia-associated drug resistance, and inducing immunogenic cell death. Finally, it effectively inhibited tumor growth and eliminated lung metastasis. Transcriptome studies revealed that this strategy significantly up-regulated genes involved in apoptosis, cell cycle, and HIF-1 signaling pathway while downregulating genes related to tumor proliferation and metastasis. These findings suggest that combining hypoxia-activated chemo-immunotherapy with HIFU is a promising strategy for enhancing cancer theranostics.

HIF‐1α‐inhibited Nanophotosensitizers for Near‐infrared Fluorescence Imaging‐guided Enhanced Photodynamic Therapy

AbstractPhotodynamic therapy (PDT) holds great potential in cancer therapy by virtue of its high precision, non‐invasiveness and low side effect. However, the hypoxic environment of solid tumor significantly restricts the efficacy of PDT. To improve the hypoxic microenvironment, inhibiting the hypoxia‐inducible factor 1α (HIF‐1α) is a rational approach. However, the related small molecule inhibitors suffer from the issue of poor tumor targeting. Herein, we design a nanophotosensitizer AmPPa NP which can inhibit HIF‐1α and conduct PDT with improved efficacy. AmPPa NP is prepared by first encapsulating a hydrophobic NIR photosensitizer mPPa into a carboxyl‐rich amphiphilic copolymer PSMA‐PEG, and then loading a positively charged HIF‐1α inhibitor acriflavine (ACF) on the surface of nanoparticle via electrostatic interaction. Under 635 nm laser irradiation, mPPa within nanoparticles can not only generate 1O2 for PDT but also emit NIR fluorescence signal for tumor imaging. In addition, such design makes ACF can be selectively released under acidic tumor microenvironment. Compared with mPPa NP without ACF loading, AmPPa NP can effectively inhibit HIF‐1α and shows improved PDT efficacy both in vitro and in vivo. This study thus provides a nanotheranostic platform for NIR fluorescence imaging‐guided enhanced PDT.

Indocyanine green-equipped upconversion nanoparticles/CeO2 trigger mutually reinforced dual photodynamic therapy

Although photodynamic-based tumor therapy has attracted considerable attention, the antitumor effect is limited due to the low reactive oxygen species (ROS) generation of photosensitizers. Therefore, it is an urgent need for improving ROS production and promoting therapeutic outcome of tumor. We developed a nanoplatform of indocyanine green (ICG)-equipped upconversion nanoparticles (UCNPs)/CeO2 modified with NH2-PEG1000-cRGDfK (UICCIP). This nanoplatform has two pathways of ROS production for mutually enhanced dual photodynamic therapy (PDT) of tumors. The ultraviolet (UV) emission of UCNPs could trigger CeO2 to produce ROS for PDT under 808 nm laser irradiation, and ICG can also produce singlet oxygen (1O2) at the meantime. Importantly, ICG can enhance the luminescence of UCNPs through energy transfer, thus promoting the PDT effect of CeO2. For another, CeO2 could catalyze endogenous H2O2 to provide O2 then overcome the hypoxic environment of tumor to enhance the PDT effect. By highlighting the full use of the various components of the nanoplatform and establishing interrelationships, ROS production can be increased significantly, resulting in efficient PDT of tumor. It is believed that UICCIP will become a potential ROS producer, which will broaden the thought of exploring new antitumor nanoplatforms.

Synergistic strategy based on mild phototherapy and deep tumor hypoxia reversal comprehensively remodels the tumor microenvironment for improved immunotherapy

Immunotherapy has shown remarkable therapeutic efficacy in triple-negative breast cancer (TNBC), but successful immune responses occur in only a subset of patients due to the hostile tumor microenvironment (TME). Specifically, low immunogenicity, dense extracellular matrix, and immunosuppressive environment in the TME are difficult to bypass for immunotherapy. The hypoxic environment of solid tumors not only contributes to an unfavorable TME but also functions in inhibiting the therapeutic effect of multiple antitumor methods, especially photodynamic therapy (PDT). In this study, we successfully developed a synergistic regulation nanosystem with albumin-mediated tumor targeted delivery of the photosensitizer IR780 and oxygen-generating nanoenzyme MnO2. As expected, MnO2 responsively catalyzed the decomposition of endogenous tumor H2O2 into O2, thereby enhancing the effect of PDT in triggering immunogenic cell death (ICD) and boosting tumor immunogenicity. Additionally, the enhanced PDT also functions in eliminating the tumor stromal barrier, facilitating the infiltration of effector T cells and therapeutics. The subsequent delivery of nanosystems containing MnO2 could reach deeper into the core of the tumor to alleviate severe hypoxia. Furthermore, relief of deep tumor hypoxia could significantly induce vascular normalization and reversal of tumor immunosuppression, decreasing the negative immunomodulatory cells such as Tregs and MDSCs. Resultantly, a positive feedback loop between mild phototherapy and deep hypoxia reversal was established using the synergistic strategy, which achieved comprehensive TME remodeling. Its combination with PD-L1 checkpoint blockades could lead to the regression of primary tumors and untreated metastasis tumors by inducing a strong systemic immune response, enhancing the immunotherapeutic efficacy for TNBC.

Hypoxia-driven ncRNAs in breast cancer.

Low oxygen tension, or hypoxia is the driving force behind tumor aggressiveness, leading to therapy resistance, metastasis, and stemness in solid cancers including breast cancer, which now stands as the leading cause of cancer-related mortality in women. With the great advancements in exploring the regulatory roles of the non-coding genome in recent years, the wide spectrum of hypoxia-responsive genome is not limited to just protein-coding genes but also includes multiple types of non-coding RNAs, such as micro RNAs, long non-coding RNAs, and circular RNAs. Over the years, these hypoxia-responsive non-coding molecules have been greatly implicated in breast cancer. Hypoxia drives the expression of these non-coding RNAs as upstream modulators and downstream effectors of hypoxia inducible factor signaling in the favor of breast cancer through a myriad of molecular mechanisms. These non-coding RNAs then contribute in orchestrating aggressive hypoxic tumor environment and regulate cancer associated cellular processes such as proliferation, evasion of apoptotic death, extracellular matrix remodeling, angiogenesis, migration, invasion, epithelial-to-mesenchymal transition, metastasis, therapy resistance, stemness, and evasion of the immune system in breast cancer. In addition, the interplay between hypoxia-driven non-coding RNAs as well as feedback and feedforward loops between these ncRNAs and HIFs further contribute to breast cancer progression. Although the current clinical implications of hypoxia-driven non-coding RNAs are limited to prognostics and diagnostics in breast cancer, extensive explorations have established some of these hypoxia-driven non-coding RNAs as promising targets to treat aggressive breast cancers, and future scientific endeavors hold great promise in targeting hypoxia-driven ncRNAs at clinics to treat breast cancer and limit global cancer burden.

Multi-Site Attack, Neutrophil Membrane-Camouflaged Nanomedicine with High Drug Loading for Enhanced Cancer Therapy and Metastasis Inhibition.

Advanced breast cancer is a highly metastatic tumor with high mortality. Simultaneous elimination of primary tumor and inhibition of neutrophil-circulation tumor cells (CTCs) cluster formation are urgent issues for cancer therapy. Unfortunately, the drug delivery efficiency to tumors and anti-metastasis efficacy of nanomedicine are far from satisfactory. To address these problems, we designed a multi-site attack, neutrophil membrane-camouflaged nanoplatform encapsulating hypoxia-responsive dimeric prodrug hQ-MMAE2 (hQNM-PLGA) for enhanced cancer and anti-metastasis therapy. Encouraged by the natural tendency of neutrophils to inflammatory tumor sites, hQNM-PLGA nanoparticles (NPs) could target delivery of drug to tumor, and the acute hypoxic environment of advanced 4T1 breast tumor promoted hQ-MMAE2 degradation to release MMAE, thus eliminating the primary tumor cells to achieve remarkable anticancer efficacy. Alternatively, NM-PLGA NPs inherited the similar adhesion proteins of neutrophils so that NPs could compete with neutrophils to interrupt the formation of neutrophil-CTC clusters, leading to a reduction in extravasation of CTCs and inhibition of tumor metastasis. The in vivo results further revealed that hQNM-PLGA NPs possessed a perfect safety and ability to inhibit tumor growth and spontaneous lung metastasis. This study demonstrates the multi-site attack strategy provides a prospective avenue with the potential to improve anticancer and anti-metastasis therapeutic efficacy.

Nanomedicine-based combination therapies for overcoming temozolomide resistance in glioblastomas.

Glioblastoma (GBM) is the most common malignant brain tumor. Although current treatment strategies, including surgery, chemotherapy, and radiotherapy, have achieved clinical effects and prolonged the survival of patients, the gradual development of resistance against current therapies has led to a high recurrence rate and treatment failure. Mechanisms underlying the development of resistance involve multiple factors, including drug efflux, DNA damage repair, glioma stem cells, and a hypoxic tumor environment, which are usually correlative and promote each other. As many potential therapeutic targets have been discovered, combination therapy that regulates multiple resistance-related molecule pathways is considered an attractive strategy. In recent years, nanomedicine has revolutionized cancer therapies with optimized accumulation, penetration, internalization, and controlled release. Blood-brain barrier (BBB) penetration efficiency is also significantly improved through modifying ligands on nanomedicine and interacting with the receptors or transporters on the BBB. Moreover, different drugs for combination therapy usually process different pharmacokinetics and biodistribution, which can be further optimized with drug delivery systems to maximize the therapeutic efficiency of combination therapies. Herein the current achievements in nanomedicine-based combination therapy for GBM are discussed. This review aimed to provide a broader understanding of resistance mechanisms and nanomedicine-based combination therapies for future research on GBM treatment.

Mitochondria-Targeted Nanosystem Enhances Radio-Radiodynamic-Chemodynamic Therapy on Triple Negative Breast Cancer.

Radiodynamic therapy (RDT), which produces 1O2 and other reactive oxygen species (ROS) in response to X-rays, can be used in conjunction with radiation therapy (RT) to drastically lower X-ray dosage and reduce radio resistance associated with conventional radiation treatment. However, radiation-radiodynamic therapy (RT-RDT) is still impotent in a hypoxic environment in solid tumors due to its oxygen-dependent nature. Chemodynamic therapy (CDT) can generate reactive oxygen species and O2 by decomposing H2O2 in hypoxic cells and thus potentiate RT-RDT to achieve synergy. Herein, we developed a multifunctional nanosystem, AuCu-Ce6-TPP (ACCT), for RT-RDT-CDT. Ce6 photosensitizers were conjugated to AuCu nanoparticles via Au-S bonds to realize radiodynamic sensitization. Cu can be oxidized by H2O2 and catalyze the degradation of H2O2 to generate •OH through the Fenton-like reaction to realize CDT. Meanwhile, the degradation byproduct oxygen can alleviate hypoxia while Au can consume glutathione to increase the oxidative stress. We then attached mercaptoethyl-triphenylphosphonium (TPP-SH) to the nanosystem, targeting ACCT to mitochondria (colocalization Pearson coefficient 0.98) to directly disrupt mitochondrial membranes and more efficiently induce apoptosis. We confirmed that ACCT efficiently generates 1O2 and •OH upon X-ray irradiation, resulting in strong anticancer efficacy in both normoxic and hypoxic 4T1 cells. The down-regulation of hypoxia-inducible factor 1α expression and reduction of intracellular H2O2 concentrations suggested that ACCT could significantly alleviate hypoxia in 4T1 cells. ACCT-enhanced RT-RDT-CDT can successfully shrink or remove tumors in radioresistant 4T1 tumor-bearing mice upon 4 Gy of X-ray irradiation. Our work thus presents a new strategy to treat radioresistant hypoxic tumors.

Vanadium Oxide Nanozymes with Multiple Enzyme-Mimic Activities for Tumor Catalytic Therapy.

Using tumors containing high concentrations of hydrogen peroxide to design nanozymes is a new and effective strategy, and vanadium-based nanomaterials receive increasing attention. In this paper, four kinds of vanadium oxide nanozymes with different valences of vanadium are synthesized by a simple method to verify the effect of valence on enzyme activity. Vanadium oxide nanozyme-III (Vnps-III) with a low valence of vanadium (V4+) exhibits good peroxidase (POD) and oxidase (OXD) activities, which can effectively produce reactive oxygen species (ROS) in the tumor microenvironment for tumor treatment. In addition, Vnps-III can also consume glutathione (GSH) to reduce ROS consumption. Vanadium oxide nanozyme-I (Vnps-I) containing a high valence of vanadium (V5+) has catalase (CAT) activity, which can catalyze hydrogen peroxide (H2O2) into oxygen (O2), which is beneficial to alleviate the hypoxic environment of solid tumors. Finally, a vanadium oxide nanozyme with both trienzyme simulation activity and GSH consumption ability was screened out by adjusting the ratio of V4+ to V5+ in vanadium oxide nanozymes. In cell and animal experiments, we successfully demonstrate that vanadium oxide nanozymes have excellent antitumor ability and high safety, which may bring great potential for clinical cancer treatment.

An Engineered Design of Self-Assembly Nanomedicine Guided by Molecular Dynamic Simulation for Photodynamic and Hypoxia-Directed Therapy.

To overcome the hypoxia barrier in tumor therapy, a hypoxia-activated prodrug of docetaxel (DTX-PNB) was synthesized and self-assembled with indocyanine green (ICG), forming a combination nanomedicine ISDNN. With the guidance of molecular dynamic simulation, the ISDNN construction could be accurately controlled, achieving uniform size distribution and high drug loading up to 90%. Within the hypoxic tumor environment, ISDNN exerted ICG-mediated photodynamic therapy and aggravated hypoxia to boost DTX-PNB activation for chemotherapy, enabling enhanced antitumor efficacy.

MiR-21 Is Induced by Hypoxia and Down-Regulates RHOB in Prostate Cancer.

Tumour hypoxia is a well-established contributor to prostate cancer progression and is also known to alter the expression of several microRNAs. The over-expression of microRNA-21 (miR-21) has been consistently linked with many cancers, but its role in the hypoxic prostate tumour environment has not been well studied. In this paper, the link between hypoxia and miR-21 in prostate cancer is investigated. A bioinformatic analysis of The Cancer Genome Atlas (TCGA) prostate biopsy datasets shows the up-regulation of miR-21 is significantly associated with prostate cancer and clinical markers of disease progression. This up-regulation of miR-21 expression was shown to be caused by hypoxia in the LNCaP prostate cancer cell line in vitro and in an in vivo prostate tumour xenograft model. A functional enrichment analysis also revealed a significant association of miR-21 and its target genes with processes related to cellular hypoxia. The over-expression of miR-21 increased the migration and colony-forming ability of RWPE-1 normal prostate cells. In vitro and in silico analyses demonstrated that miR-21 down-regulates the tumour suppressor gene Ras Homolog Family Member B (RHOB) in prostate cancer. Further a TCGA analysis illustrated that miR-21 can distinguish between different patient outcomes following therapy. This study presents evidence that hypoxia is a key contributor to the over-expression of miR-21 in prostate tumours, which can subsequently promote prostate cancer progression by suppressing RHOB expression. We propose that miR-21 has good potential as a clinically useful diagnostic and prognostic biomarker of hypoxia and prostate cancer.

Ultrasound-Triggered Piezocatalysis for Selectively Controlled NO Gas and Chemodrug Release to Enhance Drug Penetration in Pancreatic Cancer.

Nitric oxide (NO) is drawing widespread attention in treating pancreatic ductal adenocarcinoma (PDAC) as a safe and therapeutically efficient technique through modulating the dense fibrotic stroma in the tumor microenvironment to enhance drug penetration. Considerable NO nanogenerators and NO releasing molecules have been developed to shield the systemic toxicity caused by free diffusion of NO gas. However, on-demand controlled release of NO and chemotherapy drugs at tumor sites remains a problem limited by the complex and dynamic tumor microenvironment. Herein, we present an ultrasound-responsive nanoprodrug of CPT-t-R-PEG2000@BaTiO3 (CRB) which encapsulates piezoelectric nanomaterials barium titanate nanoparticle (BaTiO3) with amphiphilic prodrug molecules that consisted of thioketal bond (t) linked chemotherapy drug camptothecin (CPT) and NO-donor l-arginine (R). Based on ultrasound-triggered piezocatalysis, BaTiO3 can continuously generate ROS in the hypoxic tumor environment, which induces a cascade of reaction processes to break the thioketal bond to release CPT and oxidize R to release NO, simultaneously delivering CPT and NO to the tumor site. It is revealed that CRB shows a uniform size distribution, prolonged blood circulation time, and excellent tumor targeting ability. Moreover, controlled release of CPT and NO were observed both in vitro and in vivo under the stimulation of ultrasound, which is beneficial to the depletion of dense stroma and subsequently enhanced delivery and efficacy of CPT. Taken together, CRB significantly increased the antitumor efficacy against highly malignant Panc02 tumors in mice through inhibiting chemoresistance, representing a feasible approach for targeted therapies against Panc02 and other PDAC.

Mitochondria-Targeting and Multiresponsive Nanoplatform Based on AIEgens for Synergistic Chemo-Photodynamic Therapy and Enhanced Immunotherapy.

Although photodynamic therapy (PDT) has become an attractive strategy for cancer treatment, its clinical application still suffers from some limitations, including insufficient delivery of photosensitizers, hypoxic tumor environment, and the development of PDT resistance. To address these limitations, a new class of mitochondria-targeting and fluorinated polymer with aggregation-induced emission characteristics was fabricated to sensitize PDT and co-deliver chemotherapeutic drugs. The amphiphilic fluoropolymer was able to efficiently carry oxygen and SN-38 (the active metabolite of irinotecan) and self-assemble into multifunctional micellar nanoparticles (SN-38-TTCF@O2 NPs). Upon internalization into tumor cells, these NPs could successfully escape lysosomes, selectively target mitochondria, efficiently produce reactive oxygen species (ROS) under light irradiation, and release drugs in response to ROS. In the HCT116 tumor xenograft model, they preferentially accumulated in tumor tissue and significantly alleviated tumor hypoxia, resulting in synergistic chemo-PDT efficacy without distinct toxicity. Furthermore, the nanoscale chemo-PDT induced immunogenic cell death, promoted the recruitment and activation of cytotoxic T lymphocytes, and ultimately augmented the anti-tumor efficacy of anti-PD-1 antibody in the murine CT26 tumor model. These results may provide novel insights into the development of efficient chemo-PDT nanomedicine to improve the outcome of immunotherapy.

Eribulin Treatment Promotes Re-expression of Estrogen Receptor in Endocrine Therapy-resistant Hormone Receptor-positive Breast Cancer Cells.

Hypoxia is significantly associated with the development of drug resistance, and endocrine therapy is ineffective against hormone receptor (HR)-positive breast cancer in hypoxic tumor environments. Eribulin has a unique anticancer effect in breast cancer cells and improves tumor hypoxia by vascular remodeling. Therefore, we investigated the effect of eribulin on HR-positive breast cancer cells that were resistant to endocrine blockade. We established hypoxia-resistant breast cancer cell lines by continuous culture in a hypoxic environment. Parental and hypoxia-resistant cell lines were treated with eribulin and/or tamoxifen, and estrogen receptor (ER)-, epithelial-mesenchymal transition-, and hypoxia-related gene and protein expression changes in each surviving cell line were assessed. In addition, proliferation was assessed after eribulin treatment in the parental and hypoxia-resistant cell lines. We also assessed the effect of eribulin in vivo using subcutaneous xenograft models. Hypoxia-resistant cell lines showed significantly decreased expression of epithelial and ER-related markers and exhibited a higher level of resistance to tamoxifen. Conversely, eribulin treatment increased epithelial and ER-related gene and protein expression in hypoxia-resistant cell lines and enhanced the anticancer effect of tamoxifen. In in vivo xenograft models, eribulin treatment of hypoxia- and tamoxifen-resistant tumors slightly induced the re-expression of ER. In addition, hypoxia-resistant tumors treated with eribulin tended to respond better to tamoxifen. Eribulin ameliorated the aggressive behavior caused by hypoxia and induced the re-expression of ER in hypoxia-resistant breast cancer cells. Eribulin treatment of HR-positive breast cancer may resensitize cells to hormone blockade.

Catalase-like pleated niobium carbide MXene loaded with polythiophene for oxygenated sonodynamic therapy in solid tumor.

Sonodynamic therapy (SDT), an emerging treatment for solid tumors, has the advantages of deep tissue penetration, non-invasiveness, low side effects, and negligible drug resistance. However, the hypoxic environment of deep solid tumors can discount the efficacy of oxygenated dependent SDT. Here, we synthesized a polythiophene-based sonosensitizer (PT2) and a two-dimensional pleated niobium carbide (Nb2C) Mxene. PT2 was loaded onto the surface of poly(vinylpyrrolidone) (PVP)-coated Nb2C MXene through electrostatic interaction to obtain Nb2C-PVP-PT2 nanosheets (NSs) with a high loading efficiency of 153.7%. Nb2C MXene exhibited catalase-like activity, which could catalyze hydrogen peroxide (H2O2) to produce O2, in turn alleviating tumor hypoxia and enhancing the efficacy of SDT. The depletion of H2O2 further results in abnormal cellular H2O2 levels and reduced tumor cell activity. Moreover, the decomposed NSs led to the release of the sonosensitizer PT2 that can efficiently generate both singlet oxygen and superoxide anions under ultrasound irradiation. These events led to the inhibition of DNA replication of tumor cells, causing tumor cell death, allowing for enhanced SDT efficacy.

Hypoxia-Responsive Aggregation of Iron Oxide Nanoparticles for T1-to-T2 Switchable Magnetic Resonance Imaging of Tumors

Magnetic resonance imaging (MRI), one of the most general imaging techniques in the clinic, is widely employed for tumor diagnosis with the assistance of contrast agents (CAs). However, currently available CAs in the clinic suffer from shortcomings of a short blood circulation time, lack of specificity to pathological location, insufficient imaging window, and potential biotoxicity of the gadolinium ion. To overcome these problems, on the basis of extremely small iron oxide nanoparticles (ESIONPs), a hypoxia-responsive T1-to-T2 switchable MRI contrast agent was designed and constructed. In detail, polyacrylic acid-modified ESIONPs (ESIONPs-PAA) were first synthesized, and then, nitroimidazole derivatives and cysteine molecules were sequentially coupled on the surface of ESIONPs-PAA to obtain a hypoxia-responsive MRI contrast agent (HR-ESIONPs). Since 2-nitroimidazole and cysteine molecules on the surface of HR-ESIONPs can form an irreversible bond induced by the nitroreductase in the hypoxic tumor microenvironment, monodispersed HR-ESIONPs could transform into the nanocluster form, which can specially provide T2 contrast enhancement. In vitro experiments show that monodispersed HR-ESIONPs could effectively aggregate in the mimical hypoxic environment of tumors and switch from a T1 to T2 contrast agent. Moreover, in vivo experiments further confirm that HR-ESIONPs could effectively accumulate and realize the MRI signal switch from T1 to T2 contrast enhancement in tumors originating from the aggregation of HR-ESIONPs induced by the hypoxic environment, which promotes the diagnostic precision of tumors. Additionally, with the confirmation of favorable biosafety on cells and mice, hypoxia-responsive HR-ESIONPs are potential platforms to improve the diagnostic accuracy and sensitivity of MRI for tumors.

RBCK1 regulates the progression of ER-positive breast cancer through the HIF1α signaling

Breast cancer is the most common malignancy in women on a global scale. It can generally be divided into four main categories, of which estrogen receptor ER-positive breast cancer accounts for most breast cancer cases. RBCK1 protein is an E3 ubiquitin ligase containing the UBL, NZF, and RBR domains. It is well known to exhibit abnormal expression in breast tumors, making it a valuable diagnostic marker and drug target. Additionally, studies have confirmed that in breast cancer, about 25 to 40% of tumors appear as visible hypoxic regions, while in hypoxia, tumor cells can activate the hypoxia-inducing factor HIF1 pathway and widely activate the expression of downstream genes. Previous studies have confirmed that in the hypoxic environment of tumors, HIF1α promotes the remodeling of extracellular matrix, induces the recruitment of tumor-associated macrophages (TAM) and immunosuppression of allogeneic tumors, thereby influencing tumor recurrence and metastasis. This research aims to identify RBCK1 as an important regulator of HIF1α signaling pathway. Targeted therapy with RBCK1 could be a promising treatment strategy for ER-positive breast cancer.