Additive manufacturing of bioactive and biodegradable poly (lactic acid)-tricalcium phosphate scaffolds modified with zinc oxide for guided bone tissue repair.

Bioactive and biodegradable scaffolds that mimic the natural extracellular matrix of bone serve as temporary structures to guide new bone tissue growth. In this study, 3D-printed scaffolds composed of poly (lactic acid) (PLA)-tricalcium phosphate (TCP) (90-10 wt.%) were modified with 1%, 5%, and 10 wt.% of ZnO to enhance bone tissue regeneration. A commercial chain extender named Joncryl was incorporated alongside ZnO to ensure the printability of the composites. Filaments were manufactured using a twin-screw extruder and subsequently used to print 3D scaffolds via fused filament fabrication (FFF). The scaffolds exhibited a homogeneous distribution of ZnO and TCP particles, a reproducible structure with 300 µm pores, and mechanical properties suitable for bone tissue engineering, with an elastic modulus around 100 MPa. The addition of ZnO resulted in enhanced surface roughness on the scaffolds, particularly for ZnO microparticles, achieving values up to 241 nm. This rougher topography was responsible for enhancing protein adsorption on the scaffolds, with an increase of up to 85% compared to the PLA-TCP matrix. Biological analyses demonstrated that the presence of ZnO promotes mesenchymal stem cell (MSC) proliferation and differentiation into osteoblasts. Alkaline phosphatase (ALP) activity, an important indicator of early osteogenic differentiation, increased up to 29%. The PLA-TCP composite containing 5% ZnO microparticles exhibited an optimized degradation rate and enhanced bioactivity, indicating its promising potential for bone repair applications.

A Multifunctional Therapeutic Strategy Using P7C3 as A Countermeasure Against Bone Loss and Fragility in An Ovariectomized Rat Model of Postmenopausal Osteoporosis.

By 2060, an estimated one in four Americans will be elderly. Consequently, the prevalence of osteoporosis and fragility fractures will also increase. Presently, no available intervention definitively prevents or manages osteoporosis. This study explores whether Pool 7 Compound 3 (P7C3) reduces progressive bone loss and fragility following the onset of ovariectomy (OVX)-induced osteoporosis. Results confirm OVX-induced weakened, osteoporotic bone together with a significant gain in adipogenic body weight. Treatment with P7C3 significantly reduced osteoclastic activity, bone marrow adiposity, whole-body weight gain, and preserved bone area, architecture, and mechanical strength. Analyses reveal significantly upregulated platelet derived growth factor-BB and leukemia inhibitory factor, with downregulation of interleukin-1 R6, and receptor activator of nuclear factor kappa-B (RANK). Together, proteomic data suggest the targeting of several key regulators of inflammation, bone, and adipose turnover, via transforming growth factor-beta/SMAD, and Wingless-related integration site/be-catenin signaling pathways. To the best of the knowledge, this is first evidence of an intervention that drives against bone loss via RANK. Metatranscriptomic analyses of the gut microbiota show P7C3 increased Porphyromonadaceae bacterium, Candidatus Melainabacteria, and Ruminococcaceae bacterium abundance, potentially contributing to the favorable inflammatory, and adipo-osteogenic metabolic regulation observed. The results reveal an undiscovered, and multifunctional therapeutic strategy to prevent the pathological progression of OVX-induced bone loss.

A therapeutically targetable positive feedback loop between lnc-HLX-2-7, HLX, and MYC that promotes group 3 medulloblastoma.

Recent studies suggest that long non-coding RNAs (lncRNAs) contribute to medulloblastoma (MB) formation and progression. We have identified an lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 (G3) MBs. lnc-HLX-2-7 RNA specifically accumulates in the promoter region of HLX, a sense-overlapping gene of lnc-HLX-2-7, which activates HLX expression by recruiting multiple factors, including enhancer elements. RNA sequencing and chromatin immunoprecipitation reveal that HLX binds to and activates the promoters of several oncogenes, including TBX2, LIN9, HOXM1, and MYC. Intravenous treatment with cerium-oxide-nanoparticle-coated antisense oligonucleotides targeting lnc-HLX-2-7 (CNP-lnc-HLX-2-7) inhibits tumor growth by 40%-50% in an intracranial MB xenograft mouse model. Combining CNP-lnc-HLX-2-7 with standard-of-care cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared with CNP-lnc-HLX-2-7 monotherapy. Thus, the lnc-HLX-2-7-HLX-MYC axis is important for regulating G3 MB progression, providing a strong rationale for using lnc-HLX-2-7 as a therapeutic target for G3 MBs.

miRNA-211 maintains metabolic homeostasis in medulloblastoma through its target gene long-chain acyl-CoA synthetase 4.

The prognosis of childhood medulloblastoma (MB) is often poor, and it usually requires aggressive therapy that adversely affects quality of life. microRNA-211 (miR-211) was previously identified as an important regulator of cells that descend from neural cells. Since medulloblastomas primarily affect cells with similar ontogeny, we investigated the role and mechanism of miR-211 in MB. Here we showed that miR-211 expression was highly downregulated in cell lines, PDXs, and clinical samples of different MB subgroups (SHH, Group 3, and Group 4) compared to normal cerebellum. miR-211 gene was ectopically expressed in transgenic cells from MB subgroups, and they were subjected to molecular and phenotypic investigations. Monoclonal cells stably expressing miR-211 were injected into the mouse cerebellum. miR-211 forced expression acts as a tumor suppressor in MB both in vitro and in vivo, attenuating growth, promoting apoptosis, and inhibiting invasion. In support of emerging regulatory roles of metabolism in various forms of cancer, we identified the acyl-CoA synthetase long-chain family member (ACSL4) as a direct miR-211 target. Furthermore, lipid nanoparticle-coated, dendrimer-coated, and cerium oxide-coated miR-211 nanoparticles were applied to deliver synthetic miR-211 into MB cell lines and cellular responses were assayed. Synthesizing nanoparticle-miR-211 conjugates can suppress MB cell viability and invasion in vitro. Our findings reveal miR-211 as a tumor suppressor and a potential therapeutic agent in MB. This proof-of-concept paves the way for further pre-clinical and clinical development.

Inorganic Nanoparticles as Radiosensitizers for Cancer Treatment.

Nanotechnology has expanded what can be achieved in our approach to cancer treatment. The ability to produce and engineer functional nanoparticle formulations to elicit higher incidences of tumor cell radiolysis has resulted in substantial improvements in cancer cell eradication while also permitting multi-modal biomedical functionalities. These radiosensitive nanomaterials utilize material characteristics, such as radio-blocking/absorbing high-Z atomic number elements, to mediate localized effects from therapeutic irradiation. These materials thereby allow subsequent scattered or emitted radiation to produce direct (e.g., damage to genetic materials) or indirect (e.g., protein oxidation, reactive oxygen species formation) damage to tumor cells. Using nanomaterials that activate under certain physiologic conditions, such as the tumor microenvironment, can selectively target tumor cells. These characteristics, combined with biological interactions that can target the tumor environment, allow for localized radio-sensitization while mitigating damage to healthy cells. This review explores the various nanomaterial formulations utilized in cancer radiosensitivity research. Emphasis on inorganic nanomaterials showcases the specific material characteristics that enable higher incidences of radiation while ensuring localized cancer targeting based on tumor microenvironment activation. The aim of this review is to guide future research in cancer radiosensitization using nanomaterial formulations and to detail common approaches to its treatment, as well as their relations to commonly implemented radiotherapy techniques.

Nanotechnology enabled radioprotectants to reduce space radiation-induced reactive oxidative species.

Interest in space exploration has seen substantial growth following recent launch and operation of modern space technologies. In particular, the possibility of travel beyond low earth orbit is seeing sustained support. However, future deep space travel requires addressing health concerns for crews under continuous, longer-term exposure to adverse environmental conditions. Among these challenges, radiation-induced health issues are a major concern. Their potential to induce chronic illness is further potentiated by the microgravity environment. While investigations into the physiological effects of space radiation are still under investigation, studies on model ionizing radiation conditions, in earth and micro-gravity conditions, can provide needed insight into relevant processes. Substantial formation of high, sustained reactive oxygen species (ROS) evolution during radiation exposure is a clear threat to physiological health of space travelers, producing indirect damage to various cell structures and requiring therapeutic address. Radioprotection toward the skeletal system components is essential to astronaut health, due to the high radio-absorption cross-section of bone mineral and local hematopoiesis. Nanotechnology can potentially function as radioprotectant and radiomitigating agents toward ROS and direct radiation damage. Nanoparticle compositions such as gold, silver, platinum, carbon-based materials, silica, transition metal dichalcogenides, and ceria have all shown potential as viable radioprotectants to mitigate space radiation effects with nanoceria further showing the ability to protect genetic material from oxidative damage in several studies. As research into space radiation-induced health problems develops, this review intends to provide insights into the nanomaterial design to ameliorate pathological effects from ionizing radiation exposure. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Nanotechnology Approaches to Biology > Cells at the Nanoscale Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

A novel approach for the prevention of ionizing radiation-induced bone loss using a designer multifunctional cerium oxide nanozyme.

The disability, mortality and costs due to ionizing radiation (IR)-induced osteoporotic bone fractures are substantial and no effective therapy exists. Ionizing radiation increases cellular oxidative damage, causing an imbalance in bone turnover that is primarily driven via heightened activity of the bone-resorbing osteoclast. We demonstrate that rats exposed to sublethal levels of IR develop fragile, osteoporotic bone. At reactive surface sites, cerium ions have the ability to easily undergo redox cycling: drastically adjusting their electronic configurations and versatile catalytic activities. These properties make cerium oxide nanomaterials fascinating. We show that an engineered artificial nanozyme composed of cerium oxide, and designed to possess a higher fraction of trivalent (Ce3+) surface sites, mitigates the IR-induced loss in bone area, bone architecture, and strength. These investigations also demonstrate that our nanozyme furnishes several mechanistic avenues of protection and selectively targets highly damaging reactive oxygen species, protecting the rats against IR-induced DNA damage, cellular senescence, and elevated osteoclastic activity in vitro and in vivo. Further, we reveal that our nanozyme is a previously unreported key regulator of osteoclast formation derived from macrophages while also directly targeting bone progenitor cells, favoring new bone formation despite its exposure to harmful levels of IR in vitro. These findings open a new approach for the specific prevention of IR-induced bone loss using synthesis-mediated designer multifunctional nanomaterials.

Potent Inactivation of Human Respiratory Viruses Including SARS-CoV-2 by a Photoactivated Self-Cleaning Regenerative Antiviral Coating.

The COVID-19 pandemic marks an inflection point in the perception and treatment of human health. Substantial resources have been reallocated to address the direct medical effects of COVID-19 and to curtail the spread of the virus. Thereby, shortcomings of traditional disinfectants, especially their requirement for regular reapplication and the related complications (e.g., dedicated personnel and short-term activity), have become issues at the forefront of public health concerns. This issue became especially pressing when infection-mitigating supplies dwindled early in the progression of the pandemic. In consideration of the constant threat posed by emerging novel viruses, we report a platform technology for persistent surface disinfection to combat virus transmission through nanomaterial-mediated, localized UV radiation emission. In this work, two formulations of Y2SiO5-based visible-to-UV upconversion nanomaterials were developed using a facile sol-gel-based synthesis. Our formulations have shown substantial antiviral activities (4 × 104 to 0 TCID50 units in 30 min) toward an enveloped, circulating human coronavirus strain (OC43) under simple white light exposure as an analogue to natural light or common indoor lighting. Additionally, we have shown that our two formulations greatly reduce OC43 RNA recovery from surfaces. Antiviral activities were further demonstrated toward a panel of structurally diverse viruses including enveloped viruses, SARS-CoV-2, vaccinia virus, vesicular stomatitis virus, parainfluenza virus, and Zika virus, as well as nonenveloped viruses, rhinovirus, and calicivirus, as evidence of the technology's broad antiviral activity. Remarkably, one formulation completely inactivated 105 infectious units of SARS-CoV-2 in only 45 min. The detailed technology has implications for the design of more potent, long-lived disinfectants and modified/surface-treated personal protective equipment targeting a wide range of viruses.

Lung function improves after delayed treatment with CNP-miR146a following acute lung injury.

Acute respiratory distress syndrome (ARDS) is a highly morbid pulmonary disease characterized by hypoxic respiratory failure. Its pathogenesis is characterized by unrestrained oxidative stress and inflammation, with long-term sequelae of pulmonary fibrosis and diminished lung function. Unfortunately, prior therapeutic ARDS trials have failed and therapy is limited to supportive measures. Free radical scavenging cerium oxide nanoparticles (CNP) conjugated to the anti-inflammatory microRNA-146a (miR146a), termed CNP-miR146a, have been shown to prevent acute lung injury in a pre-clinical model. In this study, we evaluated the potential of delayed treatment with CNP-miR146a at three or seven days after injury to rescue the lung from acute injury. We found that intratracheal CNP-miR146a administered three days after injury lowers pulmonary leukocyte infiltration, reduce inflammation and oxidative stress, lower pro-fibrotic gene expression and collagen deposition in the lung, and ultimately improve pulmonary function.

Sensitization of breast cancer to Herceptin by redox active nanoparticles.

Herceptin-resistant tumor relapse remains a major clinical issue responsible for the poor prognosis of HER2+ breast cancer. Understanding the underlying mechanisms and finding a therapeutic solution are of paramount urgency to improve the patient management. Here we report that anticancer redox active cerium oxide nanoparticles (CONPs) can potently sensitize the cancer cells to the cytotoxicity of Herceptin. By comparing between Herceptin-sensitive and Herceptin-resistant human breast cancer cell lines under normoxic as well as hypoxic culture conditions, we found that in the presence of CONPs, Herceptin can kill the Herceptin-resistant cells equally effectively as it kills the Herceptin-sensitive cells under the hypoxic, but not normoxic, culture conditions by inhibiting the cell viability, survival and proliferation. Signaling analysis reveals that under the normoxic conditions, the levels of hypoxia induced factor 1α as well as vascular endothelial growth factor are higher in the Herceptin-resistant cells than that in the Herceptin-sensitive cells and are strongly induced once the culture is switched to the hypoxic conditions, which can be potently suppressed by CONPs. Treatment with CONPs plus Herceptin significantly slows down the primary tumor growth and lung metastasis of the Herceptin-resistant cells in a xenograft mouse model of orthotopic breast cancer through inhibiting the cell proliferation and survival as well as tumor angiogenesis. These results shed new lights on the mechanisms underlying the Herceptin resistance of the HER2+ breast cancer and provide insights into introducing CONPs-like agents to Herceptin-based therapy to improve treatment outcomes.

Nanoceria, the versatile nanoparticles: Promising biomedical applications.

Nanotechnology has been a boon for the biomedical field due to the freedom it provides for tailoring of pharmacokinetic properties of different drug molecules. Nanomedicine is the medical application of nanotechnology for the diagnosis, treatment and/or management of the diseases. Cerium oxide nanoparticles (CNPs) are metal oxide-based nanoparticles (NPs) which possess outstanding reactive oxygen species (ROS) scavenging activities primarily due to the availability of "oxidation switch" on their surface. These NP have been found to protect from a number of disorders with a background of oxidative stress such as cancer, diabetes etc. In fact, the CNPs have been found to possess the environment-dependent ROS modulating properties. In addition, the inherent catalase, SOD, oxidase, peroxidase and phosphatase mimetic properties of CNPs provide them superiority over a number of NPs. Further, chemical reactivity of CNPs seems to be a function of their surface chemistry which can be precisely tuned by defect engineering. However, the contradictory reports make it necessary to critically evaluate the potential of CNPs, in the light of available literature. The review is aimed at probing the feasibility of CNPs to push towards the clinical studies. Further, we have also covered and censoriously discussed the suspected negative impacts of CNPs before making our way to a consensus. This review aims to be a comprehensive, authoritative, critical, and accessible review of general interest to the scientific community.

Cerium oxide nanoparticles protect against irradiation-induced cellular damage while augmenting osteogenesis.

Increased bone loss and risk of fracture are two of the main challenges for cancer patients who undergo ionizing radiation (IR) therapy. This decline in bone quality is in part, caused by the excessive and sustained release of reactive oxygen species (ROS). Cerium oxide nanoparticles (CeONPs) have proven antioxidant and regenerative properties and the purpose of this study was to investigate the effect of CeONPs in reducing IR-induced functional damage in human bone marrow-derived mesenchymal stromal cells (hBMSCs). hBMSCs were supplemented with CeONPs at a concentration of either 1 or 10 µg/mL 24 h prior to exposure to a single 7 Gy irradiation dose. ROS levels, cellular proliferation, morphology, senescence, DNA damage, p53 expression and autophagy were evaluated as well as alkaline phosphatase, osteogenic protein gene expression and bone matrix deposition following osteogenic differentiation. Results showed that supplementation of CeONPs at a concentration of 1 µg/mL reduced cell senescence and significantly augmented cell autophagy (p = 0.01), osteogenesis and bone matrix deposition >2-fold (p = 0.0001) while under normal, non-irradiated culture conditions. Following irradiation, functional damage was attenuated and CeONPs at both 1 or 10 µg/mL significantly reduced ROS levels (p = 0.05 and 0.001 respectively), DNA damage by >4-fold (p < 0.05) while increasing autophagy >3.5-fold and bone matrix deposition 5-fold (p = 0.0001 in both groups). When supplemented with 10 µg/mL, p53 expression increased 3.5-fold (p < 0.05). We conclude that cellular uptake of CeONPs offered a significant, multifunctional and protective effect against IR-induced cellular damage while also augmenting osteogenic differentiation and subsequent new bone deposition. The use of CeONPs holds promise as a novel multifunctional therapeutic strategy for irradiation-induced bone loss.

Multi-functional cerium oxide nanoparticles regulate inflammation and enhance osteogenesis.

Oxidative stress increases bone loss and limits repair, in part, through immunoregulation and the formation and maintenance of low-grade chronic inflammation. The aim of this study was to investigate the effect of cerium oxide nanoparticles (CeONPs) on (i) macrophage phenotype and cytokine expression under normal and simulated acute and chronic inflammatory conditions and, (ii) human mesenchymal stem cell (hBMSCs) proliferation, osteoinduction and osteogenic differentiation. Spherical particles composed of 60% Ce3+ with a hydrodynamic size of ~35 nm and surface charge of 25.4 mV were internalized within cells. Under both acute and chronic conditions, inducible nitric oxide synthase (iNOS) activity decreased with a significant reduction seen in the 1 and 10 µg/mL groups (p < 0.001). A dose dependent and significant increase in anti-inflammatory cytokine gene expression was observed in all CeONP groups under chronic inflammatory condition. No increase in alkaline phosphatase (ALP) activity or mineral deposits were measured following hBMSCs cultured without osteogenic media in any of the CeONP groups, however, a significant increase in osteogenic-related gene expression, ALP activity and bone mineral deposits was measured when supplemented with both CeONPs and osteogenic media. CeONP activity was multifaceted and exhibited low toxicity. A therapeutic dose of 1 µg/mL delivered a disparate but protective effect when under both acute and chronic inflammatory conditions while at the same dose, potentiated osteogenesis.

Ceria Nanoparticles Decrease UVA-Induced Fibroblast Death Through Cell Redox Regulation Leading to Cell Survival, Migration and Proliferation.

Exposure to ultraviolet radiation is a major contributor to premature skin aging and carcinogenesis, which is mainly driven by overproduction of reactive oxygen species (ROS). There is growing interest for research on new strategies that address photoaging prevention, such as the use of nanomaterials. Cerium oxide nanoparticles (nanoceria) show enzyme-like activity in scavenging ROS. Herein, our goal was to study whether under ultraviolet A rays (UVA)-induced oxidative redox imbalance, a low dose of nanoceria induces protective effects on cell survival, migration, and proliferation. Fibroblasts cells (L929) were pretreated with nanoceria (100 nM) and exposed to UVA radiation. Pretreatment of cells with nanoceria showed negligible cytotoxicity and protected cells from UVA-induced death. Nanoceria also inhibited ROS production immediately after irradiation and for up to 48 h and restored the superoxide dismutase (SOD) activity and GSH level. Additionally, the nanoceria pretreatment prevented apoptosis by decreasing Caspase 3/7 levels and the loss of mitochondrial membrane potential. Nanoceria significantly improved the cell survival migration and increased proliferation, over a 5 days period, as compared with UVA-irradiated cells, in wound healing assay. Furthermore, it was observed that nanoceria decreased cellular aging and ERK 1/2 phosphorylation. Our study suggests that nanoceria might be a potential ally to endogenous, antioxidant enzymes, and enhancing the redox potentials to fight against UVA-induced photodamage and consequently modulating the cells survival, migration, and proliferation.

Ceria Nanoparticles Mitigate the Iron Oxidative Toxicity of Human Retinal Pigment Epithelium.

Oxidative injury is implicated in retinal damage observed in age-related macular degeneration (AMD), as well as other degenerative conditions. Abnormally elevated levels of iron accumulation within the retinal pigment epithelium have been detected in eyes with AMD, and it is suspected to play a role in the pathogenesis through the production of reactive oxygen species (ROS). Ceria nanoparticles (CNP) have the ability to scavenge ROS. This study sought to evaluate the ability of CNP to mitigate iron-induced oxidative stress and assess cell viability in the human ARPE-19 cell line in vitro. Cell viability was measured by an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and compared between experimental groups undergoing 48-hr exposure to a ferrous iron solution with and without 24-hr CNP pre-treatment. The CNP effect on ROS formation was evaluated additionally by H2DCFDA (2,7-dichlorodihydrofluorescein diacetate) fluorescent probe assay and superoxide dismutase assay. CNP demonstrated a three-fold increase in cell viability and a reduction in ROS generation. The results show a promising treatment modality for diseases causing oxidative damage in the eye.

Ultra-high arsenic adsorption by graphene oxide iron nanohybrid: Removal mechanisms and potential applications.

Iron (Fe)-based adsorbents have been promoted for aqueous arsenic adsorption because of their low cost and potential ease of scale-up in production. However, their field application is, so far, limited because of their low Fe use efficiency (i.e., not all available Fe is used), slow adsorption kinetics, and low adsorption capacity. In this study, we synthesized graphene oxide iron nanohybrid (GFeN) by decorating iron/iron oxide (Fe/FexOy) core-shell structured iron nanoparticles (FeNPs) on the surface of graphene oxide (GO) via a sol-gel process. The deposition of FeNPs on GO for the nanohybrid (GFeN) improves Fe use efficiency and arsenic mobility in the nanohybrid, thereby improving the arsenic removal capacity and kinetics. We achieved removal capacities of 306 mg/g for As(III) and 431 mg/g for As(V) using GFeN. Rapid reduction (>99% in <10 min) of As(III) and As(V) (initial concentration, C0 = 100 µg/L) was achieved with the nanohybrid (250 mg/L). There were no significant interferences by the coexisting anions and organic matters at environmentally relevant concentrations. Based on the experimental data, we have proposed that both electrostatic interaction and surface complexation contributed to ultra-high arsenic removal by GFeN. The GO sheets acted as the reservoirs for the electrons released during surface corrosion of the FeNPs and the electrons were transferred back to the FeNPs to rejuvenate the oxidized surface. The rejuvenated FeNP surface layer helped in additional arsenic removal.

Cerium oxide nanoparticles at the nano-bio interface: size-dependent cellular uptake.

The authors investigated the role of different size and morphology of cerium oxide nanoparticles (CNPs) in cellular uptake and internalization at the nano-bio interface. Atomic force microscopy (AFM) has been utilized to record changes in the membrane elasticity as a function of ceria particle morphology and concentration. Young's Modulus was estimated in presence and absence of CNPs of different sizes by gauging the membrane elasticity of CCL30 (squamous cell carcinoma) cells. Significant change in Young's Modulus was observed for CNP treatments at higher concentrations, while minimum membrane disruption was observed at lower concentrations. Studies using blocking agents specific to energy-dependent cellular internalization pathways indicated passive cellular uptake for smaller CNPs (3-5 nm). Other observations showed that larger CNPs were unable to permeate the cell membrane, which indicates an active uptake mechanism by the cell membrane. The ability of smaller CNPs (3-5 nm) to permeate the cell membrane without energy consumption by uptake pathways suggests potential for use as nanovectors for the delivery of bioactive molecules. Specifically, the passive uptake mechanism allows for the delivery of surface-bound molecules directly to the cytoplasm, avoiding the extreme chemical conditions of endosomal pathways.

Cerium Oxide Nanoparticles Sensitize Pancreatic Cancer to Radiation Therapy through Oxidative Activation of the JNK Apoptotic Pathway.

Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. Cerium oxide nanoparticles (CONPs) are currently being tested in pre-clinical trials as an adjuvant to sensitize pancreatic cancer cells to RT and protect normal tissues from the harmful side effects. CONPs were not able to significantly affect RT-induced DNA damage in cancer cells, thereby ruling out sensitization through increased mitotic catastrophe. However, activation of c-Jun terminal kinase (JNK), a key driver of RT-induced apoptosis, was significantly enhanced by co-treatment with CONPs and RT in pancreatic cancer cells in vitro and human pancreatic tumors in nude mice in vivo compared to CONPs or RT treatment alone. Further, CONP-driven increase in RT-induced JNK activity was associated with a marked increase in Caspase 3/7 activation, indicative of apoptosis. We have previously shown that CONPs increase reactive oxygen species (ROS) production in cancer cells. ROS has been shown to drive the oxidation of thioredoxin 1 (TRX1) which results in the activation of apoptosis signaling kinase 1 (ASK1). The increase in ASK1 activation following the co-treatment with CONPs followed by RT suggests that the increased JNK activation is the result of increased TRX1 oxidation. The ability of CONPs to sensitize pancreatic cancer cells to RT was mitigated when the TRX1 oxidation was prevented by mutagenesis of a cysteine residue or when the JNK activation was blocked by an inhibitor. Taken together, these data demonstrate an important mechanism for CONPs in specifically killing cancer cells and provide novel insights into the utilization of CONPs as a radiosensitizer and therapeutic agent for pancreatic cancer.

Engineered nanoceria cytoprotection in vivo: mitigation of reactive oxygen species and double-stranded DNA breakage due to radiation exposure.

Cerium oxide nanomaterials are known to absorb ionizing radiation energy, as well as to neutralize free radicals in solution, by undergoing redox changes. We, therefore, proposed that ceria nanoparticles could be used in biomedical applications as an injectable, radio-protectant material. In this study, we examine the effectiveness of engineered nanoparticles in protecting germ cells from the damaging effects of irradiation-induced cell death, in vivo. C57BL/6J male mice were used as a model and irradiation was localized to the scrotal region at 2.5, 5, and/or 10 Gy intensities. Ceria nanoparticles were introduced as 100 µL injections at 100 nM and 100 µM via tail vein injections, weekly, for one month. Following this, the animals were sacrificed and their organs (heart, brain, kidneys) were harvested. Tissues were fixed, sectioned, and stained for instances of cell death, DNA damage (TUNEL assay), and ROS (nitro-tyrosine evolution). Tissues from mice treated with ceria nanoparticles showed significantly less (∼13% decrease; *P < 0.05) tissue damage (per immunohistochemistry) over controls at up to 5 Gy radiation. DNA damage and ROS also decrease substantially with ceria treatment, confirming ceria's capacity as an injectable, radio-protectant material. The study also highlights the ability of ceria nanoparticles to protect cells/tissues from both direct and indirect effects of ionizing radiation.

Nanoparticle delivery of curcumin induces cellular hypoxia and ROS-mediated apoptosis via modulation of Bcl-2/Bax in human neuroblastoma.

In this study, several formulations of nanoceria and dextran-nanoceria with curcumin, each demonstrated to have anti-cancer properties, were synthesized and applied as treatment for human childhood neuroblastoma. The anti-cancer activities of these formulations were explored in neuroblastoma models of both MYCN-amplified and non-amplified cell lines. Ceria nanoparticles, coated with dextran and loaded with curcumin, were found to induce substantial cell death in neuroblastoma cells (up to a 2-fold and a 1.6-fold decrease in cell viability for MYCN-upregulated and normal expressing cell lines, respectively; *p < 0.05) while producing no or only minor toxicity in healthy cells (no toxicity at 100 µM; **p < 0.01). This formulation evokes prolonged oxidative stress, stabilizing HIF-1α, and inducing caspase-dependent apoptosis (up to a 2.4-fold increase over control; *p < 0.05). Overall, nano-therapeutic treatments showed a more pronounced effect in MYCN-amplified cells, which are traditionally more resistant to drug therapies. These results represent a very promising alternative to small molecule drug therapies for robust cancers.