Excess GSH Research Articles

Carbon dot-based nanomaterials with enzyme-like activity for fluorescence imaging and potential combination withtherapy of cancer.

Carbon dot-based nanomaterials (o-CDs@Mn) were fabricated by assembling fluorescent o-CDs with enzyme-like activity and Mn nanoparticles with photothermal properties for realizing fluorescence imaging and combined therapy of cancer. Due to the inherent optical properties of o-CDs, o-CDs@Mn can be effectively used for bioimaging. In addition, o-CDs@Mn possess peroxidase-like (POD-like) and glutathione (GSH) degradation capabilities, which can effectively deplete excessive H2O2 and GSH in the tumor microenvironment (TME), generating ·OH and reduced GSSH for regulating the TME and triggering ROS-mediated apoptosis in cancer cells. More importantly, it is synergistically supplemented with fluorescence imaging and photothermal therapy (PTT), which realizes the integration of monitoring and combined treatment, providing a promising potential pathway for accurate and efficient cancer treatment.

Tumor therapy utilizing dual-responsive nanoparticles: A multifaceted approach integrating calcium-overload and PTT/CDT/chemotherapy

The advancement of rational nano drug delivery systems offers robust tools for achieving synergistic therapeutic outcomes in tumor treatment. In this study, we present the development of pH and near-infrared laser dual-responsive nanoparticles (DOX-CuS@CaCO3@PL-PEG, DCCP NPs) based on calcium carbonate, utilizing a one-pot gas diffusion reaction. These nanoparticles enable combined photothermal therapy (PTT), chemodynamic therapy (CDT), chemotherapy, and Ca2+-overloading synergistic therapy. Doxorubicin (DOX) and copper sulfide (CuS) NPs were co-loaded in CaCO3, followed by PEG surface functionalization. The presence of PEG enhanced the stability of DCCP NPs in aqueous environments. Controlled release of DOX, CuS NPs, and Ca2+ occurs specifically in the acidic tumor microenvironment. Released DOX enhances chemotherapy efficiency, while CuS NPs, upon laser irradiation, induce thermal damage, promoting further drug release and cellular uptake. Additionally, CuS NPs in our system consume excess GSH and generate toxic hydroxyl radicals (·OH) through a Fenton-like reaction, contributing to CDT. These radicals not only directly eliminate tumor cells but also disrupt mitochondrial Ca2+ buffering capacity. Furthermore, Ca2+ released from CaCO3 induces Ca2+-overloading, intensifying mitochondrial disruption and oxidative damage. The synergistic combination of PTT, CDT, chemotherapy, and Ca2+-overloading showcases significant therapeutic potential, indicating broad applications in tumor therapy. This multifaceted approach holds promise for advancing the field of tumor therapeutics.

Dual Stimuli-Responsive Nanoprecursor of Ascorbic Acid and Quinone Methide Disrupting Redox Homeostasis for Cancer Treatment.

Disrupting the redox balance through reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion presents a promising strategy for cancer therapy. Megadoses of ascorbic acid (AA) can induce oxidative stress in cancer cells, leading to cell death. However, achieving enhanced oxidative stress using ultrahigh doses of AA is challenging because of the intricate delivery of high-concentration AA to the targeted sites while the cancer cells could also re-establish more robust redox homeostasis by upregulating antioxidants such as GSH. Recently, quinone methide and its analogues (QMs) have been recognized as effective GSH scavengers, offering a new dimension to accelerate oxidative stress. In this study, we formulated a dual stimuli-responsive nanoprecursor of AA and QM using gold nanoparticles. The nanoprecursor can release AA in response to the intracellular acidic pH in tumor cells, elevating the intracellular ROS levels and triggering the production of ample QMs to quench excessive GSH. This positive feedback mechanism significantly amplifies oxidative stress and disrupts redox homeostasis in cancer cells at a relatively low concentration of AA, leading to selective apoptosis without affecting normal cells. These results highlight the potential of the nanoprecursor as an effective anticancer therapeutic.

Pt(IV) complexes loaded hollow copper sulfide nanoparticles for tumor chemo/photothermal/photodynamic therapy

Hollow CuS nanoparticles can achieve photothermal and photodynamic therapy (PDT) in tumor treatment. However, excessive GSH in the tumor cells will consume the reactive oxygen species produced by PDT and reduce the PDT effect. Cisplatin is a broad-spectrum antineoplastic drug that can be used in a variety of tumor treatments. However, cisplatin is cytotoxic to normal cells while it kills tumor cells. Therefore, we construct Pt(IV) complexes loaded hollow CuS nanoparticles to attenuate the toxicity of cisplatin and enhance the PDT effect of the hollow CuS nanoparticles. The nanoparticles were proved to be able to accumulate around the tumor site through the enhanced permeability and retention (EPR) effect to achieve a synergistic chemo/photothermal/photodynamic therapy.

Biomimetic Cancer-Targeting Nanoplatform Boosting AIEgens-Based Photodynamic Therapy and Ferroptosis by Disrupting Redox-Homeostasis.

Photodynamic therapy (PDT) using aggregation-induced emission photosensitizer (AIE-PS) holds tremendous potential but is limited by its inherent disadvantages and the high concentrations of reduced glutathione (GSH) in tumor cells that can neutralize ROS to weaken PDT. Herein, we designed a nanodelivery system (CM-HSADSP@[PS-Sor]) in which albumin was utilized as a carrier for hydrophobic drug AIE-PS and Sorafenib, cross-linkers with disulfide bonds were introduced to form a nanogel core, and then cancer cell membranes were wrapped on its surface to confer homologous tumor targeting ability. A two-way strategy was employed to disturb redox-homeostasis through blocking GSH synthesis by Sorafenib and consuming excess GSH via abundant disulfide bonds, thereby promoting the depletion of GSH, which in turn increased the ROS levels in cancer cells to amplify the efficacy of ferroptosis and PDT, achieving an efficient in vivo antibreast cancer effect. This study brings a new strategy for ROS-based cancer therapy and expands the application of an albumin-based drug delivery system.

Copper(II)-based metal-organic framework delivery of calcium ascorbate for enhanced chemodynamic therapy via H2O2 self-supply and glutathione depletion.

Chemodynamic therapy (CDT) is a promising cancer treatment strategy. However, mild acidic pH, insufficient H2O2 content, and overexpressed glutathione (GSH) in the tumor microenvironment (TME) severely impair CDT efficiency. In this study, a novel therapeutic nanosystem (Cu/ZIF-8/Vc-Ca/HA) was constructed for H2O2 self-supply and GSH depletion co-enhanced CDT. Typically, calcium ascorbate (Vc-Ca) loaded on the surface of Cu2+-doped ZIF-8 (Cu/ZIF-8) was designed as an original source for H2O2 generation, and a hyaluronic acid (HA) shell was subsequently coated to act as a tumor-targeted "guide" and protective layer. Along with the HA shell disintegrated in the TME, exposed Cu/ZIF-8/Vc-Ca dissociated in the tumor acidic microenvironment, thus triggering the release of Vc-Ca and Cu2+. Vc-Ca selectively produced H2O2 in tumor cells, which provided abundant H2O2 for boosting Fenton-like reactions. Meanwhile, the released Cu2+ could get converted into Cu+ by consuming excess intracellular GSH, which could reduce the tumor antioxidant capability of the nanosystem. Moreover, byproduct Cu+ reacted with abundant H2O2 by a highly efficient Fenton-like reaction to generate toxic ˙OH. Biological assays indicated that the Cu/ZIF-8/HA@Vc-Ca nanosystem showed significant anticancer activity by enhancing the CDT process. This study may provide a new strategy for improving the effectiveness of CDT.

Dual-responsive nanoplatform for integrated cancer diagnosis and therapy: Unleashing the power of tumor microenvironment.

Chemodynamic therapy (CDT), designed to trigger a tumor-specific hydrogen peroxide (H2O2) reaction generating highly toxic hydroxyl radicals (·OH), has been investigated for cancer treatment. Unfortunately, the limited Fenton or Fenton-like reaction rate and the significant impact of excessive reducing glutathione (GSH) in the tumor microenvironment (TME) have severely compromised the effectiveness of CDT. To address this issue, we designed a dual-responsive nanoplatform utilizing a metal-polyphenol network (MPN) -coated multi-caged IrOx for efficient anti-tumor therapy in response to the acidic TME and intracellular excess of GSH, in which MPN composed of Fe3+ and tannic acid (TA). Initially, the acidic TME and intracellular excess of GSH lead to the degradation of the MPN shell, resulting in the release of Fe3+ and exposure of the IrOx core, facilitating the efficient dual-pathway CDT. Subsequently, the nanoplatform can mitigate the attenuation of CDT by consuming the excessive GSH within the tumor. Finally, the multi-caged structure of IrOx is advantageous for effectively implementing photothermal therapy (PTT) in coordination with CDT, further enhancing the therapeutic efficacy of tumors. Moreover, the outstanding Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) (T1/T2) multimodal imaging capabilities of IrOx@MPN enable early diagnosis and timely treatment. This work provides a typical example of the construction of a novel multifunctional platform for dual-responsive treatment of tumors.

Glutathione depletion based Pt(IV) hybrid mesoporous organosilica delivery system to conquer cisplatin chemoresistance: A “one stone three birds” strategy

The occurrence of acquired resistance to cisplatin (DDP) that induces the toxic drug effects has always been a huge challenge and urgently needs to be resolved in the cancer treatment. The combination of anticancer drugs with different mechanisms can remarkably improve the chemotherapeutic efficiency. Given that glutathione (GSH) plays as the driving factors in the resistance of DDP, here we have firstly proposed a “three birds, one stone” based nanoplatform to achieve triple synergetic effects simultaneously addressing DDP resistance in non-small cell lung cancer (NSCLC). Specifically, we initially designed and synthesized a DDP prodrug [Pt(IV)] bridged silsesquioxane precursor (Pt-Si). Then Pt-Si and bis[3-(triethoxysilyl)propyl]diselenide (BTESePD) were integrated into the framework of mesoporous organosilica nanoparticles (MONs) to obtain a nanocarrier MONPt/Se. After loading with norcantharidin (NCTD) and modifying with the aptamer AS1411 based G-quadruplex (Apt), the Apt@NCTD@MONPt/Se exhibit impressive tumor homing capability. Once being endocytosed, (I) the diselenide and -O-Pt(IV)-O- rich scaffold can be reduced by the excessive GSH, followed by (II) breaking the redox homeostasis via GSH depletion and precise release of the DDP. Next, the encapsulated NCTD is also released along with the degradation of the nanocarriers thereby (III) achieving the GSH depletion and synergistic anti-tumor effect of NCTD and DDP. Taken together, we believe this “one stone, three birds” strategy may be a promising paradigm to conquer drug resistance for clinical care.

Fluorinated Iron Metal-Organic Frameworks for Activatable 19F Magnetic Resonance Imaging and Synergistic Therapy of Tumors.

Due to their appealing physiochemical properties, metal-organic frameworks (MOFs) have been widely employed in biomedical fields. In this study, we utilize ferric ions and fluorine-containing organic ligands as both structural and functional units to develop a stimulus-responsive nanoagent, 19FIMOF-TA nanoparticles, for activatable 19F magnetic resonance imaging (MRI) and synergistic therapy of tumors. This nanoagent could respond to excess GSH in a tumor microenvironment, discharging fluorinated organic ligands and reduced ferrous ions. The release of these fluorine-containing small molecules results in boosting of the 19F MRI signals, which could be further enhanced by the photothermal effect of this nanoagent to achieve a responsive cascaded amplification of 19F MRI signals for tumor visualization. Meanwhile, ferroptosis promoted by the ferrous ions leads to significant tumor cell death, which is synergistically aggravated by the photothermal effect. The encouraging results illustrate the promising potential of our nanoagent for effective tumor imaging and combinative cancer therapy.

Multifunctional Tumor-Targeting Carbon Dots for Tumor Microenvironment Activated Ferroptosis and Immunotherapy in Cancer Treatment.

As an emerging cancer treatment strategy, ferroptosis is distinguished by the perturbation of lipid metabolism equilibrium and the accumulation of lipid peroxidation. However, the efficacy is consistently hindered by excessive GSH in the tumor microenvironment (TME). Here, this work designed and prepared multifunctional tumor-targeting carbon dots (FG-CDs@Cu) for ferroptosis and immunotherapy. Cu2+ in FG-CDs@Cu rapidly depletes high concentrations of GSH and inhibits glutathione peroxidase 4 (GPX4) expression in an acidic TME. Meanwhile, the generated Cu+ produced reactive oxygen species (ROS) through Fenton-like reaction. Due to the high efficiency of ROS production and GSH depletion, ferroptosis mediated by oxidative stress is significantly enhanced by FG-CDs@Cu in vivo, which can induce immunogenic cell death and promote CD8+ T cell infiltration. Meanwhile, the generated O2 effectively improves the hypoxic environment of the cells and leads to the reduction of hypoxia factor-1α (HIF-1α) expression, which activates the transformation of tumor-promoting M2-type tumor-associated macrophages (TAMs) to tumor-inhibiting M1-type TAMs, further enhancing the immune response and ferroptosis. The in vivo tests suggested that FG-CDs@Cu could efficiently suppress tumor growth in the mouse model and did not cause obvious toxicity. The combination with antiprogrammed death-ligand 1 (αPD-L1) synergy immune therapy could effectively restrain the growth of distal tumors, suggesting the significant potential of FG-CDs@Cu in augmenting ferroptosis and immunotherapy for efficacious cancer treatment.

Single-laser excitation synergistic photo- and chemodynamic therapy system based on persistent luminescence nanoparticles

Photodynamic and photothermal therapy (PDT and PTT) have been widely used in tumor treatment researches owe to its advantages of spatiotemporal controlliability and non-invasiveness. Combining two phototherapy strategies together and/or with chemodynamic therapy (CDT) could achieve better therapeutic efficiency, but the resulting inconvenient dual-laser irradiation and the potential skin toxicity limit its development. Moreover, the lack of tumor-specificity causes side-effects to normal tissues. Therefore, shortening the irradiation time, or integrating two lasers, and increasing tumor specificity are necessary to reduce side effects. Herein, we developed a tumor microenvironment responsive one-laser-excited PDT/PTT/CDT synergistic therapeutic nanosystem ZPPSC (refers to ZGGC-PDA-PEI-Si-Pc-Cu) for precise tumor phototherapy. In this nanosystem, the simultaneous PTT and PDT activation using a single laser, enhancing phototherapy efficiency while reducing phototoxicity were achieved. Specifically, persistent luminescence nanoparticle ZnGa1.6Ge0.2O4:Cr (ZGGC) is coated with polydopamine (PDA) through self-polymerization of dopamine, modified with polyethyleneimine (PEI), Si-Pc, and adsorbed with Cu2+. Cu2+ quenches the persistent luminescence (PersL) in physiological environment, and could be reduced to Cu+ under the excess GSH in tumor cells, resulting in removing from nanosystem. Whereafter, PersL is restored, and Fenton-like reaction between Cu+ and overexpressed H2O2 is triggered to generate ·OH for CDT therapy. Under single 808-nm irradiation, PDA will be irradiated to perform PTT, and the opening persistent luminescence could irradiate photosensitizers for PDT and continues to stimulate them even after the laser stops, reducing external excitation time. The in vivo results shown that ZPPSC exhibit ideal PDT performance, and increased local temperature close to 60 °C. Most importantly, the tumor inhibition rate by combined PTT, PDT, CDT with 5-min 808-nm laser irradiation is 99%, and even one mouse was completely cured with the bearing tumor completely disappeared. By using this nanosystem, PDT and PTT were achieved by only on laser with relatively short irradiation time. Moreover, the weak tissue penetration of the 660-nm PS excitation source was also addressed. Our design achieves tumor-specific one-laser three-mode phototherapy with shortened irradiation time, enhancing therapy effectiveness while minimizing side effects. These results exhibit great therapeutic outcomes of ZPPSC for precious tumor phototherapy.

Photothermal enhanced polyphenol-based nanofibers ameliorate catalytic efficiency of ferroptosis for synergistic tumor therapy

Ferroptosis is an emerging antitumor treatment modality with the superiority for evading apoptotic cell death pathway. However, how to elevate catalytic efficacy of Fe2+-mediated Fenton reaction and efficiently elicit ferroptosis remain enormously challenging. Herein, inspired by hyperthermia-enhanced Fenton reaction kinetics, we firstly designed iron-polyphenol-aspirin-coordinated nanochelates for photothermal-enhanced ferroptosis antitumor immunotherapy. Specifically, we modulated optimal mass feeding ratio of gallic acid (GA), aspirin (ASA), Fe (II) and polyvinylpyrrolidone (PVP) to construct novel nanofibrous GA-ASA-Fe (II) metalchelates named GAFs. The variations in size and structure allowed the nanomedicines to avoid the risk of premature renal clearance in vivo, compared with the reported ultrasmall GA-Fe (II) nanocomplexes (GFs). Under NIR laser irradiation, GAFs could constantly amplify toxic hydroxyl radicals (OH) generation and deplete excessive GSH to induce more accumulation of lethal lipid peroxidation (LPO), thereby triggering ferroptosis pathway in vitro and in vivo. Besides, the introduction of ASA could inhibit cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2), in combination with photothermal-enhanced ferroptosis tumor therapy to induce immunogenic cell death (ICD), promote maturation of dendritic cells (DCs) and activate cytotoxic T cells for synergistic antitumor immunotherapy. GAFs with laser irradiation exhibited the capacity of inhibition of pulmonary metastasis. This work presented a strategy for incorporating small molecule immunomodulator into the metal-polyphenolic coordination to ameliorate its deficiencies, thereby inspiring a new design concept for tumor treatment.

In-situ fabrication of novel Au nanoclusters-Cu2+@sodium alginate/hyaluronic acid nanohybrid gels for cuproptosis enhanced photothermal/photodynamic/chemodynamic therapy via tumor microenvironment regulation

Multimodal combined therapy (MCT) is an emerging avenue to eliminate tumor cells by the synergistic effect of various therapeutic methods. However, the complex tumor microenvironment (TME) is becoming the key barrier to the therapeutic effect of MCT due to the excessive existence of H+ ions, H2O2, and glutathione (GSH), the lack of O2, and the relaxation of ferroptosis. To overcome these limitations, smart nanohybrid gels with excellent biocompatibility, stability and targeting function were prepared by using gold nanoclusters as cores and an in situ cross-linking composite gel of sodium alginate (SA)/hyaluronic acid (HA) as the shell. The obtained Au NCs-Cu2+@SA-HA core–shell nanohybrid gels possessed near-infrared light response synergistically benefitting photothermal imaging guided photothermal therapy (PTT) and photodynamic therapy (PDT). Meanwhile, the H+-triggered release of Cu2+ ions from the nanohybrid gels not only induces cuproptosis to avoid the relaxation of ferroptosis, but also catalyzes H2O2 in the TME to generate O2 to simultaneously improve the hypoxic microenvironment and PDT effect. Furthermore, the released Cu2+ ions could consume the excessive GSH to form Cu+ ions effectively, which caused the formation of hydroxyl free radicals (·OH) to kill tumor cells, synergistically realizing GSH consumption-enhanced PDT and chemodynamic therapy (CDT). Hence, the novel design in our work provides another research avenue for cuproptosis-enhanced PTT/PDT/CDT via TME modulation.

Engineering Multifunctional Thylakoid as an Oxygen Self-Supplying Photosensitizer for Esophageal Squamous Cell Carcinoma-Targeted Photodynamic Therapy

Open AccessCCS ChemistryRESEARCH ARTICLES19 Dec 2022Engineering multifunctional thylakoid as an oxygen self-suppling photosensitizer for esophageal squamous cell carcinoma-targeted photodynamic therapy Yingqiu Qi, Hui Wang, Anni Du, Chen Liu, Xiaofan Sun, Xiaocao Meng, Jinxiu Shen, Sai-Yang Zhang, Li-Rong Zhang, Bing Jiang, Guangjun Nie and Huan Min Yingqiu Qi Google Scholar More articles by this author , Hui Wang Google Scholar More articles by this author , Anni Du Google Scholar More articles by this author , Chen Liu Google Scholar More articles by this author , Xiaofan Sun Google Scholar More articles by this author , Xiaocao Meng Google Scholar More articles by this author , Jinxiu Shen Google Scholar More articles by this author , Sai-Yang Zhang Google Scholar More articles by this author , Li-Rong Zhang Google Scholar More articles by this author , Bing Jiang Google Scholar More articles by this author , Guangjun Nie Google Scholar More articles by this author and Huan Min Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202202404 SectionsSupplemental MaterialAboutPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Photodynamic therapy (PDT) has emerged as an alternative treatment strategy for esophageal squamous cell carcinoma (ESCC). However, the clinical therapeutic efficiency of PDT is severely limited by poorly targeted photosensitizer delivery, insufficient oxygen supply and neutralization by excessive glutathione (GSH) in tumor tissue. Herein, an engineered multifunctional thylakoid nanostructure, [email protected]@GA (abbreviated as TEPG), composed of a thylakoid membrane (TM) and ESCC cell membrane (EM)-fused biomembrane shell (TM-EM) and gambogic acid (GA)-loaded poly (lactic-co-glycolic acid) nanocore, was designed for enhanced PDT for ESCC. When fused with EM, TM-EM exhibits a tumor targeting advantage due to the homologous affinity of tumor membrane camouflage. The catalase present on TM-EM catalytically decomposes endogenous hydrogen peroxide into oxygen to alleviate hypoxia in the tumor tissue. Moreover, when TEPG was selectively internalized by ESCC cells, GA was released to consume the excessive intracellular GSH. Under infrared irradiation, the PDT effects were enhanced by the self-oxygen supply and GSH scavenging ability provided by TEPG. An in vivo study showed that TEPG effectively induced ESCC tumor cell apoptosis and greatly inhibited the growth of ESCC tumors under infrared irradiation. This study constructed an engineered multifunctional thylakoid-based nanomedicine as an integrated solution to enhance PDT for ESCC. Download figure Download PowerPoint Previous articleNext article FiguresReferencesRelatedDetails Issue AssignmentNot Yet AssignedSupporting Information Copyright & Permissions© 2022 Chinese Chemical Society Downloaded 50 times PDF downloadLoading ...

Hydrogel co-loading SO2 prodrug and FeGA nanoparticles for enhancing chemodynamic therapy by photothermal-triggered SO2 gas therapy.

Chemodynamic therapy (CDT) is an effective anti-tumor method, while CDT alone cannot achieve a good therapeutic effect. Moreover, the overexpression of glutathione (GSH) in tumor cells dramatically limits the efficiency of CDT. Here, we proposed a hydrogel co-loading SO2 prodrug and FeGA nanoparticles (NPs) for enhancing CDT by photothermal-triggered SO2 gas therapy (FBH) system by mixing benzothiazolyl sulfonates (BTS) and FeGA NPs in a certain ratio and encapsulating them in a heat-sensitive hydrogel. FeGA NPs could accelerate the release of Fe2+ under acidic conditions and light, and combine with excess H2O2 in the tumor for chemokinetic treatment. BTS, as a water-soluble prodrug of SO2, can accurately control the release of SO2 gas by virtue of the excellent photothermal conversion ability of FeGA NPs and the acidic pH value of tumor site. SO2 can not only induce cell apoptosis, but also consume excess GSH in cancer cells and increase the content of reactive oxygen species, which seriously destroyed the redox balance in cancer cells and further promotes the therapeutic effect of Fenton reaction. The intelligent FBH system provided a new approach for the synergistic treatment of CDT and SO2 gas, which demonstrated good anticancer effects both in vivo and in vitro.

Abstract LB562: L1-ATP8B1 exacerbated pathogenic high-level reduction-oxidation homeostasis to promote carcinogenesis in lung squamous cell carcinoma via affecting mitochondrial prohibitin 1 SUMOylation and increasing SLC1A5 expression

Abstract Long Interspersed Nuclear Element-1 (LINE-1, L1) plays important roles in carcinogenesis by forming L1 chimeric transcripts (LCTs) in somatic cells. However, the regulation and function of LCTs in lung squamous cell carcinoma (LUSC) remains unclear. Previously we identified L1-ATP8B1 as a prognostic LCT in LUSC. In this study we confirmed that L1-ATP8B1 was overexpressed in LUSC patients suffering from shorter survival and correlated with upregulation of LINE-1 ORF1, impaired expression of ATPase phospholipid transporting 8B1 (ATP8B1) and distinct mitochondria dysfunction in both TCGA dataset and TJMUCH cohort. Over-expression of L1-ATP8B1 in LUSC cell lines and xenograft-bearing mice promoted cell proliferation, migration and invasion in vitro and facilitated LUSC xenografts growth in vivo which could be attenuated by inhibiting LINE-1 activity via nevirapine (NVR). In addition, L1-ATP8B1 affected cardiolipin-dependent mitochondrial prohibitin 1 (PHB1) SUMOylation and increased GSH synthesis transporter protein SLC1A5 expression which produced excessive ROS and GSH to induce cellular high-level reduction-oxidation (REDOX) homeostasis. Interfering with REDOX homeostasis using antioxidant could inhibit L1-ATP8B1 overexpression, reverse L1-ATP8B1-related mitochondrial dysfunction and carcinogenesis. Furthermore, combined therapy of NVR and antioxidant dramatically abolished L1-ATP8B1-induced growth and metastasis of LUSC xenografts in vivo. In conclusion, we at the first time demonstrated metabolic disorder plays a vital role in LCTs-related carcinogenesis and L1-ATP8B1 promotes LUSC development and progression by exacerbating pathogenic high-level REDOX homeostasis, therefore L1-ATP8B1 is a promising prognostic biomarker and therapeutic target in LUSC. Citation Format: Jinpu Yu, Xiao Zhang, Rui Zhang, Zeguo Sun, Weijia Zhang. L1-ATP8B1 exacerbated pathogenic high-level reduction-oxidation homeostasis to promote carcinogenesis in lung squamous cell carcinoma via affecting mitochondrial prohibitin 1 SUMOylation and increasing SLC1A5 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB562.

In situ-transition nanozyme triggered by tumor microenvironment boosts synergistic cancer radio-/chemotherapy through disrupting redox homeostasis

Disrupting redox homeostasis in the tumor microenvironment (TME), like excessive H2O2, glutathione (GSH) and weak acidity, has been proved as an effective tumor therapeutic strategy. Herein, we constructed a TME-responsive nanozyme, DOX@HMSN/Mn3O4(R), with reversible Mn3+/Mn2+ transition in situ triggered by TME to perturb the intrinsic redox homeostasis and catalyze reactive oxygen species (ROS) overproduction. In addition, this nanozyme could react with excess GSH in TME to produce GSSG, resulting in the consumption of reducing agents to suppress ROS clearance. Density functional theory calculations further confirmed that the nanozyme mainly exhibited the oxidase-like activity to catalyze the formation of hydroxyl radicals from O2, thus strengthening the oxidation environment in the TME. Combined with radiotherapy, the high-energy X-ray could excite the outer-layer electrons in the nanozyme, forming photoelectrons that participate in the oxidase-like enzymatic reaction, thus intensifying ROS accumulation and amplifying the radio-/chemotherapeutic efficacy.

Cobalt(III) Complexes for Light-Activated Delivery of Acetylacetonate-BODIPY, Cellular Imaging, and Photodynamic Therapy.

Cobalt(III) complexes [Co(TPA)(L1)](ClO4)2 (1), [Co(4-COOH-TPA)(L1)](ClO4)2 (2), [Co(TPA)(L2)]Cl2 (3), and [Co(4-COOH-TPA)(L2)]Cl2 (4) having acetylacetonate-linked boron-dipyrromethene ligands (L1, acac-BODIPY; L2, acac-diiodo-BODIPY) were prepared and characterized, and their utility as bioimaging and phototherapeutic agents was evaluated (TPA, tris-(2-pyridylmethyl)amine; 4-COOH-TPA, 2-((bis-(2-pyridylmethyl)amino)methyl)isonicotinic acid). HL1, HL2, and complex 1 were structurally characterized by X-ray crystallography. Complexes 1 and 2 on photoactivation or in a reducing environment (excess GSH, ascorbic acid, and 3-mercaptopropionic acid) released the acac-BODIPY ligand. They exhibited strong absorbance near 501 nm (ε ∼ (5.2-5.8) × 104 M-1 cm-1) and emission bands near 513 nm (ΦF ∼ 0.13, λex = 490 nm) in dimethyl sulfoxide (DMSO). Complexes 3 and 4 with absorption maxima at ∼536 and ∼538 nm (ε ∼ (1.2-1.8) × 104 M-1 cm-1), respectively, afforded high singlet oxygen quantum yield (ΦΔ ∼ 0.79) in DMSO. Complexes 1-4 showed Co(III)-Co(II) redox responses near -0.2 V versus saturated calomel electrode (SCE) in dimethylformamide (DMF)-0.1 M tetrabutylammonium perchlorate (TBAP). The photocleavage of pUC19 DNA by complex 4 revealed the formation of both singlet oxygen and superoxide anion radicals as the reactive oxygen species (ROS). Confocal fluorescence microscopy showed the selective accumulation of complex 1 in the endoplasmic reticulum (ER) in A-549 cells. Complex 4 exhibited a high phototherapeutic index value (PI > 7000) in HeLa cancer cells (IC50 ∼ 0.007 μM in visible light of 400-700 nm, total dose ∼5 J cm-2). The ancillary ligands in the complexes demonstrated a structure-activity relationship and modulated the Co(III)-Co(II) redox potential, the complex solubility, acac-BODIPY ligand release kinetics, and phototherapeutic efficacy.

Peroxidase-like Active Nanomedicine with Dual Glutathione Depletion Property to Restore Oxaliplatin Chemosensitivity and Promote Programmed Cell Death.

The nanocatalytic activity of nanozymes provides a vision for tumor treatment. However, the glutathione (GSH)-related antioxidant defense system (ADS) formed on the basis of excessive GSH in the tumor microenvironment limits its catalytic activity. Here, dendritic mesoporous silica nanoparticles (DMSNs) were employed as nanocarrier; ultrasmall Fe3O4 nanoparticles, Mn2+ ions, and glutaminase inhibitor Telaglenastat (CB-839) were subsequently integrated into large mesopores of DMSNs, forming DMSN/Fe3O4-Mn@CB-839 (DFMC) nanomedicine. This nanomedicine exhibits peroxidase mimicking activities under acidic conditions, which catalyzes the decomposition of hydrogen peroxide (H2O2) into hydroxyl radical (•OH). This also promotes the formation of lipid peroxides, which is required for ferroptosis. Furthermore, this nanomedicine can effectively deplete the existing GSH, thereby enhancing reactive oxygen species (ROS)-mediated tumor catalytic therapy. Moreover, the introduced CB-839 blocks the endogenous synthesis of GSH, further enhancing GSH depletion performance, which reduces the excretion of oxaliplatin (GSH-related resistance) from tumor cells, thereby restoring the chemical sensitivity of oxaliplatin. The dual GSH depletion property significantly weakens the GSH-related ADS and restores the chemical sensitivity of oxaliplatin, leading to the high DFMC-induced apoptosis and ferroptosis of tumor cells. Our developed nanomedicine based on integrated nanotechnology and clinical drug may aid the development of tumor treatment.

A tumor microenvironment-responsive poly(amidoamine) dendrimer nanoplatform for hypoxia-responsive chemo/chemodynamic therapy

BackgroundChemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction in the tumor microenvironment (TME) with low pH and high level of endogenous hydrogen peroxide. However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict the curative outcomes of conventional chemodynamic therapy.ResultsIn this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) nanoplatform has good stability and hemocompatibility, and could release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro experiments showed that the GPPCT nanoplatforms can efficiently target murine breast cancer cells (4T1) cells overexpressing sialic acid residues, and show a significantly enhanced inhibitory effect on hypoxic cells by the activation of TPZ. The excessive GSH in tumors could be depleted by the reduction of Cu(II) to Cu(I), and abundant of toxic ·OH would be generated in tumor cells by Fenton reaction for chemodynamic therapy. In vivo experiments demonstrated that the GPPCT nanoplatform could specifically accumulate at tumors, effectively inhibit the growth and metastasis of tumors by the combination of CDT and chemotherapy, and be metabolized with no systemic toxicity.ConclusionsThe targeted GPPCT nanoplatform may represent an effective model for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.Graphical