ABSTRACT
Despite the considerable potential of immune checkpoint blockade (ICB) therapy in treating various cancer types, it faces several challenges, of which the constrained objective response rate and relatively short duration of response observed in patients with cancer are the most important. This study introduces an injectable temperature-sensitive hydrogel, Pluronic F-127 (PF-127)@MnCl2/ alginate microspheres (ALG-MS)@MgCl2, that enhances the therapeutic efficacy of programmed cell death-ligand 1 (PD-L1) in cancer cells. The hydrogel material used in this study facilitated the rapid release of a significant amount of manganese ions (Mn2+) and the gradual and sustained release of magnesium ions (Mg2+) within the tumor microenvironment. This staged release profile promotes an immune microenvironment conducive to the cytotoxicity of CD8+ T cells and natural killer cells, thereby enhancing the efficacy of ICB therapy. Furthermore, the PF-127@MnCl2/ALG-MS@MgCl2 composite hydrogel exhibits the ability to convert drug-resistant tumor ("cold tumor") with a low PD-L1 response to a "hot tumor" with a high PD-L1 response. In summary, the PF-127@MnCl2/ALG-MS@MgCl2 hydrogel manipulates the immune microenvironment through the precise discharge of Mg2+ and Mn2+, thus, augmenting the efficacy of ICB therapy.
Subject(s)
Alginates , Delayed-Action Preparations , Hydrogels , Immunotherapy , Magnesium , Manganese , Microspheres , Neoplasms , Poloxamer , Tumor Microenvironment , Hydrogels/chemistry , Hydrogels/administration & dosage , Animals , Immunotherapy/methods , Magnesium/chemistry , Magnesium/administration & dosage , Tumor Microenvironment/drug effects , Manganese/chemistry , Manganese/administration & dosage , Humans , Neoplasms/drug therapy , Neoplasms/therapy , Neoplasms/immunology , Poloxamer/chemistry , Alginates/chemistry , Cell Line, Tumor , Manganese Compounds/chemistry , Manganese Compounds/administration & dosage , Female , Chlorides/chemistry , Mice, Inbred C57BL , B7-H1 Antigen , Mice , Immune Checkpoint Inhibitors/administration & dosage , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effectsABSTRACT
Ferroptosis-related tumor therapy based on nanomedicines has recently gained significant attention. However, the therapeutic performance is still hindered by the tumor's physical barriers such as the fibrotic tumor matrix and elevated interstitial fluid pressure, as well as chemical barriers like glutathione (GSH) overabundance. These physicochemical barriers impede the bioavailability of nanomedicines and compromise the therapeutic efficacy of lipid reactive oxygen species (ROS). Thus, this study pioneers a manganese-mediated overcoming of physicochemical barriers in the tumor microenvironment using organosilica-based nanomedicine (MMONs), which bolsters the synergy of photothermal-ferroptosis treatment. The MMONs display commendable proficiency in overcoming tumor physical barriers, due to their MnO2-mediated shape-morphing and softness-transformation ability, which facilitates augmented cellular internalization, enhanced tumor accumulation, and superior drug penetration. Also, the MMONs possess excellent capability in chemical barrier overcoming, including MnO2-mediated dual GSH clearance and enhanced ROS generation, which facilitates ferroptosis and heat shock protein inhibition. Notably, the resulting integration of physical and chemical barrier overcoming leads to amplified photothermal-ferroptosis synergistic tumor therapy both in vitro and in vivo. Accordingly, the comparative proteomic analysis has identified promoted ferroptosis with a transient inhibitory response observed in the mitochondria. This research aims to improve treatment strategies to better fight the complex defenses of tumors.
Subject(s)
Ferroptosis , Manganese , Mice, Inbred BALB C , Reactive Oxygen Species , Animals , Ferroptosis/drug effects , Humans , Reactive Oxygen Species/metabolism , Cell Line, Tumor , Mice , Manganese/administration & dosage , Manganese/chemistry , Mice, Nude , Tumor Microenvironment/drug effects , Female , Manganese Compounds/administration & dosage , Manganese Compounds/chemistry , Photothermal Therapy/methods , Neoplasms/therapy , Neoplasms/pathology , Neoplasms/drug therapy , Glutathione/metabolism , Nanomedicine/methods , Antineoplastic Agents/administration & dosageABSTRACT
BACKGROUND: Targeted rapid degradation of bilirubin has the potential to thwart incipient bilirubin encephalopathy. We investigated a novel spinel-structured citrate-functionalized trimanganese tetroxide nanoparticle (C-Mn3O4 NP, the nanodrug) to degrade both systemic and neural bilirubin loads. METHOD: Severe neonatal unconjugated hyperbilirubinemia (SNH) was induced in neonatal C57BL/6j mice model with phenylhydrazine (PHz) intoxication. Efficiency of the nanodrug on both in vivo bilirubin degradation and amelioration of bilirubin encephalopathy and associated neurobehavioral sequelae were evaluated. RESULTS: Single oral dose (0.25 mg kg-1 bodyweight) of the nanodrug reduced both total serum bilirubin (TSB) and unconjugated bilirubin (UCB) in SNH rodents. Significant (p < 0.0001) UCB and TSB-degradation rates were reported within 4-8 h at 1.84 ± 0.26 and 2.19 ± 0.31 mg dL-1 h-1, respectively. Neural bilirubin load was decreased by 5.6 nmol g-1 (p = 0.0002) along with improved measures of neurobehavior, neuromotor movements, learning, and memory. Histopathological studies confirm that the nanodrug prevented neural cell reduction in Purkinje and substantia nigra regions, eosinophilic neurons, spongiosis, and cell shrinkage in SNH brain parenchyma. Brain oxidative status was maintained in nanodrug-treated SNH cohort. Pharmacokinetic data corroborated the bilirubin degradation rate with plasma nanodrug concentrations. CONCLUSION: This study demonstrates the in vivo capacity of this novel nanodrug to reduce systemic and neural bilirubin load and reverse bilirubin-induced neurotoxicity. Further compilation of a drug-safety-dossier is warranted to translate this novel therapeutic chemopreventive approach to clinical settings. IMPACT: None of the current pharmacotherapeutics treat severe neonatal hyperbilirubinemia (SNH) to prevent risks of neurotoxicity. In this preclinical study, a newly investigated nano-formulation, citrate-functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs), exhibits bilirubin reduction properties in rodents. Chemopreventive properties of this nano-formulation demonstrate an efficacious, efficient agent that appears to be safe in these early studies. Translation of C-Mn3O4 NPs to prospective preclinical and clinical trials in appropriate in vivo models should be explored as a potential novel pharmacotherapy for SNH.
Subject(s)
Hyperbilirubinemia, Neonatal , Kernicterus , Manganese Compounds , Animals , Mice , Bilirubin , Chemoprevention , Hyperbilirubinemia, Neonatal/prevention & control , Kernicterus/prevention & control , Mice, Inbred C57BL , Prospective Studies , Animals, Newborn , Disease Models, Animal , Manganese Compounds/administration & dosage , Nanoparticles/administration & dosageABSTRACT
Magnetic resonance imaging (MRI) has excellent potential in the clinical monitoring of tumors because it can provide high-resolution soft tissue imaging. However, commercial contrast agents (CAs) used in MRI still have some problems such as potential toxicity to the human body, low relaxivity, and a short MRI acquisition window. In this study, ultrasmall MnSe nanoparticles are synthesized by living Staphylococcus aureus cells. The as-prepared MnSe nanoparticles are monodispersed with a uniform particle size (3.50 ± 0.52 nm). Due to the ultrasmall particle size and good water solubility, the MnSe nanoparticles exhibit in vitro high longitudinal relaxivity properties (14.12 ± 1.85 mM-1·s-1). The CCK-8 colorimetric assay, histological analysis, and body weight results show that the MnSe nanoparticles do not have appreciable toxicity on cells and organisms. Besides, the MnSe nanoparticles as T1-MRI CAs offer a long MRI acquisition window to tumor imaging (â¼7 h). This work provides a promising T1-MRI CA for clinical tumor imaging and a good reference for the application of functional MnSe nanoparticles in the biomedicine field.
Subject(s)
Contrast Media/chemistry , Magnetic Resonance Imaging/methods , Manganese Compounds/chemistry , Nanoparticles/chemistry , Neoplasms/diagnostic imaging , Selenium Compounds/chemistry , Animals , Cell Line, Tumor , Cell Survival/drug effects , Contrast Media/administration & dosage , Contrast Media/adverse effects , Disease Models, Animal , Female , Injections, Intravenous , Manganese Compounds/administration & dosage , Manganese Compounds/adverse effects , Manganese Compounds/pharmacology , Mice, Inbred BALB C , Nanoparticles/administration & dosage , Nanoparticles/adverse effects , Particle Size , Selenium Compounds/administration & dosage , Selenium Compounds/adverse effects , Selenium Compounds/pharmacology , Solubility , Staphylococcus aureus/metabolismABSTRACT
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. Antioxidative treatment combined with chemotherapy holds great promise for RA treatment, and the ability to efficiently deliver drugs and antioxidants to the RA synovial joint is highly desired. Herein, we developed a programmable polymeric microneedle (MN) platform for transdermal delivery of methotrexate (MTX) and reactive oxygen species (ROS) scavengers for RA treatment. The biodegradable MNs made of polyvinylpyrrolidone (PVP) were incorporated with polydopamine/manganese dioxide (termed PDA@MnO2) and MTX. After insertion into skin tissue, the MNs degraded, thus enabling release of loaded MTX and PDA@MnO2. The PDA@MnO2 could be utilized as an MRI contrast agent in the RA synovial microenvironment. It also acted as a robust antioxidant to remove ROS and decrease RA inflammation, which when combined with the MTX-mediated chemotherapy led to an ideal outcome for RA treatments in a murine model. This work not only represents a valuable MN-assisted RA therapeutic agent transdermal delivery approach but also opens a new avenue for chemotherapy and antioxidative synergistic treatment of RA.
Subject(s)
Antioxidants/therapeutic use , Arthritis, Rheumatoid/drug therapy , Polymers/therapeutic use , 3T3 Cells , Administration, Cutaneous , Animals , Antioxidants/administration & dosage , Arthritis, Rheumatoid/metabolism , Drug Therapy, Combination , Indoles/administration & dosage , Indoles/therapeutic use , Manganese Compounds/administration & dosage , Manganese Compounds/therapeutic use , Methotrexate/administration & dosage , Methotrexate/therapeutic use , Mice , Oxides/administration & dosage , Oxides/therapeutic use , Particle Size , Polymers/administration & dosage , RAW 264.7 Cells , Reactive Oxygen Species/metabolism , Surface PropertiesABSTRACT
Pathological angiogenesis is a crucial factor that causes atherosclerotic plaque rupture. Sinoporphyrin sodium-mediated sonodynamic therapy (DVDMS-SDT) induces regression of plaque neovascularization in humans without causing obvious side effects. However, a clinical noninvasive theranostic strategy for atherosclerotic plaque neovascularization is urgently needed. A nanoplatform designed for multimodality imaging-guided SDT in plaque angiogenesis theranostics, termed PFP-HMME@PLGA/MnFe2 O4 -ramucirumab nanoparticles (PHPMR NPs), is fabricated. It encapsulates manganese ferrite (MnFe2 O4 ), hematoporphyrin monomethyl ether (HMME), and perfluoropentane (PFP) stabilized by polylactic acid-glycolic acid (PLGA) shells and is conjugated to an anti-VEGFR-2 antibody. With excellent magnetic resonance imaging (MRI)/photoacoustic/ultrasound imaging ability, the distribution of PHPMR NPs in plaque can be observed in real time. Additionally, they actively accumulate in the mitochondria of rabbit aortic endothelial cells (RAECs), and the PHPMR NP-mediated SDT promotes mitochondrial-caspase apoptosis via the production of reactive oxygen species and inhibits the proliferation, migration, and tubulogenesis of RAECs. On day 3, PHPMR NP-mediated SDT induces apoptosis in neovessel endothelial cells and improves hypoxia in the rabbit advanced plaque. On day 28, PHPMR NP-mediated SDT reduces the density of neovessels, subsequently inhibiting intraplaque hemorrhage and inflammation and eventually stabilizing the plaque. Collectively, PHPMR NP-mediated SDT presents a safe and effective theranostic strategy for inhibiting plaque angiogenesis.
Subject(s)
Ferric Compounds/administration & dosage , Manganese Compounds/administration & dosage , Neovascularization, Pathologic/complications , Neovascularization, Pathologic/therapy , Plaque, Atherosclerotic/complications , Plaque, Atherosclerotic/therapy , Theranostic Nanomedicine/methods , Ultrasonic Therapy/methods , Animals , Disease Models, Animal , Male , Nanoparticles , Neovascularization, Pathologic/pathology , Plaque, Atherosclerotic/pathology , RabbitsABSTRACT
Manganese (Mn2+) has been reported to activate macrophages and NK cells, and to induce the production of type-I interferons (IFNs) by activating the cGAS-STING pathway. Few studies have been conducted on its adjuvanticity to microbial vaccines, and on the involvement of the interferon regulatory factor (IRF) 5 signaling pathway in the adjuvanticity. In this study, we demonstrated that Mn2+ could facilitate various microbial vaccines to induce enhanced antibody responses, and facilitate the influenza virus vaccine to induce protective immunity against the influenza virus challenge. When formulated in vaccines, Mn2+ could activate murine CD4+ T cells, CD8+ T cells, B cells and DCs, and induce the expression and phosphorylation of TANK-binding kinase 1 (TBK1) and IRF5 in the splenocytes of the immunized mice, resulting in the increased expression of type-I IFNs, TNF-α, B cell-activating factor of the TNF family (BAFF) and B lymphocyte-induced maturation protein-1 (Blimp-1). The induced TBK1 could recruit and bind the IRF5. Furthermore, the Mn2+ induced expression of IRF5 and Blimp-1 was prohibited by a IRF5 interfering oligonucleotide. The data suggest the Mn2+ could be used as a novel type of adjuvants for microbial vaccines, and the activation of IRF5 signaling pathway might involve in the adjuvanticity.
Subject(s)
Bacterial Vaccines/administration & dosage , Bacterial Vaccines/metabolism , Interferon Regulatory Factors/metabolism , Manganese/administration & dosage , Signal Transduction/physiology , Animals , Bacterial Vaccines/immunology , Chlorides/administration & dosage , Female , Interferon Regulatory Factors/immunology , Manganese Compounds/administration & dosage , Mice , Mice, Inbred ICR , Signal Transduction/drug effectsABSTRACT
Photodynamic therapy (PDT) has provided a promising approach for the treatment of solid tumors, while the therapeutic efficacy is often limited due to the hypoxic tumor microenvironment, resulting in tumor metastasis. Herein, we report an oxygen-producing proenzyme hydrogel (OPeH) with photoactivatable enzymatic activity for PDT enabled metastasis-inhibiting combinational therapy of breast cancer. This OPeH based on alginate is composed of protoporphyrin IX (PpIX) conjugated manganese oxide (MnO2) nanoparticles, which act as both the photosensitizer and oxygen-producing agent, and singlet oxygen (1O2)-responsive proenzyme nanoparticles. In the hypoxic and acidic tumor microenvironment, MnO2 can generate 1O2 to promote PpIX-mediated PDT with an amplified 1O2 generation efficiency, which also triggers the cleavage of 1O2-responsive linkers and cascade activation of proenzymes for cancer cell death. This combinational therapy upon photoactivation not only greatly inhibited the tumor growth, but also suppressed lung metastasis in a mouse xenograft breast tumor model, which is impossible in the case of PDT alone. This study thus provides a proenzyme hydrogel platform with photoactivatable activity for metastasis-inhibiting cancer therapy with high efficacy and safety.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Enzyme Precursors/metabolism , Hydrogels/metabolism , Oxygen/metabolism , Photochemotherapy , Photosensitizing Agents/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Enzyme Precursors/chemistry , Hydrogels/chemistry , Injections, Subcutaneous , Manganese Compounds/administration & dosage , Manganese Compounds/chemistry , Manganese Compounds/pharmacology , Mice , Mice, Inbred BALB C , Nanoparticles/chemistry , Oxides/administration & dosage , Oxides/chemistry , Oxides/pharmacology , Oxygen/chemistry , Photosensitizing Agents/administration & dosage , Photosensitizing Agents/chemistry , Protoporphyrins/administration & dosage , Protoporphyrins/chemistry , Protoporphyrins/pharmacologyABSTRACT
Amyloid plaques are a hallmark of Alzheimer's disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats. Animals were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4 T Bruker scanner. MnCl2 improved signal-to-noise ratio but was not necessary to detect plaques in high-resolution images. Plaques were visible in all transgenic animals and no wild-types, and quantitative susceptibility mapping showed that they were more paramagnetic than the surrounding tissue. This, combined with beta-amyloid and iron staining, indicate that plaque MR visibility in both animal models was driven by plaque size and iron load. Longitudinal relaxation rate mapping revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. This was limited to the rhinencephalon in the TgF344-AD rats, while it was most significantly increased in the cortex of the 5xFAD mice. Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats. Multi-parametric MEMRI is a simple, viable method for detecting amyloid plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present the first in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.
Subject(s)
Alzheimer Disease/diagnosis , Cerebral Cortex/diagnostic imaging , Chlorides/administration & dosage , Manganese Compounds/administration & dosage , Multiparametric Magnetic Resonance Imaging/methods , Plaque, Amyloid/diagnosis , Alzheimer Disease/pathology , Amyloid beta-Peptides/analysis , Animals , Cerebral Cortex/chemistry , Cerebral Cortex/pathology , Disease Models, Animal , Female , Humans , Injections, Subcutaneous , Iron/analysis , Male , Mice , Mice, Transgenic , Plaque, Amyloid/pathology , Rats , Rats, TransgenicABSTRACT
The optimal therapy effect of tumors is frequently restricted by the dense extracellular matrix (ECM) and anoxia. Herein, an intelligent BPNs-Arg-GOx@MnO2 (BAGM) nanozyme is innovatively designed as a multimodal synergistic therapeutic paradigm that possesses both nitric oxide (NO) self-supplying and ECM degradation properties to reinforce the therapy effect by a tumor microenvironment (TME)-activatable cyclic cascade catalytic reaction. This theranostic nanoplatform is constructed by using polyethyleneimine-modified black phosphorus nanosheets as a "fishnet" to attach l-Arginine (l-Arg) and glucose oxidase (GOx) and then depositing mini-sized MnO2 nanosheets (MNs) on the surface by a facile situ biomineralization method. As an intelligent "switch", the MNs can effectively trigger the cascade reaction by disintegrating intracellular H2O2 to release O2. Then, the conjugated GOx can utilize O2 production to catalyze intracellular glucose to generate H2O2, which not only starves the tumor cells but also promotes oxidation of l-Arg to NO. Thereafter, matrix metalloproteinases will be activated by NO production to degrade the dense ECM and transform matrix collagen into a loose state. In turn, a loose ECM can enhance the accumulation of the BAGM nanozyme and thereby reinforce synergistic photothermal therapy/starvation therapy/NO gas therapy. Both in vitro and in vivo results indicate that the TME-tunable BAGM therapeutic nanoplatform with cascade anticancer property and satisfactory biosecurity shows potential in nanomedicine.
Subject(s)
Breast Neoplasms/therapy , Glucose Oxidase/pharmacology , Manganese Compounds/pharmacology , Nanostructures , Oxides/pharmacology , Tumor Microenvironment , Animals , Breast Neoplasms/metabolism , Extracellular Matrix/drug effects , Extracellular Matrix/pathology , Female , Glucose Oxidase/administration & dosage , Humans , Hydrogen Peroxide/metabolism , MCF-7 Cells , Manganese Compounds/administration & dosage , Mice , Nanomedicine , Nanostructures/administration & dosage , Nanostructures/chemistry , Nitric Oxide/metabolism , Oxides/administration & dosage , Oxygen/metabolism , Tumor Microenvironment/drug effectsABSTRACT
Manganese chloride (MnCl2) has been shown to inhibit the Yes-associated protein (YAP) in high-fat diet-fed ApoE-/- mice. Although YAP has been implicated in atherogenesis, there are limited data on the effects of MnCl2 on cardiac remodeling. In this study, we discovered, by electrocardiography, that hyperlipidemia led to spontaneous supraventricular arrhythmia (SVA) in ApoE-/- (KO) mice, with 3 of 9 KO + MnCl2 mice (33%) exhibiting lower incidence of spontaneous SVA than KO mice (6 of 10 mice, 60%). Echocardiography revealed that reduced systolic function in KO mice was reversed by MnCl2 treatment. Oil Red O staining of the aortas and biochemical analysis of lipid levels showed that MnCl2 inhibited plaque formation in a lipid metabolism-independent manner. MnCl2 inhibited inflammatory cell infiltration and reduced fibrosis, as evidenced by hematoxylin and eosin, immunohistochemical and Masson's trichrome staining, respectively. Our findings demonstrate that spontaneous SVA and reduced systolic function were blocked by MnCl2. Our findings show that MnCl2 was useful in delaying cardiac remodeling and reducing susceptibility to spontaneous SVA in a mouse model of hyperlipidemia.
Subject(s)
Chlorides/administration & dosage , Hyperlipidemias/drug therapy , Manganese Compounds/administration & dosage , Tachycardia, Supraventricular/prevention & control , Tachycardia, Supraventricular/physiopathology , Ventricular Remodeling , Administration, Oral , Animals , Chlorides/pharmacology , Disease Models, Animal , Hyperlipidemias/complications , Male , Manganese Compounds/pharmacology , Mice, Inbred C57BL , Mice, Knockout , Tachycardia, Supraventricular/etiology , Ventricular Remodeling/drug effectsABSTRACT
Pancreatic cancer represents one of the most aggressive in nature with a miserable prognosis that warrants efficient diagnostic and therapeutic interventions. Herein, a MnO2 overlaid gold nanoparticle (AuNPs) based photothermal theranostic nanoenvelope (PTTNe:MnO2@AuNPs) was fabricated to substantiate surface-enhanced Raman spectroscopy (SERS) guided real-time monitoring of photothermal therapy (PTT) in pancreatic cancer cells. A sharp enhancement of the fingerprint Raman signature of MnO2 at 569 cm-1 exhibited as a marker peak for the first time to elucidate the intracellular PTT event. In this strategic design, the leftover bare AuNPs after the degradation of the MnO2 layer from the nanoenvelope in the presence of intracellular H2O2 enabled real-time tracking of biomolecular changes of Raman spectral variations during PTT. Moreover, the surface of the as-synthesized nanoenvelope was functionalized with a pancreatic cancer cell targeting peptide sequence for cholecystokinin fashioned the PTTNe with admirable stability and biocompatibility. Finally, the precise cell death mechanism was explicitly assessed by SERS spectral analysis as a complementary technique. This targeted phototheranostic approach demonstrated in pancreatic cancer cells presented a therapeutically viable prototype for futuristic personalized cancer nanomedicine.
Subject(s)
Antineoplastic Agents/administration & dosage , Gold/administration & dosage , Manganese Compounds/administration & dosage , Metal Nanoparticles/administration & dosage , Oxides/administration & dosage , Pancreatic Neoplasms/therapy , Peptides/administration & dosage , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Erythrocytes/drug effects , Gold/chemistry , Hemolysis/drug effects , Humans , Hydrogen Peroxide/chemistry , Manganese Compounds/chemistry , Metal Nanoparticles/chemistry , Oxides/chemistry , Peptides/chemistry , Photothermal Therapy , Spectrum Analysis, Raman , Theranostic NanomedicineABSTRACT
Today, cancer still poses a serious threat to human, but there is no exact cure. Therefore, exploring to accomplish high therapeutic performance is a challenging and urgent task. Since the nanoparticles unique properties were discovered, they have displayed promising potential for more effective therapies and have been widely used in photodynamic therapy (PDT) and radiation therapy (RT). However, some special properties of the tumour microenvironment (TME) have seriously affected the therapeutic outcomes, so the modulation of the TME becomes critical. Manganese dioxide (MnO2), as a transition metal oxide, has been widely used in biomedical fields with special physical and chemical properties, especially in regulating the TME. Furthermore, MnO2 has widely applications in various cancer treatments, such as PDT, chemodynamic therapy (CDT), immunotherapy, and some specific collaborative treatment. Herein, we reviewed the recent applications of MnO2 modified nanomaterials in tumour therapies and theranostics, including TME regulation, controlled drug loading/delivery/release, and imaging.
Subject(s)
Manganese Compounds/administration & dosage , Nanostructures , Neoplasms/drug therapy , Oxides/administration & dosage , Animals , Drug Delivery Systems , Humans , Immunotherapy/methods , Manganese Compounds/pharmacology , Oxides/pharmacology , Photochemotherapy/methods , Theranostic Nanomedicine , Tumor Microenvironment/drug effectsABSTRACT
Self-regulating temperature-controlled nanoparticles such as Mn-Zn ferrite nanoparticles based magnetic fluid can be a better choice for magnetic fluid hyperthermia because of its controlled regulation of hyperthermia temperature window of 43-45 °C. To test this hypothesis magnetic fluid with said properties was synthesized, and its effect on cervical and breast cancer cell death was studied. We found that the hyperthermia window of 43-45 °C was maintained for one hour at the smallest possible concentration of 0.35 mg/mL without altering the magnetic field applicator parameters. Their hyperthermic effect on HeLa and MCF7 was investigated at the magnetic field of 15.3 kA/m and frequency 330 kHz, which is close to the upper safety limit of 5 * 109 A/m s. We have tested the cytotoxicity of synthesized Mn-Zn ferrite fluid using MTT assay and the results were validated by trypan blue dye exclusion assay that provides the naked eye microscopic view of actual cell death. Since cancer cells tend to resist treatment and show re-growth, we also looked into the effect of multiple sessions hyperthermia using a 24 h window till 72 h using trypan blue assay. The multiple sessions of hyperthermia showed promising results, and it indicated that a minimum of 3 sessions, each of one-hour duration, is required for the complete killing of cancer cells. Moreover, to simulate an in vivo cellular environment, a phantom consisting of magnetic nanoparticles dispersed in 1 and 5% agarose gel was constituted and studied. These results will help to decide the magnetic fluid based hyperthermic therapeutic strategies using temperature-sensitive magnetic fluid.
Subject(s)
Breast Neoplasms/therapy , Hyperthermia, Induced/methods , Magnetic Iron Oxide Nanoparticles/administration & dosage , Uterine Cervical Neoplasms/therapy , Breast Neoplasms/pathology , Cell Death , Cell Survival , Culture Media , Female , Ferric Compounds/administration & dosage , Ferric Compounds/chemistry , HeLa Cells , Hot Temperature/therapeutic use , Humans , In Vitro Techniques , MCF-7 Cells , Magnetic Fields , Magnetic Iron Oxide Nanoparticles/chemistry , Manganese Compounds/administration & dosage , Manganese Compounds/chemistry , Phantoms, Imaging , Sepharose , Uterine Cervical Neoplasms/pathology , Zinc Compounds/administration & dosage , Zinc Compounds/chemistryABSTRACT
PROCEDURES: To preliminary assess the relationship between Manganese Enhanced Magnetic Resonance Imaging (MEMRI) and the expression of calcium receptors in human prostate and breast cancer animal models. METHODS: NOD/SCID mice were inoculated with MDA-MB-231 breast cancer cells and prostate PC3 cancer cells to develop orthotopic or pseudometastatic cancer animal models. Mice were studied on a clinical 3T scanner by using a prototype birdcage coil before and after intravenous injection of MnCl2. Assessment of receptor's status was carried out after the MR images acquisition by immunohistochemistry on excised tumours. RESULTS: Manganese contrast enhancement in breast or prostate cancer animal models well correlated with CaSR expression (p<0.01), whereas TRPV6 expression levels appeared not relevant to the Mn uptake. CONCLUSION: Our preliminary results suggest that MEMRI appears an efficient tool to characterize human breast and prostate cancer animal models in the presence of different expression level of calcium receptors.
Subject(s)
Breast Neoplasms/diagnostic imaging , Chlorides/administration & dosage , Contrast Media/administration & dosage , Magnetic Resonance Imaging/methods , Manganese Compounds/administration & dosage , Prostatic Neoplasms/diagnostic imaging , Animals , Breast Neoplasms/pathology , Calcium/metabolism , Cell Line, Tumor , Chlorides/pharmacokinetics , Contrast Media/pharmacokinetics , Feasibility Studies , Female , Humans , Immunohistochemistry , Injections, Intravenous , Male , Manganese Compounds/pharmacokinetics , Mice , Pilot Projects , Prostatic Neoplasms/pathology , Receptors, Calcium-Sensing/metabolism , TRPV Cation Channels/metabolism , Tissue Distribution , Xenograft Model Antitumor AssaysABSTRACT
Tumor hypoxia, acidosis, and excessive reactive oxygen species (ROS) were the main characteristics of the bladder tumor microenvironment (TME), and abnormal TME led to autophagy activation, which facilitated cancer cell proliferation. The therapeutic efficacy of autophagy inhibitors might also be impeded by abnormal TME. To address these issues, we proposed a new strategy that utilized manganese dioxide (MnO2) nanoparticles to optimize the abnormal TME and revitalize autophagy inhibitors, and both oxygenation and autophagy inhibition may sensitize the tumor cells to radiation therapy. Methods: By taking advantage of the strong affinity between negatively charged MnO2 and positively charged chloroquine (CQ), the nanoparticles were fabricated by integrating MnO2 and CQ in human serum albumin (HSA)-based nanoplatform (HSA-MnO2-CQ NPs). Results: HSA-MnO2-CQ NPs NPs efficiently generated O2 and increased pH in vitro after reaction with H+/H2O2 and then released the encapsulated CQ in a H+/H2O2 concentration-dependent manner. The NPs restored the autophagy-inhibiting activity of chloroquine in acidic conditions by increasing its intracellular uptake, and markedly blocked hypoxia-induced autophagic flux. In vivo studies showed the NPs improved pharmacokinetic behavior of chloroquine and effectively accumulated in tumor tissues. The NPs exhibited significantly decreased tumor hypoxia areas and increased tumor pH, and had remarkable autophagy inhibition efficacy on bladder tumors. Finally, a significant anti-tumor effect achieved by the enhanced autophagy inhibition and radiation sensitization. Conclusions: HSA-MnO2-CQ NPs synergistically regulated the abnormal TME and inhibited autophagic flux, and effectively sensitized radiation therapy to treat bladder cancers.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Chemoradiotherapy/methods , Drug Carriers/chemistry , Radiation-Sensitizing Agents/administration & dosage , Urinary Bladder Neoplasms/therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Autophagy/drug effects , Autophagy/radiation effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Cell Survival/drug effects , Cell Survival/radiation effects , Chloroquine/administration & dosage , Chloroquine/pharmacokinetics , Drug Synergism , Humans , Hydrogen-Ion Concentration/drug effects , Male , Manganese Compounds/administration & dosage , Manganese Compounds/pharmacokinetics , Mice , Nanoparticles/chemistry , Oxides/administration & dosage , Oxides/pharmacokinetics , Radiation Tolerance/drug effects , Radiation-Sensitizing Agents/pharmacokinetics , Reactive Oxygen Species/metabolism , Serum Albumin, Human/chemistry , Tumor Hypoxia/drug effects , Tumor Hypoxia/radiation effects , Tumor Microenvironment/drug effects , Tumor Microenvironment/radiation effects , Urinary Bladder/pathology , Urinary Bladder Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
In The present project, a variety of MnFe2O4 (Mn) and Cr2Fe6O12 (Cr)-based nanocarriers (NCs) were synthesized as photosensitizer and NCs for delivery of chemotherapeutic curcumin (CUR) and provide a new structure for Photodynamic Therapy (PDT). For determining efficiency of NCs release study, MTT assay, lethal dose test and hemolysis assay were carried out. The release study showed the release of CUR from NCs was pH-dependent, but, every NCs had its own behavior for releasing the drug. The data acquired from the release study showed the CUR release from Mn can reach to over 90% at acidic media instead of 41% at neutral media. However, the CUR released from Cr were approximately equal as Cr had equal zeta potential at both media. Hemolysis activity and lethal dose test displayed the cytotoxicity of NCs was neglectable at both in vitro and in vivo study. Also, the results of anti-cancer activity assay (MTT assay) showed that both of Cr and Mn NCs are suitable systems for PDT. Therefore, the results demonstrated that Mn is suitable NCs for PDT and anticancer drugs delivery of therapeutic drugs.
Subject(s)
Antineoplastic Agents/administration & dosage , Chromium/administration & dosage , Drug Delivery Systems/methods , Ferric Compounds/administration & dosage , Manganese Compounds/administration & dosage , Photochemotherapy/methods , Photosensitizing Agents/administration & dosage , Animals , Antineoplastic Agents/metabolism , Biocompatible Materials/administration & dosage , Biocompatible Materials/metabolism , Cell Survival/drug effects , Cell Survival/physiology , Chromium/metabolism , Dose-Response Relationship, Drug , Female , Ferric Compounds/metabolism , HEK293 Cells , Humans , MCF-7 Cells , Male , Manganese Compounds/metabolism , Mice , Photosensitizing Agents/metabolismABSTRACT
PURPOSE: The aim of this study was to characterize changes in hippocampal inflammasomes, pyroptosis and apoptosis in juvenile rats after brain irradiation and to assess whether manganese-enhanced magnetic resonance imaging (MEMRI) reflected those changes. MATERIALS AND METHODS: Four-week-old male Sprague-Dawley rats received a whole-brain radiation dose of 15 Gy or 25 Gy. Hippocampal inflammasomes and apoptosis were measured using Western blot analysis at 4 days and 8 weeks after irradiation. MEMRI and magnetic resonance spectroscopy (MRS) were performed at the same time points. RESULTS: Neither the 15 Gy nor 25 Gy group showed changes in the expression of inflammasome proteins absent in melanoma 2 (AIM2), gasdermin-D (GSDMD), nucleotide oligomerization domain-like receptor protein 1 (NLRP1) and NLRP3 at 4 days or 8 weeks after radiation injury (P > 0.05). Furthermore, the expression levels of the inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 were not significantly different among the groups (P > 0.05). The expression levels of cleaved caspase-1 and -3, indicators of apoptosis, were higher in the irradiation groups than in the control group at 4 days post irradiation, especially for caspase-3 (P < 0.05), but this increase was slightly attenuated at 8 weeks after radiation injury. Four days post irradiation, the MEMRI signal intensity (SI) in the irradiation groups, especially the 25 Gy group, was significantly lower than that in the control group (P < 0.05). Eight weeks after radiation injury, the SI of the 15 Gy group and the 25 Gy group recovered by different degrees, but the SI of the 25 Gy group was still significantly lower than that of the control group (P < 0.05). On day 4 post irradiation, the metabolic ratio of N-acetylaspartate (NAA) to creatine (Cr) in the 15 Gy group and 25 Gy group was significantly lower than that in the control group (P < 0.05). The NAA/Cr ratio in the 15 Gy group recovered to control levels at 8 weeks (P > 0.05), but the NAA/Cr ratio in the 25 Gy group remained significantly lower than that in the control group (P < 0.05). CONCLUSION: Radiation-induced brain injury is dose-dependently associated with apoptosis but not inflammasomes or pyroptosis, and the change in apoptosis can be detected by MEMRI.
Subject(s)
Apoptosis/radiation effects , Brain Injuries/pathology , Hippocampus/radiation effects , Radiation Injuries, Experimental/pathology , Animals , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Brain Injuries/diagnostic imaging , Brain Injuries/etiology , Brain Injuries/metabolism , Caspases/metabolism , Creatine/metabolism , Hippocampus/diagnostic imaging , Hippocampus/metabolism , Hippocampus/pathology , Inflammasomes/metabolism , Inflammasomes/radiation effects , Magnetic Resonance Imaging , Male , Manganese Compounds/administration & dosage , Radiation Dosage , Radiation Injuries, Experimental/diagnostic imaging , Radiation Injuries, Experimental/etiology , Radiation Injuries, Experimental/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
Manganese-based nanomaterials have piqued great interest in cancer nanotheranostics, owing to their excellent physicochemical properties. Here we report a facile wet-chemical synthesis of size-controllable, biodegradable, and metastable γ-phase manganese sulfide nanotheranostics, which is employed for tumor pH-responsive traceable gas therapy primed chemodynamic therapy (CDT), using bovine serum albumin (BSA) as a biological template (The final product was denoted as MnS@BSA). The as-prepared MnS@BSA can be degraded in response to the mildly acidic tumor microenvironment, releasing hydrogen sulfide (H2S) for gas therapy and manganese ions for magnetic resonance imaging (MRI) and CDT. In vitro experiments validated the pH-responsiveness of MnS@BSA at pH 6.8 and both H2S gas and â¢OH radicals were detected during its degradation. In vivo experiments showed efficiently tumor turn-on T1-weighted MRI, significantly suppressed tumor growth and greatly prolonged survival of tumor-bearing mice following intravenous administration of MnS@BSA. Our findings indicated that MnS@BSA nanotheranostics hold great potential for traceable H2S gas therapy primed CDT of cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Hydrogen Sulfide/pharmacology , Manganese Compounds/pharmacology , Neoplasms/therapy , Sulfides/pharmacology , Theranostic Nanomedicine/methods , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cell Line, Tumor , Cell Survival/drug effects , Gases/administration & dosage , Gases/pharmacology , Hydrogen Sulfide/administration & dosage , Hydrogen-Ion Concentration/drug effects , Magnetic Resonance Imaging/methods , Manganese Compounds/administration & dosage , Manganese Compounds/chemistry , Mice , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Neoplasms/diagnostic imaging , Serum Albumin, Bovine/administration & dosage , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/pharmacology , Sulfides/administration & dosage , Sulfides/chemistry , Tumor Microenvironment/drug effectsABSTRACT
The objective of the current study was to evaluate increasing levels of manganese hydroxychloride (MHC) in 45-wk-old white leghorn laying hens, using yolk and shell manganese (Mn) content as a potential marker for Mn concentration. A total of 80, 45-wk-old white leghorns were assigned to 6 dietary treatments, each consisting of 14 individually caged laying hens, with the exception of the reference diet containing 10 individually caged laying hens. The experiment consisted of a reference diet that contained 70 ppm of supplemental inorganic Mn in the form of Mn oxide and 5 experimental treatments each containing 0, 15, 30, 60, and 90 ppm supplemental MHC. Experimental birds were subjected to a 21 D depletion phase in which no supplemental Mn was included in the diet; however, during this time reference fed birds were fed the control diet (70 ppm Mn). After the 21 D depletion phase, the depleted birds were fed experimental diets for a 35 D evaluation period. Yolk and shell Mn content were analyzed at the end of the depletion phase and during the experimental phase on day 5, 10, 15, 25, and 35. During the experimental phase, Mn was replenished in the yolk and shell in all experimental treatments containing supplemental Mn; however, dose and time impacted the rate of replenishment. The yolk tended to be more sensitive to variations in Mn level as increases in Mn inclusion significantly (P < 0.05) increased concentration. These data demonstrate the ability to deplete and replenish Mn, and the use of egg yolk Mn concentration as measurement for determining changes in dietary Mn. At the conclusion of the experiment at 35 D, 60 ppm of Mn hydroxychloride seemed to be adequate in replenishing Mn to the level of the reference.