A Hollow Amorphous Bimetal Organic Framework for Synergistic Cuproptosis/Ferroptosis/Apoptosis Anticancer Therapy via Disrupting Intracellular Redox Homeostasis and Copper/Iron Metabolisms

Advanced Functional Materials, Journal Year: 2022, Volume and Issue: 32(40)

Published: July 30, 2022

Abstract Cuproptosis is a very newly recognized regulated cell death modality that distinct from known mechanisms and shows enormous prospect in cancer treatment. However, its efficacy copper‐dependent restricted by strictly copper metabolism. Herein, novel copper/iron hybrid hollow amorphous metal organic framework (HaMOF) developed as an oxidative stress amplifier metabolic disrupter for synergistic cuproptosis/ferroptosis/apoptosis anticancer therapy. The HaMOF fabricated Cu 2+ , 3,3′‐dithiobis(propionohydrazide) Fe 3+ via unsaturated coordination‐etching integration strategy, then doxorubicin loaded followed surface decoration with hyaluronan. obtained DOX@Fe/CuTH exhibits tumor microenvironment‐triggered catalytic therapeutic property, wherein it can amplify cellular simultaneously boosting H 2 O production depleting glutathione. Moreover, cause mitochondrial dysfunction downregulate the expressions of transporter ATP7A iron FPN 1, thereby leading to disorders high retentions cytoplasm •OH generation. overloaded lipoylated protein dihydrolipoamide S‐acetyltransferase aggregation lead cuproptosis. Collectively, both augmented induce potent ferroptosis, which synergizes cuproptosis DOX‐mediated apoptosis efficiently suppress growth. This bimetallic nanoplatform provides new paradigm boost cuproptosis‐related therapies.

Language: Английский

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Biodegradable Ca²⁺ Nanomodulators Activate Pyroptosis through Mitochondrial Ca²⁺ Overload for Cancer Immunotherapy

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(36)

Published: June 10, 2022

Abstract Pyroptosis provides a new direction and broad prospects for cancer immunotherapy. However, the development of nanoplatform as pyroptosis inducer is limited, discovery type nano‐pyroptosis immunotherapy still imminent. Herein, biodegradable Ca 2+ nanomodulators (CaNMs) are prepared inducers via mitochondrial overload. The obtained CaNMs can decompose under low pH to release curcumin, leading sudden surge in ions, eventually resulting pyroptosis. We not only confirm occurrence overload‐triggered first time but also reveal robust immune responses CaNMs, along with remarkably suppressing tumor proliferation lung metastasis. This work will provide strategies inspiration pyroptosis‐mediated treatments, greatly contributing further nanomodulators.

Language: Английский

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Calcium homeostasis and cancer: insights from endoplasmic reticulum-centered organelle communications

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 33(4), P. 312 - 323

Published: July 30, 2022

The dysregulation of calcium ion (Ca2+) homeostasis is an emerging feature cancer and plays essential roles in the initiation progression malignant diseases.Endoplasmic reticulum, a major intracellular Ca2+ store, modulates coordination with other organelles, such as mitochondria lysosomes.Cancer cells establish hallmarks by altering expression activity modulators (Ca2+ pumps, channels, exchangers).The cancer-driven events mediated activation oncogenes or inhibition tumor suppressors are closely associated key handling toolkits.Ca2+ has become attractive target for development novel anticancer drugs. Calcium ubiquitous versatile signaling molecule controlling wide variety cellular processes, proliferation, cell death, migration, immune response, all fundamental processes establishment cancer. In recent decades, loss been considered important driving force diseases. primary endoplasmic reticulum (ER), role maintaining coordinating organelles plasma membrane. Here, we discuss ER-centered cancer, summarize Ca2+-based therapeutics, highlight significance furthering our understanding regulation serves universal secondary messenger, involved diverse biological response [1.Giorgi C. et al.Calcium dynamics machine decoding signals.Trends Cell Biol. 2018; 28: 258-273Abstract Full Text PDF PubMed Scopus (155) Google Scholar]. Despite changes having recognized long time, this area research only recently gained traction [2.Monteith G.R. al.The calcium-cancer signalling nexus.Nat. Rev. Cancer. 2017; 17: 367-380Crossref (326) Accumulating evidence now demonstrates that dysregulated driver also influences treatment responses patients [3.Marchi S. al.Ca fluxes cancer.Mol. Cell. 2020; 78: 1055-1069Abstract (105) increased interest field attributed to in-depth mechanisms responsible achieving homeostasis, well successful application specific signal-targeted therapies, example, cardiovascular neuronal diseases [4.Lei M. al.Modernized classification cardiac antiarrhythmic drugs.Circulation. 138: 1879-1896Crossref (129) Scholar,5.Tiscione S.A. al.IPR-driven increases mitochondrial Ca promote death NPC disease.Proc. Natl. Acad. Sci. U. A. 2021; 118e2110629118Crossref (17) Consequently, highly drugs [6.Cui al.Targeting therapy.Acta Pharm. Sin. B. 7: 3-17Crossref (360) Playing fate regulation, it not surprising rigorously regulated complex set components, including exchangers These Ca2+-regulating 'toolkits' distributed at organelle membranes, acting maintain low concentration cytosolic free Ca2 against steep gradients extracellular sequestered Ca2+. ER site storage Scholar], along additional stores like Golgi and, more recently, lysosomes [7.Vandecaetsbeek I. pumps apparatus.Cold Spring Harb. Perspect. 2011; 3a004184Crossref (162) Scholar,8.Wu Y. al.Lysosomal channels autophagy cancer.Cancers (Basel). 13: 1299Crossref (20) within relatively under resting conditions. Nonetheless, upon stimuli events, almost orchestrating order transmit signal As central response. extensively reviewed elsewhere Scholar,3.Marchi focus on its association protein lipid synthesis largest reservoir [9.Raffaello center signaling: interplay between mitochondria, lysosomes.Trends Biochem. 2016; 41: 1035-1049Abstract (316) high provides optimal environment local enzymes required physiological functions ER, whilst contributing maintenance Upon stimulus, releases Ca2+, which facilitates rapid transmission signals, leading distinctive outcomes, proliferation determined finely tuned balance influx outflux. Sarcoplasmic-endoplasmic type ATPases (SERCAs) (see Glossary), ER-resident Whereas outflux inositol 1,4,5-trisphosphate receptors (IP3Rs), enhanced IP3 hormone growth factor stimulation ryanodine (RyRs), latter process known Ca2+-induced release (CICR) reduction concentration, transmembrane protein, stromal interaction 1 (STIM1), activated, interacts activates release-activated modulator (ORAI1) channel, localized membrane, subsequent SERCA2-mediated refilling, named store operated entry (SOCE) coiled-coil domains (TMCO1) controls how restore case overload. TMCO1 present inactive monomer During overload, forms selective channel through monomer-to-tetramer transformation, recovery, overload-induced (SOICR) [10.Wang Q.-C. al.TMCO1 load-activated channel.Cell. 165: 1454-1466Abstract (99) Scholar] (Figure 1A ). Enhanced sourced from either space can trigger uptake latest demonstrated two distinct physiologically functionally connected multiple sites [called mitochondria-associated membrane (MAM)] various regulating Mechanistically, IP3Rs voltage-dependent anion (VDACs) form spanning MAM, promoting outer contrast, inner mainly driven negative potential (ΔΨm: ~–180mV) gradient uniporter (MCU) 1B). Lysosomes typically deal waste. They be significant stores, functional hubs [8.Wu An increase ER–lysosome interface sensitizes IP3R, thus evoking transport lysosome nicotinic acid adenine dinucleotide phosphate (NAADP)-regulated two-pore (TPCs) [11.Marchant J.S. al.NAADP-binding proteins find their identity.Trends 2022; 47: 235-249Abstract (9) mucolipin (MCOLN) family transient receptor (TRPML) [12.Rosato A.S. al.Two-pore TRPML cation channels: regulators phagocytosis, lysosomal exocytosis.Pharmacol. Ther. 220107713Crossref (19) elicit similar CICR [13.Capel R.A. (TPC2s) (NAADP) lysosomal-sarcoplasmic reticular junctions contribute acute chronic β-adrenoceptor heart.J. Chem. 2015; 290: 30087-30098Abstract (52) 1C). coordinates 1). stimulation, activated outcomes magnitude, frequency, localization flux, linked carcinogenesis. Given frequently altered human cancers Table S1 (in supplemental information online) summary differential isoform type-specific homeostasis. This turn leads resistance apoptosis, evasion, discussed further detail later. Under conditions, controlled cycle-dependent manner. Some IP3R members have senescence [14.Wiel al.Endoplasmic ITPR2 accumulation senescence.Nat. Commun. 2014; 5: 3792Crossref (132) Scholar,15.Ziegler D.V. mitochondria-ER contacts aging.Nat. 12: 720Crossref (54) Although remains whether these directly confer carcinogenesis sensitivity, knockout thymocytes was found decrease suppress lymphoblastic leukemia [16.Ouyang K. al.Loss IP3R-dependent aberrant leukemia.Nat. 4814Crossref (49) Among three proteins, IP3R3 upregulated (Table online). Genetic pharmacological significantly reduces [17.Szatkowski al.Inositol 1,4,5-trisphosphate-induced estradiol-induced breast epithelial growth.Mol. 2010; 9: 156Crossref (70) Scholar, 18.Guerra M.T. al.Expression 3 InsP final common event hepatocellular carcinoma.Gut. 2019; 68: 1676-1687Crossref 19.Ueasilamongkol P. al.Type enhances properties cholangiocarcinoma.Hepatology. 71: 583-599Crossref (42) implying therapeutic reduce growth. SOCE established. A potent inhibitor, RP4010, produces dramatic antiproliferation effect inducing G0/G1 arrest esophageal [20.Cui Orai1-mediated store-operated RP4010 anti-tumor esophagus squamous carcinoma.Cancer Lett. 432: 169-179Crossref (30) knocking down STIM1 cervical arrests cycle S G2/M phases [21.Chen Y.-F. sensor stromal-interaction 1-dependent growth, angiogenesis.Proc. 108: 15225-15230Crossref (280) suggesting components may act checkpoints, context-dependent low-level, constitutive transfer critical survival [22.Cárdenas al.Selective vulnerability mitochondria.Cell Rep. 14: 2313-2324Abstract (152) Scholar,23.Zhao H. al.AMPK-mediated MCU stimulates mitotic progression.Nat. 21: 476-486Crossref (85) Mitochondrial Ca2+-sensitive dehydrogenases tricarboxylic biosynthetic bioenergetic needs [23.Zhao Scholar,24.Young M.P. al.Metabolic adaptation induced KO IP uniporter.J. 298101436Abstract (7) involvement MAM exemplified (as earlier) additionally VDAC1 lung [25.Arif T. al.Silencing siRNA inhibits vivo.Mol. Nucleic Acids. 3e159Abstract (104) colorectal [26.Liu al.MCU-induced promotes biogenesis growth.Signal Transduct. Target. 59Crossref Scholar,27.Zeng F. al.RIPK1 binds mediate induction oncogenesis.Cancer Res. 2876-2885Crossref (56) Dysregulated shown energy expenditure, vulnerable targets metabolic stress [24.Young Scholar,28.Cardenas al.Cancer defective oxidative phosphorylation require reticulum-to-mitochondria survival.Sci. Signal. eaay1212Crossref (39) moderate while massive overload triggers [29.Loncke J. al.Balancing ER-mitochondrial health disease.Trends 31: 598-612Abstract (53) SERCAs protect stem (CSCs) glucose starvation-induced apoptosis limiting [30.Park K.C. al.Survival stem-like via CaMK2α-mediated upregulation sarco/endoplasmic ATPase expression.Clin. Cancer 24: 1677-1690Crossref (26) We reported SOICR protects colon staurosporine-induced [31.Zheng al.iASPP suppresses Gp78-mediated degradation control drug resistance.Proc. 119e2111380119Crossref (6) Another study urinary bladder urothelial carcinoma, but related regulatory [32.Li C.-F. al.Transmembrane domain impairs AKT pathway carcinoma: characterization suppressor.Clin. 23: 7650-7663Crossref (21) It possible Ca2+-independent function, acts differentially Undoubtedly, researching actions will guide TMCO1-targeted therapies. Increased another apoptosis. Loss abolish cisplatin-induced non-small carcinoma [33.Gualdani R. al.Store-operated contributes carcinoma.Cancers 11: 430Crossref (32) Similar ORAI1 detected prostate treated thapsigargin (TG), necrosis α (TNF-α), cisplatin/oxaliplatin [34.Flourakis al.Orai1 apoptosis-resistant phenotype cells.Cell Death Dis. 1e75Crossref (171) At VDAC isoforms stimulus ways. activities [18.Guerra Scholar,35.Liao al.Identification BBOX1 triple-negative cancer.Cancer Discov. 10: 1706-1721Crossref induces cells. Paradoxically, elicits proapoptotic effects ovarian cells, resulting cisplatin sensibility enhancing [36.Xue al.SMARCA4/2 chemotherapy-induced restricting IP3R3-mediated flux mitochondria.Nat. 5404Crossref (12) Additionally, anti- assigned IP3R1, respectively, same context [37.Rezuchova antiapoptotic proliferative 186Crossref (46) Why produce still explored. Similarly, facilitating [38.De Stefani D. al.VDAC1 selectively transfers apoptotic signals Differ. 2012; 19: 267-273Crossref (230) VDAC2 possibly independently line finding, ER-to-mitochondria proposed general strategy [28.Cardenas Metastasis multistep process, accounts than 90% mortality [39.Wang J.Y. al.STIM1 overexpression progression, motility COX-2 expression.Oncogene. 34: 4358-4367Crossref (107) poor Consistently, STIM1- ORAI1-mediated oscillations invasion invadopodium assembly matrix (ECM) [40.Sun al.STIM1- oscillation orchestrates formation melanoma invasion.J. 207: 535-548Crossref (123) blockade metastasis vivo vitro Scholar,41.Lee S.K. al.Metastasis enhancer PGRMC1 boosts uncoiling focal adhesion turnover actomyosin formation.Cell 38110281Abstract (8) affect metastasis, reactive oxygen species (ROS) production Conversely, pancreatic ductal adenocarcinoma activating KEAP1-NRF2 antioxidant program [42.Wang X. al.Mitochondrial drives confers targetable cystine dependency 82: 2254-2268Crossref (24) regulate migration liver, breast, modulating global Ca2+-mediated exocytosis Whether communications addition ECM remodeling, angiogenesis. TRPML1 able angiogenesis, observed overexpress responses, [43.Xie al.SOCE cancer: progress new perspectives.Int. 2067-2077Crossref (73) Defects SOCE, caused depletion, result dysfunction clearance increasing number studies established connection SOCE-regulated For mice conditional CD8+ T lose ability engulf both [44.Weidinger STIM2-mediated regulates antitumour immunity cells.EMBO Mol. Med. 2013; 1311-1321Crossref (80) Alternatively, ablation mouse myeloid crosspresentation dendritic (DC) impaired cytotoxic reduced [45.Nunes-Hasler phagosomal maturation antigen cross-presentation cells.Nat. 8: 1852Crossref Recently, SERCA V(D)J recombination [46.Chen C.-C. al.Sarco/endoplasmic Ca2+-ATPase (SERCA) recombination.J. Exp. 218e20201708Crossref (4) DC [47.Marongiu L. 3-kinase B mobilization inflammatory cells.Sci. eaaz2120Crossref (15) Scholar]; therefore, likely commonly responses. However, unclear. should noted glutamine

Language: Английский

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MOFs-based nanoagent enables dual mitochondrial damage in synergistic antitumor therapy via oxidative stress and calcium overload

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Nov. 4, 2021

Abstract Targeting subcellular organelle with multilevel damage has shown great promise for antitumor therapy. Here, we report a core-shell type of nanoagent iron (III) carboxylate metal-organic frameworks (MOFs) as shell while upconversion nanoparticles (UCNPs) core, which enables near-infrared (NIR) light-triggered synergistically reinforced oxidative stress and calcium overload to mitochondria. The folate decoration on MOFs shells efficient cellular uptake nanoagents. Based the ability UCNPs, NIR light mediates Fe 3+ -to-Fe 2+ reduction simultaneously activates photoacid generator (pHP) encapsulated in cavities, release free acidification intracellular microenvironment, respectively. overexpressed H 2 O mitochondria, highly reactive acidic milieu reinforce Fenton reactions producing lethal hydroxyl radicals (•OH) plasma photoacidification inducing influx, leading mitochondria overload. dual-mitochondria-damage-based therapeutic potency been unequivocally confirmed cell- patient-derived tumor xenograft models vivo.

Language: Английский

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A Tumor Microenvironments‐Adapted Polypeptide Hydrogel/Nanogel Composite Boosts Antitumor Molecularly Targeted Inhibition and Immunoactivation

Advanced Materials, Journal Year: 2022, Volume and Issue: 34(21)

Published: March 15, 2022

Various macro/microscopic biomaterials have been developed for controlled drug delivery in the combination therapy of malignancies. However, uncertain loading ratio, release sequence, and spatiotemporal distribution drugs hinder their synergistic therapeutic effects clinical applications. In this work, a tumor microenvironments-adapted composite consisting thermosensitive hydrogel reactive oxygen species (ROS)-responsive nanogel is precisely sequential to enhance molecularly targeted amplify immune activation. LY3200882 (LY), selective transforming growth factor-β (TGF-β) inhibitor, encapsulated ROS-responsive dispersed uniformly with regorafenib (REG) (Gel/(REG+NG/LY)). After situ administration, REG preferentially released from inhibit promote ROS generation, which triggers subsequent on-demand LY nanogel. contributes preventing epithelial-mesenchymal transition escape cells induced by elevated TGF-β. subcutaneous orthotopic colorectal bearing mouse models, Gel/(REG+NG/LY) effectively inhibits liver metastases increasing infiltration CD8+ T cells, reducing recruitment tumor-associated macrophages myeloid-derived suppressor promoting polarization M2 M1 type, indicating significant potential improving prognosis advanced cancer patients.

Language: Английский

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Manganese carbonate nanoparticles‐mediated mitochondrial dysfunction for enhanced sonodynamic therapy

Exploration, Journal Year: 2021, Volume and Issue: 1(2)

Published: Sept. 30, 2021

Abstract Sonodynamic therapy (SDT) has attracted widespread attention due to its non‐invasiveness and deep tissue penetration. However, the development of efficient sonodynamic nanoplatforms improve therapeutic efficiency is still one main challenges current research. In this work, a new type sonosensitizer prepared by simple method, manganese carbonate nanoparticles (MnCO 3 NPs), used for enhanced SDT. MnCO NPs could generate large amounts 1 O 2 •OH under ultrasound irradiation. At same time, CO Mn ions be released in weak acid environment excellent degradability NPs. The bubbles caused cell necrosis ultrasonic cavitation imaging. And activated mitochondrial apoptosis pathway. vivo experiments proved that with regulatory capacity showed high tumor inhibition rates therapy.

Language: Английский

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H₂O₂ Self-Supplying and GSH-Depleting Nanoplatform for Chemodynamic Therapy Synergetic Photothermal/Chemotherapy

ACS Applied Materials & Interfaces, Journal Year: 2021, Volume and Issue: 13(37), P. 43925 - 43936

Published: Sept. 9, 2021

Chemodynamic therapy (CDT) that utilizes Fenton-type reactions to convert endogenous hydrogen peroxide (H2O2) into hydroxyl radicals (•OH) is a promising strategy in anticancer treatment, but the overexpression of glutathione (GSH) and limited H2O2 make efficiency CDT unsatisfactory. Here, an intelligent nanoplatform CuO2@mPDA/DOX-HA (CPPDH), which induced depletion GSH self-supply H2O2, was proposed. When CPPDH entered tumor cells through targeting effect hyaluronic acid (HA), release Cu2+ produced were triggered by acidic environment lysosomes. Then, reduced Cu+, Cu+ catalyzed produce •OH. The generation •OH could be distinctly enhanced self-sufficiency. Besides, outstanding photothermal (PTT) stimulated NIR irradiation on mesoporous polydopamine (mPDA). Meanwhile, mPDA excellent photoacoustic reagent, monitor delivery nanocomposite materials (PA) imaging. Moreover, successful doxorubicin (DOX) realized integration chemotherapy, PTT, CDT. This solve problem insufficient efficacy caused GSH. multifunctional may open broad path for self-boosting synergistic therapy.

Language: Английский

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Smart transformable nanoparticles for enhanced tumor theranostics

Applied Physics Reviews, Journal Year: 2021, Volume and Issue: 8(4)

Published: Dec. 1, 2021

The physical morphologies of nanoparticles, especially size and shape, always significantly influence their biological behaviors. In the past, nanoparticles with constant have been widely investigated applied in tumor theranostics. With increased in-depth knowledge tumors physiological microenvironments, are required to self-adjust during circulation varying microenvironments when reaching site that possess distinct microenvironments. Therefore, smart transformable nanomaterials, which can alter under different conditions, show great potential advanced This review summarizes nanoparticles' on behaviors highlights designs serving as a guideline for construction, intensively discusses recent biomedical applications these theranostics, also proposes future challenges perspectives development

Language: Английский

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Nano‐enabled Tumor Systematic Energy Exhaustion via Zinc (II) Interference Mediated Glycolysis Inhibition and Specific GLUT1 Depletion

Advanced Science, Journal Year: 2021, Volume and Issue: 9(7)

Published: Dec. 16, 2021

Despite the promise of tumor starvation therapies, they are often associated with nonspecific and incomplete energy blockade. Here, a novel paradigm therapy is proposed to synergize "Zn

Language: Английский

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Multifunctional liquid metal-based nanoparticles with glycolysis and mitochondrial metabolism inhibition for tumor photothermal therapy

Biomaterials, Journal Year: 2022, Volume and Issue: 281, P. 121369 - 121369

Published: Jan. 7, 2022

Language: Английский

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