Efficient Tumor Suppression Research Articles

Biodegradable copper-iodide clusters modulate mitochondrial function and suppress tumor growth under ultralow-dose X-ray irradiation

Both copper (Cu2+/+) and iodine (I−) are essential elements in all living organisms. Increasing the intracellular concentrations of Cu or I ions may efficiently inhibit tumor growth. However, efficient delivery of Cu and I ions into tumor cells is still a challenge, as Cu chelation and iodide salts are highly water-soluble and can release in untargeted tissue. Here we report mitochondria-targeted Cu-I cluster nanoparticles using the reaction of Cu+ and I− to form stable bovine serum albumin (BSA) radiation-induced phosphors (Cu-I@BSA). These solve the stability issues of Cu+ and I− ions. Cu-I@BSA exhibit bright radioluminescence, and easily conjugate with the emission-matched photosensitizer and targeting molecule using functional groups on the surface of BSA. Investigations in vitro and in vivo demonstrate that radioluminescence under low-dose X-ray irradiation excites the conjugated photosensitizer to generate singlet oxygen, and combines with the radiosensitization mechanism of the heavy atom of iodine, resulting in efficient tumor inhibition in female mice. Furthermore, our study reveals that BSA protection causes the biodegradable Cu-I clusters to release free Cu and I ions and induce cell death by modulating mitochondrial function, damaging DNA, disrupting the tricarboxylic acid cycle, decreasing ATP generation, amplifying oxidative stress, and boosting the Bcl-2 pathway.

A Bioinspired Photosensitizer Performs Tumor Thermoresistance Reversion to Optimize the Atraumatic Mild-Hyperthermia Photothermal Therapy for Breast Cancer.

Mild-hyperthermia photothermal therapy (mPTT) has therapeutic potential with minimized damage to normal tissues. However, the poorly vascularized tumor area severely hampers the penetration of photothermal agents (PTAs), resulting in their heterogeneous distribution and the subsequent heterogeneous local temperature during mPTT. The presence of regions below the therapeutic 42 °C threshold can lead to incomplete tumor ablation and potential recurrence. Additionally, tumor anti-apoptosis and cytoprotection pathways, particularly activated thermoresistance, can nullify mild hyperthermia-induced tumor damage. Therefore, a bioinspired photosensitizer decorated with leucine to form biomimetic nanoclusters (CP-PLeu nanoparticles (NPs)) aimed at achieving rapid and homogeneous accumulation in tumors, is introduced. Moreover, CP-PLeu exhibits photodynamic effects that reverse tumor thermoresistance and physiological repair mechanisms, thereby inhibiting tumor resistance to hyperthermia. With the addition of NIR-II laser irradiation, CP-PLeu optimizes the therapeutic efficacy of mPTT and contributes to a minimally invasive therapeutic process for breast cancer. This therapeutic strategy, utilizing a biomimetic photosensitizer for homogeneous distribution of therapeutic temperature and photoactivated reversal of tumor thermoresistance, successfully achieves efficient breast tumor inhibition through an atraumatic mPTT process.

GSH-Responsive Liposomes with Heat Shock Protein Regulatory Ability for Efficient Photodynamic/Photothermal Combined Therapy of Tumors.

Phototherapy, represented by photodynamic therapy (PDT) and photothermal therapy (PTT), has great potential in tumor treatment. However, the presence of antioxidant glutathione (GSH) and the heat shock proteins (HSPs) expression caused by high temperature can weaken the effects of PDT and PTT. Here, a multifunctional nanocomplex BT&GA@CL is constructed to realize enhanced synergistic PDT/PTT. Cinnamaldehyde liposomes (CLs) formed by cinnamaldehyde dimer self-assembly were loaded with in gambogic acid (GA) and an aggregation-induced emission molecule BT to obtain BT&GA@CL. As a drug carrier, CL can consume glutathione (GSH) and release drugs responsively. The released BT aggregates can simultaneously act as both a photothermal agent and photosensitizer to achieve PDT and PTT under 660 nm laser irradiation. Specifically, GA as an HSP90 inhibitor can attenuate PTT-induced HSP90 protein expression, thereby weakening the tolerance of tumor cells to high temperatures and enhancing PTT. Such a multifunctional nanocomplex simultaneously modulates the content of GSH and HSP90 in tumor cells, thus enhancing both PDT and PTT, ultimately achieving the goal of efficient combined tumor suppression.

Biodegradable Monometallic Aluminum as a Biotuner for Tumor Pyroptosis.

Pyroptosis is an effective anti-tumor strategy. However, monometallic pyroptosis biotuners have not been explored until now. Here, we discover for the first time that biodegradable monometallic Al can act as a pyroptosis biotuner for tumor therapy. pH-sensitive Al nanoparticles (Al@P) are obtained by equipping polyethylene glycol-b-(poly(methyl methacrylate)-co-poly(4-vinylpyridine), which can exert their effect at the tumor site without affecting normal cells. The H2 and Al3+ release by Al@P in the acidic environment of tumors disrupts the redox balance and ionic homeostasis in tumor cells, thus generating large amounts of reactive oxygen species (ROS), leading to caspase-1 activation, gasdermin D cleavage, and IL-1β/LDH release, which induces canonical pyroptotic death. Meanwhile, the prodrug Doxorubicin (Pro-DOX) is successfully loaded onto Al@P (Al@P-P) and can be activated by ROS to release DOX in the tumor cells, thus further improving the tumor-killing efficiency. Ultimately, Al@P-P is degradable and exhibits efficient tumor inhibition.

Biodegradable Monometallic Aluminum as a Biotuner for Tumor Pyroptosis

AbstractPyroptosis is an effective anti‐tumor strategy. However, monometallic pyroptosis biotuners have not been explored until now. Here, we discover for the first time that biodegradable monometallic Al can act as a pyroptosis biotuner for tumor therapy. pH‐sensitive Al nanoparticles (Al@P) are obtained by equipping polyethylene glycol‐b‐(poly(methyl methacrylate)‐co‐poly(4‐vinylpyridine), which can exert their effect at the tumor site without affecting normal cells. The H2 and Al3+ release by Al@P in the acidic environment of tumors disrupts the redox balance and ionic homeostasis in tumor cells, thus generating large amounts of reactive oxygen species (ROS), leading to caspase‐1 activation, gasdermin D cleavage, and IL‐1β/LDH release, which induces canonical pyroptotic death. Meanwhile, the prodrug Doxorubicin (Pro‐DOX) is successfully loaded onto Al@P (Al@P‐P) and can be activated by ROS to release DOX in the tumor cells, thus further improving the tumor‐killing efficiency. Ultimately, Al@P‐P is degradable and exhibits efficient tumor inhibition.

Study of Iron Complex Photosensitizer with Hollow Double-Shell Nano Structure Used to Enhance Ferroptosis and Photodynamic Therapy.

Ferroptosis therapy, which uses ferroptosis inducers to produce lethal lipid peroxides and induce tumor cell death, is considered a promising cancer treatment strategy. However, challenges remain regarding how to increase the accumulation of reactive oxygen species (ROS) in the tumor microenvironment (TME) to enhance antitumor efficacy. In this study, a hyaluronic acid (HA) encapsulated hollow mesoporous manganese dioxide (H-MnO2) with double-shell nanostructure is designed to contain iron coordinated cyanine near-infrared dye IR783 (IR783-Fe) for synergistic ferroptosis photodynamic therapy against tumors. The nano photosensitizer IR783-Fe@MnO2-HA, in which HA actively targets the CD44 receptor, subsequently dissociates and releases Fe3+ and IR783 in acidic TME. First, Fe3+ consumes glutathione to produce Fe2+, which promotes the Fenton reaction in cells to produce hydroxyl free radicals (·OH) and induce ferroptosis of tumor cells. In addition, MnO2 catalyzes the production of O2 from H2O2 and enhances the production of singlet oxygen (1O2) by IR783 under laser irradiation, thus increasing the production and accumulation of ROS to provide photodynamic therapy. The highly biocompatible IR783-Fe@MnO2-HA nano-photosensitizers have exhibited tumor-targeting ability and efficient tumor inhibition in vivo due to the synergistic effect of photodynamic and ferroptosis antitumor therapies.

A Pt nanoenzyme- and BODIPY-loaded nanoscale covalent organic framework for relieving intratumoural hypoxia to enhance photodynamic therapy.

Herein, we report a composite COF material loaded with a Pt nanoenzyme and an organic photosensitizer BODIPY, synthesized via a stepwise post-synthetic modification. The obtained Pt@COF-BDP nanoparticles can efficiently and continuously convert H2O2 to O2, thereby increasing the efficiency of single-linear oxygen production and achieving efficient tumor inhibition.

A novel electrospun nanofiber system with PEGylated paclitaxel nanocrystals enhancing the transmucus permeability and in situ retention for an efficient cervicovaginal cancer therapy

Overcoming the vaginal barrier to achieve sufficient drug penetration and retention is a huge obstacle for drug delivery in chemotherapeutics for cervical cancer. In this study, we investigate the feasibility of a novel composite nanocrystal/nanofiber system for improving the transmucus penetration and, thus, enhancing retention and drug delivery to the lesion of a cervicovaginal tumor. Herein, paclitaxel (PTX) was sequentially formulated in the form of nanocrystals, coated with polydopamine (PDA), and modified with PEG. The nanocrystals (NCs@PDA–PEG) were creatively fabricated to create a composite nanofibrous membrane (NCs@PDA-PEG NFs) by using an electrospinning technique. The morphology, size distribution, drug loading, encapsulation efficiency, X-ray powder diffraction (XRD), Fourier transform infrared (FTIR) spectra, in vitro release, in vivo vaginal retention, apoptosis index, anti-tumor efficacy in a murine cervicovaginal tumor model, and local irritation were characterized. The NCs@PDA-PEG were formulated in a cube-like shape with an average size of 385.6 ± 35.47 nm; they were dispersed in electrospun nanofibers, and the drug loading was 7.94 %. The XRD curves indicated that the phase state of PTX changed after the creation of the nanocrystals. The FTIR spectra showed that the drug and the excipients were compatible with each other. In vitro delivery showed that the dissolution of PTX in the electrospun nanofibers was significantly faster than that when using bulk PTX. Compared with the PTX NC NFs, the NC@PDA-PEG NFs exhibited prolonged vaginal residence, superior transmucus penetration, minimal mucosal irritation, and significant tumor inhibition efficacy after the intravaginal administration of the NFs in tumor-bearing mice. In conclusion, by acting as novel pharmaceutical repositories, NCs@PDA-PEG NFs can be promising candidates for non-invasive local treatment, leading to efficient tumor inhibition in cervicovaginal cancer.

A dual-receptor T-cell platform with Ab-TCR and costimulatory receptor achieves specificity and potency against AML

AbstractChimeric antigen receptor T-cell (CAR T) therapy has produced remarkable clinical responses in B-cell neoplasms. However, many challenges limit this class of agents for the treatment of other cancer types, in particular the lack of tumor-selective antigens for solid tumors and other hematological malignancies, such as acute myeloid leukemia (AML), which may be addressed without significant risk of severe toxicities while providing sufficient abundance for efficient tumor suppression. One approach to overcome this hurdle is dual targeting by an antibody–T-cell receptor (AbTCR) and a chimeric costimulatory signaling receptor (CSR) to 2 different antigens, in which both antigens are found together on the cancer cells but not together on normal cells. To explore this proof of concept in AML, we engineered a new T-cell format targeting Wilms tumor 1 protein (WT1) and CD33; both are highly expressed on most AML cells. Using an AbTCR comprising a newly developed TCR-mimic monoclonal antibody against the WT1 RMFPNAPYL (RMF) epitope/HLA-A2 complex, ESK2, and a secondary CSR comprising a single-chain variable fragment directed to CD33 linked to a truncated CD28 costimulatory fragment, this unique platform confers specific T-cell cytotoxicity to the AML cells while sparing healthy hematopoietic cells, including CD33+ myelomonocytic normal cells. These data suggest that this new platform, named AbTCR-CSR, through the combination of a AbTCR CAR and CSR could be an effective strategy to reduce toxicity and improve specificity and clinical outcomes in adoptive T-cell therapy in AML.

Living Cell‐Derived Intelligent Nanobots for Precision Oncotherapy

AbstractThe progress of precision oncology medicine is always limited by the tumor off‐targeting, the drug side effects, and the treatment inefficiency due to the complex and ever‐changing tumor microenvironment. Living cells, such as blood cells and immune cells, exhibit natural tumor tropism, controllable physicochemical modification, and excellent biocompatibility, which provide an advantageous pathway for innovative and efficient tumor suppression. Armed with nanoengineering techniques, artificial living cells harness their inherent biological properties to precisely identify and eradicate tumors, demonstrating broad biological application prospects and great transformational potential in personalized cancer therapy. Here, the recent advances of living cell‐based bionanobots including platelets, red blood cells, neutrophil, macrophage, and CAR‐T cells for cancer precision therapy and immune regulation are summarized, and the efficient anti‐tumor strategies for engineering living cell nanorobots to overcome complex biological barriers and immune suppression are also outlined (e.g., immunotherapy, sonodynamic therapy, chemo/radiotherapy, and phototherapy). In addition, the study discusses the advantages, limitations, and current challenges of artificial living cell‐based drug delivery systems, and provide perspectives on the future development of living cell‐mediated precision tumor nanomedicine.

Enzyme-Silenced Nanosponges Prolong Intratumoral Lifetime to Facilitate Intercellular Relay Drug Delivery and Treatment Efficacy.

The clinical application of nanomedicines faces the dilemma of improved safety but restricted efficacy due to the poor intratumoral bioavailability of chemotherapeutics. We here design an enzyme-silenced nanosponge that shares a long-term lifespan to reversibly exhale/inhale doxorubicin (DOX) for continuous intercellular relay delivery and improved intratumoral retention. The nanosponge is composed of a cationic lipid overlaying a hyaluronic acid derivative polyampholyte core for enveloping of DOX and hyaluronidase-1-targeted siRNA (siHyal1), and a lipoprotein shell decorated with fusion peptide 4F-tLyP-1 that was fused with apolipoprotein A-I (apoA-I) mimetic peptide 4F and tLyP-1 for tumor homing and extravasation into the tumor interstitium. Triggered by the intra/intercellular pH variation, the nanosponge core could reversibly swell in endo/lysosome (pH 5.0) for DOX release. Owing to the deprotonation, the nanosponge core shrinks back in cytoplasm (pH 7.4) for DOX reloading and continues the behavior after being secreted to the extracellular matrix (pH 6.8) via Golgi apparatus, which dramatically improves intratumoral DOX retention and availability. Concurrently, the intratumoral lifespan of the nanosponge is prolonged by siHyal1-specific silencing, ensuring spatiotemporal consistency of carrier and drug when shuttling multilayer tumor cells. As a result, the nanosponge achieves efficient tumor inhibition in 99.1% of tumor spheroids and 80.1% of orthotopic tumor models. Collectively, this study provides an intelligent nanosponge design for active intercellular relay drug delivery, achieving improved intratumoral bioavailability of drugs and amplified chemotherapy on solid tumors.

Surface curvature-induced oriented assembly of sushi-like Janus therapeutic nanoplatform for combined chemodynamic therapy

BackgroundChemodynamic therapy (CDT) based on Fenton/Fenton-like reaction has emerged as a promising cancer treatment strategy. Yet, the strong anti-oxidation property of tumor microenvironment (TME) caused by endogenous glutathione (GSH) still severely impedes the effectiveness of CDT. Traditional CDT nanoplatforms based on core@shell structure possess inherent interference of different subunits, thus hindering the overall therapeutic efficiency. Consequently, it is urgent to construct a novel structure with isolated functional units and GSH depletion capability to achieve desirable combined CDT therapeutic efficiency.ResultsHerein, a surface curvature-induced oriented assembly strategy is proposed to synthesize a sushi-like novel Janus therapeutic nanoplatform which is composed of two functional units, a FeOOH nanospindle serving as CDT subunit and a mSiO2 nanorod serving as drug-loading subunit. The FeOOH CDT subunit is half covered by mSiO2 nanorod along its long axis, forming sushi-like structure. The FeOOH nanospindle is about 400 nm in length and 50 nm in diameter, and the mSiO2 nanorod is about 550 nm in length and 100 nm in diameter. The length and diameter of mSiO2 subunit can be tuned in a wide range while maintaining the sushi-like Janus structure, which is attributed to a Gibbs-free-energy-dominating surface curvature-induced oriented assembly process. In this Janus therapeutic nanoplatform, Fe3+ of FeOOH is firstly reduced to Fe2+ by endogenous GSH, the as-generated Fe2+ then effectively catalyzes overexpressed H2O2 in TME into highly lethal ·OH to achieve efficient CDT. The doxorubicin (DOX) loaded in the mSiO2 subunit can be released to achieve combined chemotherapy. Taking advantage of Fe3+-related GSH depletion, Fe2+-related enhanced ·OH generation, and DOX-induced chemotherapy, the as-synthesized nanoplatform possesses excellent therapeutic efficiency, in vitro eliminating efficiency of tumor cells is as high as ~ 87%. In vivo experiments also show the efficient inhibition of tumor, verifying the synthesized sushi-like Janus nanoparticles as a promising therapeutic nanoplatform.ConclusionsIn general, our work provides a successful paradigm of constructing novel therapeutic nanoplatform to achieve efficient tumor inhibition.

Low-temperature photothermal-induced alkyl radical release facilitates dihydroartemisinin-triggered “valve-off” starvation therapy

The high nutrient and energy demand of tumor cells compared to normal cells to sustain rapid proliferation offer a potentially auspicious avenue for implementing starvation therapy. However, conventional starvation therapy, such as glucose exhaustion and vascular thrombosis, can lead to systemic toxicity and exacerbate tumor hypoxia. Herein, we developed a new “valve-off” starvation tactic, which was accomplished by closing the valve of glucose transporter protein 1 (GLUT1). Specifically, dihydroartemisinin (DHA), 2,20-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AI), and Ink were co-encapsulated in a sodium alginate (ALG) hydrogel. Upon irradiation with the 1064 nm laser, AI rapidly disintegrated into alkyl radicals (R•), which exacerbated the DHA-induced mitochondrial damage through the generation of reactive oxygen species and further reduced the synthesis of adenosine triphosphate (ATP). Simultaneously, the production of R• facilitated DHA-induced starvation therapy by suppressing GLUT1, which in turn reduced glucose uptake. Systematic in vivo and in vitro results suggested that this radical-enhanced “valve-off” strategy for inducing tumor cell starvation was effective in reducing glucose uptake and ATP levels. This integrated strategy induces tumor starvation with efficient tumor suppression, creating a new avenue for controlled, precise, and concerted tumor therapy.

Biodegradable mesoporous Co3O4 based nanocarriers with intrinsic lung carcinoma suppression for NIR II fluorescence bioimaging and photothermal augmented photodynamic therapy

As the highest prevalence and mortality, malignant lung carcinoma is still regarded to be an unabating cancer until now. Besides, mesoporous nanocarrier-based therapeutics delivery system has drawn plenty of attention and Co3O4 nanoparticles have been demonstrated intrinsic Fenton-like activity which is much higher than analogous synthesized Fe3O4. In this work, in order to precisely diagnose and effectively eliminate lung tumor cells, we have synthesized mesoporous hollowed Co3O4 nanocarriers with ICG loading and surface grafting of RGD peptides. We have demonstrated that the biodegradable nanoplatform is a promising NIR II fluorescent contrast agent for accurately delineating tumor counters and phototheranostic agent with photo-heat conversion efficiency as ∼59.93% under 808 nm light exposure. More importantly, the corresponded hyperthymia progressively potentiates the ROS production via Co ions catalyzation. Our Co-based nanocomposite could efficaciously suppress the tumorigenesis both in vitro and in vivo accompanied by 808 nm laser illumination. In summary, all data highlights the potency of biodegradable Co-based mesoporous nanocarriers as contrast agents for multimodal imaging and photothermal augmented ROS amplification for efficient lung tumor inhibition.

Synergistic ROS generation and directional overloading of endogenous calcium induce mitochondrial dysfunction in living cells

Taking advantage of endogenous Ca2+ to upregulate intramitochondrial Ca2+ level has become a powerful mean for mitochondrial dysfunction-mediated tumor therapy. However, the Ca2+ entered into mitochondria is limited ascribing to the uncontrollability and non-selectivity of endogenous Ca2+ transport. It remains a great challenge to make the maximum use of endogenous Ca2+ to ensure sufficient Ca2+ overloading in mitochondria. Herein, we smartly fabricate an intracellular Ca2+ directional transport channel to selectively transport endogenous Ca2+ from endoplasmic reticulum (ER) to mitochondria based on cascade release nanoplatform ABT-199@liposomes/doxorubicin@FeIII-tannic acid (ABT@Lip/DOX@Fe-TA). In tumor acidic microenvironment, Fe3+ ions are firstly released and reduced by tannic acid (TA) to Fe2+ for ROS generation. Subsequently, under the NIR light irradiation, the released ABT-199 molecules combine with ROS contribute to the formation of IP3R-Grp75-VDAC1 channel between ER and mitochondria, thus Ca2+ ions are directionally delivered and intramitochondrial Ca2+ level is significantly upregulated. The synergetic ROS generation and mitochondrial Ca2+ overloading effectively intensifies mitochondrial dysfunction, thereby achieving efficient tumor inhibition. This work presents a new insight and promising avenue for endogenous Ca2+-involved tumor therapies.

Preferential B cell differentiation by combined immune checkpoint blockade for renal cell carcinoma is associated with clinical response and autoimmune reactions.

Combined immune checkpoint blockade (ICB) is effective therapy for renal cell carcinoma (RCC). However, the dynamic changes in circulating B cells induced by combined ICB have not been clarified. The present study prospectively examined 22 patients scheduled to receive ICB for unresectable or metastatic RCC between March 2018 and August 2021. Eleven patients received combined therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab), and the other 11 patients received nivolumab monotherapy. Comprehensive phenotypes of circulating immune cells obtained prior to and after ICB therapy were analyzed by flow cytometry. Although the proportion of naïve B cells among total B cells was significantly decreased, that of switched memory B cells was significantly increased after combined therapy. In responders, the proportion of B cells among peripheral blood mononuclear cells was significantly higher prior to ICB therapy, and the proportion of switched memory B cells among total B cells tended to increase after ICB therapy. Of note, the proportion of plasmablasts among total B cells was significantly increased after ICB therapy in patients who developed severe immune-related adverse events (irAEs), and the proportion of B cells among peripheral blood decreased significantly. Furthermore, in four of five patients who developed immune-related hypophysitis following combined therapy, anti-pituitary antibody was detected in the serum. These results suggested that immune-related hypophysitis was closely related to the increase in circulating plasmablasts. Collectively, this study suggests that combined ICB promotes the differentiation of B cell populations, which is associated with efficient tumor suppression and development of irAEs.

Biomimetic hypoxia-triggered RNAi nanomedicine for synergistically mediating chemo/radiotherapy of glioblastoma

Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein, to improve the therapeutic effect of RNAi on GBM, a cancer cell membrane (CCM)-disguised hypoxia-triggered RNAi nanomedicine was developed for short interfering RNA (siRNA) delivery to sensitize cells to chemotherapy and radiotherapy. Our synthesized CCM-disguised RNAi nanomedicine showed prolonged blood circulation, high BBB transcytosis and specific accumulation in GBM sites via homotypic recognition. Disruption and effective anti-GBM agents were triggered in the hypoxic region, leading to efficient tumor suppression by using phosphoglycerate kinase 1 (PGK1) silencing to enhance paclitaxel-induced chemotherapy and sensitize hypoxic GBM cells to ionizing radiation. In summary, a biomimetic intelligent RNAi nanomedicine has been developed for siRNA delivery to synergistically mediate a combined chemo/radiotherapy that presents immune-free and hypoxia-triggered properties with high survival rates for orthotopic GBM treatment.Graphical

Structure-guided identification of novel dual-targeting estrogen receptor α degraders with aromatase inhibitory activity for the treatment of endocrine-resistant breast cancer

Drug resistance is a major challenge in conventional endocrine therapy for estrogen receptor (ER) positive breast cancer (BC). BC is a multifactorial disease, in which simultaneous aromatase (ARO) inhibition and ERα degradation may effectively inhibit the signal transduction of both proteins, thus potentially overcoming drug resistance caused by overexpression or mutation of target proteins. In this study, guided by the X-ray structure of a hit compound 30a in complex with ER-Y537S, a structure-based optimization was performed to get a series of multiacting inhibitors targeting both ERα and ARO, and finally a novel class of potent selective estrogen receptor degraders (SERDs) based on a three-dimensional oxabicycloheptene sulfonamide (OBHSA) scaffold equipped with aromatase inhibitor (AI) activity were identified. Of these dual-targeting SERD-AI hybrids, compound 31q incorporating a 1H-1,2,4-triazole moiety showed excellent ERα degradation activity, ARO inhibitory activity and remarkable antiproliferative activity against BC resistant cells. Furthermore, 31q manifested efficient tumor suppression in MCF-7 tumor xenograft models. Taken together, our study reported for the first time the highly efficient dual-targeting SERD-AI hybrid compounds, which may lay the foundation of translational research for improved treatment of endocrine-resistant BC.

Missing‐Linker‐Confined Single‐Atomic Pt Nanozymes for Enzymatic Theranostics of Tumor

AbstractConventional nanozymes often possess low active site density. Pursuing effective strategies for constructing highly active single‐atomic nanosystems with maximum atom utilization efficiency is exceptionally attractive. Herein, we develop a facile “missing‐linker‐confined coordination” strategy to fabricate two self‐assembled nanozymes, i.e., conventional nanozyme (NE) and single‐atomic nanozyme (SAE), which respectively consist of Pt nanoparticles and single Pt atoms as active catalytic sites anchored in metal–organic frameworks (MOFs) with encapsulated photosensitizers for catalase‐mimicking enhanced photodynamic therapy. Compared to a Pt nanoparticle‐based conventional nanozyme, a Pt single‐atomic nanozyme shows enhanced catalase‐mimicking activity in generating oxygen for overcoming tumor hypoxia, thus exhibiting a more efficient reactive oxygen species generation and high tumor inhibition rate.

Missing-Linker-Confined Single-Atomic Pt Nanozymes for Enzymatic Theranostics of Tumor.

Conventional nanozymes often possess low active site density. Pursuing effective strategies for constructing highly active single-atomic nanosystems with maximum atom utilization efficiency is exceptionally attractive. Herein, we develop a facile "missing-linker-confined coordination" strategy to fabricate two self-assembled nanozymes, i.e., conventional nanozyme (NE) and single-atomic nanozyme (SAE), which respectively consist of Pt nanoparticles and single Pt atoms as active catalytic sites anchored in metal-organic frameworks with encapsulated photosensitizers for catalase-mimicking enhanced photodynamic therapy. Compared to Pt nanoparticle-based conventional nanozyme, Pt single-atomic nanozyme shows enhanced catalase-mimicking activity in generating oxygen for overcoming tumor hypoxia, thus presenting more efficient reactive oxygen species generation and high tumor inhibition rate.