Harnessing cerium-based biomaterials for the treatment of bone diseases.

Bone, an actively metabolic organ, undergoes constant remodeling throughout life. Disturbances in the bone microenvironment can be responsible for pathologically bone diseases such as periodontitis, osteoarthritis, rheumatoid arthritis and osteoporosis. Conventional bone tissue biomaterials are not adequately adapted to complex bone microenvironment. Therefore, there is an urgent clinical need to find an effective strategy to improve the status quo. In recent years, nanotechnology has caused a revolution in biomedicine. Cerium(III, IV) oxide, as an important member of metal oxide nanomaterials, has dual redox properties through reversible binding with oxygen atoms, which continuously cycle between Ce(III) and Ce(IV). Due to its special physicochemical properties, cerium(III, IV) oxide has received widespread attention as a versatile nanomaterial, especially in bone diseases. This review describes the characteristics of bone microenvironment. The enzyme-like properties and biosafety of cerium(III, IV) oxide are also emphasized. Meanwhile, we summarizes controllable synthesis of cerium(III, IV) oxide with different nanostructural morphologies. Following resolution of synthetic principles of cerium(III, IV) oxide, a variety of tailored cerium-based biomaterials have been widely developed, including bioactive glasses, scaffolds, nanomembranes, coatings, and nanocomposites. Furthermore, we highlight the latest advances in cerium-based biomaterials for inflammatory and metabolic bone diseases and bone-related tumors. Tailored cerium-based biomaterials have already demonstrated their value in disease prevention, diagnosis (imaging and biosensors) and treatment. Therefore, it is important to assist in bone disease management by clarifying tailored properties of cerium(III, IV) oxide in order to promote the use of cerium-based biomaterials in the future clinical setting. STATEMENT OF SIGNIFICANCE: In this review, we focused on the promising of cerium-based biomaterials for bone diseases. We reviewed the key role of bone microenvironment in bone diseases and the main biological activities of cerium(III, IV) oxide. By setting different synthesis conditions, cerium(III, IV) oxide nanostructures with different morphologies can be controlled. Meanwhile, tailored cerium-based biomaterials can serve as a versatile toolbox (e.g., bioactive glasses, scaffolds, nanofibrous membranes, coatings, and nanocomposites). Then, the latest research advances based on cerium-based biomaterials for the treatment of bone diseases were also highlighted. Most importantly, we analyzed the perspectives and challenges of cerium-based biomaterials. In future perspectives, this insight has given rise to a cascade of cerium-based biomaterial strategies, including disease prevention, diagnosis (imaging and biosensors) and treatment.

The Effect of Cerium Oxide (CeO2) on Ischemia-Reperfusion Injury in Skeletal Muscle in Mice with Streptozocin-Induced Diabetes.

Objective: Lower extremity ischemia-reperfusion injury (IRI) may occur with trauma-related vascular injury and various vascular diseases, during the use of a tourniquet, in temporary clamping of the aorta in aortic surgery, or following acute or bilateral acute femoral artery occlusion. Mitochondrial dysfunction and increased basal oxidative stress in diabetes may cause an increase in the effects of increased reactive oxygen species (ROS) and mitochondrial dysfunction due to IRI. It is of great importance to examine therapeutic approaches that can minimize the effects of IRI, especially for patient groups under chronic oxidative stress such as DM. Cerium oxide (CeO2) nanoparticles mimic antioxidant enzymes and act as a catalyst that scavenges ROS. In this study, it was aimed to investigate whether CeO2 has protective effects on skeletal muscles in lower extremity IRI in mice with streptozocin-induced diabetes. Methods: A total of 38 Swiss albino mice were divided into six groups as follows: control group (group C, n = 6), diabetes group (group D, n = 8), diabetes-CeO2 (group DCO, n = 8), diabetes-ischemia/reperfusion (group DIR, n = 8), and diabetes-ischemia/reperfusion-CeO2 (group DIRCO, n = 8). The DCO and DIRCO groups were given doses of CeO2 of 0.5 mg/kg intraperitoneally 30 min before the IR procedure. A 120 min ischemia-120 min reperfusion period with 100% O2 was performed. At the end of the reperfusion period, muscle tissues were removed for histopathological and biochemical examinations. Results: Total antioxidant status (TAS) levels were found to be significantly lower in group DIR compared with group D (p = 0.047 and p = 0.022, respectively). In group DIRCO, total oxidant status (TOS) levels were found to be significantly higher than in group DIR (p < 0.001). The oxidative stress index (OSI) was found to be significantly lower in group DIR compared with group DCO (p < 0.001). Paraoxanase (PON) enzyme activity was found to be significantly increased in group DIR compared with group DCO (p < 0.001). The disorganization and degeneration score for muscle cells, inflammatory cell infiltration score, and total injury score in group DIRCO were found to be significantly lower than in group DIR (p = 0.002, p = 0.034, and p = 0.001, respectively). Conclusions: Our results confirm that CeO2, with its antioxidative properties, reduces skeletal muscle damage in lower extremity IRI in diabetic mice.

Nanoceria: an innovative strategy for cancer treatment.

Nanoceria or cerium oxide nanoparticles characterised by the co-existing of Ce3+ and Ce4+ that allows self-regenerative, redox-responsive dual-catalytic activities, have attracted interest as an innovative approach to treating cancer. Depending on surface characteristics and immediate environment, nanoceria exerts either anti- or pro-oxidative effects which regulate reactive oxygen species (ROS) levels in biological systems. Nanoceria mimics ROS-related enzymes that protect normal cells at physiological pH from oxidative stress and induce ROS production in the slightly acidic tumour microenvironment to trigger cancer cell death. Nanoceria as nanozymes also generates molecular oxygen that relieves tumour hypoxia, leading to tumour cell sensitisation to improve therapeutic outcomes of photodynamic (PDT), photothermal (PTT) and radiation (RT), targeted and chemotherapies. Nanoceria has been engineered as a nanocarrier to improve drug delivery or in combination with other drugs to produce synergistic anti-cancer effects. Despite reported preclinical successes, there are still knowledge gaps arising from the inadequate number of studies reporting findings based on physiologically relevant disease models that accurately represent the complexities of cancer. This review discusses the dual-catalytic activities of nanoceria responding to pH and oxygen tension gradient in tumour microenvironment, highlights the recent nanoceria-based platforms reported to be feasible direct and indirect anti-cancer agents with protective effects on healthy tissues, and finally addresses the challenges in clinical translation of nanoceria based therapeutics.

Diabetic bone regeneration with nanoceria-tailored scaffolds by recapitulating cellular microenvironment: Activating integrin/TGF-ß co-signaling of MSCs while relieving oxidative stress.

Regenerating defective bone in patients with diabetes mellitus remains a significant challenge due to high blood glucose level and oxidative stress. Here we aim to tackle this issue by means of a drug- and cell-free scaffolding approach. We found the nanoceria decorated on various types of scaffolds (fibrous or 3D-printed one; named nCe-scaffold) could render a therapeutic surface that can recapitulate the microenvironment: modulating oxidative stress while offering a nanotopological cue to regenerating cells. Mesenchymal stem cells (MSCs) recognized the nanoscale (tens of nm) topology of nCe-scaffolds, presenting highly upregulated curvature-sensing membrane protein, integrin set, and adhesion-related molecules. Osteogenic differentiation and mineralization were further significantly enhanced by the nCe-scaffolds. Of note, the stimulated osteogenic potential was identified to be through integrin-mediated TGF-ß co-signaling activation. Such MSC-regulatory effects were proven in vivo by the accelerated bone formation in rat calvarium defect model. The nCe-scaffolds further exhibited profound enzymatic and catalytic potential, leading to effectively scavenging reactive oxygen species in vivo. When implanted in diabetic calvarium defect, nCe-scaffolds significantly enhanced early bone regeneration. We consider the currently-exploited nCe-scaffolds can be a promising drug- and cell-free therapeutic means to treat defective tissues like bone in diabetic conditions.

Ultrasmall polymer-coated cerium oxide nanoparticles as a traumatic brain injury therapy.

No medication has been approved for secondary injuries after traumatic brain injury (TBI). While free radicals are considered a major mediator of secondary injury, conventional antioxidants only have modest clinical efficacy. Here, we synthesized CX201 consisting of core cerium oxide nanoparticles coated with 6-aminocaproic acid and polyvinylpyrrolidone in aqueous phase. CX201 with 3.49 ± 1.11 nm of core and 6.49 ± 0.56 nm of hydrodynamic diameter showed multi-enzymatic antioxidant function. Owing to its excellent physiological stability and cell viability, CX201 had a neuroprotective effect in vitro. In a TBI animal model, an investigator-blinded randomized experiment showed a single intravenously injected CX201 significantly improved functional recovery compared to the control. CX201 reduced lipid peroxidation and inflammatory cell recruitment at the damaged brain. These suggest ultrasmall CX201 can efficiently reduce secondary brain injuries after TBI. Given the absence of current therapies, CX201 may be proposed as a novel therapeutic strategy for TBI.

Preparation of cerium-curcumin and cerium-quercetin complexes and their LEDs irradiation assisted anticancer effects on MDA-MB-231 and A375 cancer cell lines.

Cancer remains common and often is difficult to eradicate. In particular resistant forms like triple negative breast cancer and melanoma generally allow for very short survival. Curcumin and quercetin as two important polyphenols from plants which have different biological roles, potentially including anti-cancer effect. But their clinical application is limited due to poor solubility in aqueous medium. Photodynamic therapy (PDT) is a cancer treatment using select chemical compounds as photosensitizers, which when activated by light create toxic singlet oxygen. Studies done on plant based photosensitizers such as curcumin and quercetin have shown the ability to ablate tumors. Here we discuss using them as improved PS by making their complex with cerium ions as a delivery system for MDA-MB-231 and A375 cancer cell lines treatment. For this purpose, the MDA-MB-231 human breast cancer cell line exposed to red light irradiation (as pretreatment) then treated with curcumin and quercetin alone and also their complex with cerium. In another study the cells treated with curcumin-cerium and quercetin-cerium complex and then irradiated with blue light (photodynamic treatment). Cell survival and apoptosis were determined using MTT and fluorescence microscopy. The result showed that curcumin and quercetin in complex with cerium ions have better toxic effect against both breast and melanoma cancer cells as compared to each compound alone. The finding revealed that curcumin and quercetin in cerium complex could be considered as a new approach in the photodynamic treatment of breast and melanoma cancer cells.

In Vivo Regenerable Cerium Oxide Nanozyme-Loaded pH/H2O2-Responsive Nanovesicle for Tumor-Targeted Photothermal and Photodynamic Therapies.

Photodynamic therapy (PDT) and photothermal therapies (PTTs) are both promising strategies for effective tumor therapy. However, the absence of O2 at tumor sites hinders the sustained response of photosensitizers. Here, we develop a recycled cerium oxide (CeO2) catalase nanozyme-loaded hyaluronic acid nanovesicle to address the hypoxic tumor microenvironments and targeted delivery of the photosensitizers [indocyanine green (ICG)] to tumors. A polysaccharide complex effectively modifies the surface of a polyethylenimine phenylboronic acid nanostructure to achieve the CeO2 nanozyme-loading nanovesicles that exhibit both tumor-targeted enhancement and an improved hypoxic microenvironment. Also, the hydrogen peroxide responsiveness and acid-sensitive cleavage of phenylboronic acid specifically disintegrate the ICG/nanozyme coloaded nanovesicles in the tumor microenvironment. The in vitro synergistic tests and tumor suppression rate tests indicated that the cerium oxide nanozyme significantly improves the outcomes of PDT via cerium-element valence state recycling and hypoxia improvement, thus enhancing the tumor suppression efficiency. This pH/H2O2-responsive nanozyme/ICG codelivery system provides a good carrier model for improving the tumor microenvironment and increasing the efficiency of tumor-targeted PTT and PDT therapies.

Dual-path modulation of hydrogen peroxide to ameliorate hypoxia for enhancing photodynamic/starvation synergistic therapy.

The common existence of hypoxia within the tumor microenvironment severely restricts the efficacy of photodynamic therapy (PDT), which is attributed to the fact that the PDT process is strongly oxygen (O2) dependent. Here, a multifunctional composite (named CPCG), which combines polyethylene glycol (PEG) functionalized cerium oxide nanoparticles (CeO2) with photosensitizer chlorin e6 (Ce6) and glucose oxidase (GOx), is reported for generating O2 within the tumor microenvironment by the dual-path hydrogen peroxide (H2O2)-modulated ways to ameliorate hypoxia, thereby enhancing the PDT efficiency. This process is realized based on the dual enzyme-like activity of CeO2. The first modulated way is to transform the superoxide anion (O2˙-) into H2O2 by the superoxide dismutase-like activity of CeO2. The second modulated way is to decompose glucose into H2O2 through the catalysis of GOx. Subsequently, H2O2 generated from the above dual modulated ways can further produce O2via the catalase-like activity of CeO2. Additionally, the depletion of glucose could impede the nutrient supply to obtain starvation therapy. Both in vitro and in vivo experiments indicate that the CPCG composite could enhance the efficacy of photodynamic/starvation synergistic therapy. Therefore, this strategy offers great potential to modulate the O2 level in the tumor microenvironment for better therapeutic outcomes, and can act as a promising candidate in photodynamic/starvation synergistic therapy.

A one-pot synthesis of multifunctional Bi2S3 nanoparticles and the construction of core-shell Bi2S3@Ce6-CeO2 nanocomposites for NIR-triggered phototherapy.

As a direct thin band gap n-type semiconductor, bismuth sulfide (Bi2S3) nanomaterials possess great near-infrared (NIR)-triggered photothermal effects, photoacoustic (PA) and computed tomography (CT) imaging properties. Hence, Bi2S3 nanomaterials have become a research focal point in multiple domains, such as the construction of NIR-triggered nanosystems for cancer therapy. In this study, through a simple one-pot synthesis with the assistance of EDTA-2Na, we first obtained monodispersed spherical Bi2S3 of uniform particle sizes with fascinating photothermal and PA/CT imaging properties. Based on this, we introduced the photosensitizer Ce6 with photodynamic property and CeO2 with the O2-evolving characteristic, and thus designed a core-shell structure of the Bi2S3@Ce6-CeO2 nanocomposites (Bi2S3@Ce6-CeO2 NCs). The as-received Bi2S3@Ce6-CeO2 NCs exhibited a remarkable synergetic photothermal and photodynamic therapeutic effect both in vitro and in vivo, demonstrating its promising potential for cancer treatments. In the long term, the multifunctional PA/CT properties of both Bi2S3 NPs and Bi2S3@Ce6-CeO2 NCs in this study also supply a novel Bi2S3-based platform for constructing integrated diagnosis and treatment platforms.

Bespoken Nanoceria: An Effective Treatment in Experimental Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Despite the availability of new-generation drugs, hepatocellular carcinoma (HCC) is still the third most frequent cause of cancer-related deaths worldwide. Cerium oxide nanoparticles (CeO2 NPs) have emerged as an antioxidant agent in experimental liver disease because of their antioxidant, anti-inflammatory, and antisteatotic properties. In the present study, we aimed to elucidate the potential of CeO2 NPs as therapeutic agents in HCC. APPROACH AND RESULTS: HCC was induced in 110 Wistar rats by intraperitoneal administration of diethylnitrosamine for 16 weeks. Animals were treated with vehicle or CeO2 NPs at weeks 16 and 17. At the eighteenth week, nanoceria biodistribution was assessed by mass spectrometry (MS). The effect of CeO2 NPs on tumor progression and animal survival was investigated. Hepatic tissue MS-based phosphoproteomics as well as analysis of principal lipid components were performed. The intracellular uptake of CeO2 NPs by human ex vivo perfused livers and human hepatocytes was analyzed. Nanoceria was mainly accumulated in the liver, where it reduced macrophage infiltration and inflammatory gene expression. Nanoceria treatment increased liver apoptotic activity, while proliferation was attenuated. Phosphoproteomic analysis revealed that CeO2 NPs affected the phosphorylation of proteins mainly related to cell adhesion and RNA splicing. CeO2 NPs decreased phosphatidylcholine-derived arachidonic acid and reverted the HCC-induced increase of linoleic acid in several lipid components. Furthermore, CeO2 NPs reduced serum alpha-protein levels and improved the survival of HCC rats. Nanoceria uptake by ex vivo perfused human livers and in vitro human hepatocytes was also demonstrated. CONCLUSIONS: These data indicate that CeO2 NPs partially revert the cellular mechanisms involved in tumor progression and significantly increase survival in HCC rats, suggesting that they could be effective in patients with HCC.

Cerium oxide nanoparticles improve liver regeneration after acetaminophen-induced liver injury and partial hepatectomy in rats.

BACKGROUND AND AIMS: Cerium oxide nanoparticles are effective scavengers of reactive oxygen species and have been proposed as a treatment for oxidative stress-related diseases. Consequently, we aimed to investigate the effect of these nanoparticles on hepatic regeneration after liver injury by partial hepatectomy and acetaminophen overdose. METHODS: All the in vitro experiments were performed in HepG2 cells. For the acetaminophen and partial hepatectomy experimental models, male Wistar rats were divided into three groups: (1) nanoparticles group, which received 0.1 mg/kg cerium nanoparticles i.v. twice a week for 2 weeks before 1 g/kg acetaminophen treatment, (2) N-acetyl-cysteine group, which received 300 mg/kg of N-acetyl-cysteine i.p. 1 h after APAP treatment and (3) partial hepatectomy group, which received the same nanoparticles treatment before partial hepatectomy. Each group was matched with vehicle-controlled rats. RESULTS: In the partial hepatectomy model, rats treated with cerium oxide nanoparticles showed a significant increase in liver regeneration, compared with control rats. In the acetaminophen experimental model, nanoparticles and N-acetyl-cysteine treatments decreased early liver damage in hepatic tissue. However, only the effect of cerium oxide nanoparticles was associated with a significant increment in hepatocellular proliferation. This treatment also reduced stress markers and increased cell cycle progression in hepatocytes and the activation of the transcription factor NF-κB in vitro and in vivo. CONCLUSIONS: Our results demonstrate that the nanomaterial cerium oxide, besides their known antioxidant capacities, can enhance hepatocellular proliferation in experimental models of liver regeneration and drug-induced hepatotoxicity.

Light-induced Nrf2-/- mice as atrophic age-related macular degeneration model and treatment with nanoceria laden injectable hydrogel.

Elevated oxidative stress and associated reactive oxygen species (ROS) accumulation are hallmarks in the induction and progression of age-related macular degeneration (AMD). By exposing nuclear factor erythroid 2-related factor (Nrf2) knockout (Nrf2-/-) mice to mild white light, we were able to generate a new dry-AMD like murine model to the study. This animal model developed phenotypes of photoreceptor degeneration, retinal function impairment, ROS accumulation, and inflammation reaction in a relatively shorter time. In the treatment of this animal model we utilized an antioxidative and water soluble nanoparticle known as glycol chitosan coated cerium oxide nanoparticles (GCCNP). The delivery of GCCNP protected retina against progressive retinal oxidative damage. Further combination of GCCNP with alginate-gelatin based injectable hydrogel provided synergistic antioxidant effects and achieved a more rapid recovery of the retinal pigment epithelium and photoreceptor cells. This combined treatment technique has the potential to translate into a clinical intervention for the treatment of AMD.

NaCeF4:Gd,Tb Scintillator as an X-ray Responsive Photosensitizer for Multimodal Imaging-Guided Synchronous Radio/Radiodynamic Therapy.

Photosensitizers (PSs) that are directly responsive to X-ray for radiodynamic therapy (RDT) with desirable imaging abilities have great potential applications in cancer therapy. Herein, the cerium (Ce)-doped NaCeF4:Gd,Tb scintillating nanoparticle (ScNP or scintillator) is first reported. Due to the sensitization effect of the Ce ions, Tb ions can emit fluorescence under X-ray irradiation to trigger X-ray excited fluorescence (XEF). Moreover, Ce and Tb ions can absorb the energy of secondary electrons generated by X-ray to produce reactive oxide species (ROS) for RDT. With the intrinsic absorption of X-ray by lanthanide elements, the NaCeF4:Gd,Tb ScNPs also act as a computed tomography (CT) imaging contrast agent and radiosensitizers for radiotherapy (RT) sensitization synchronously. Most importantly, the transverse relaxation time of Gd3+ ions is shortened due to the doping of Ce and Tb ions, leading to the excellent performance of our ScNPs in T2-weighted MR imaging for the first time. Both in vitro and in vivo studies verify that our synthesized ScNPs have good performance in XEF, CT, and T2-weighted MR imaging, and a synchronous RT/RDT is achieved with significant suppression on tumor progression under X-ray irradiation. Importantly, no systemic toxicity is observed after intravenous injection of ScNPs. Our work highlights that ScNPs have potential in multimodal imaging-guided RT/RDT of deep tumors.

Nanoceria neuroprotective effects in the light-damaged retina: A focus on retinal function and microglia activation.

The use of nanomaterials is an emerging therapeutic approach for the treatment of several pathologies. Cerium oxide nanoparticles have been studied for biomedical application, including neurodegenerative disorders, such as age-related macular degeneration in several animal models. The light damage model is characterised by oxidative stress upregulation followed by photoreceptor death and microglia activation in the outer retina. For this reason, the light damage model mimics some aspects involved in human age-related macular degeneration pathogenesis. In this review, we focus on the neuroprotective effects on retinal function and microglia activation in the light damage model, considering the administration of the nanoparticles both before and after the injury. The electrical responses of the retina and the microglia number and morphology are clearly modulated by the treatment, supporting the beneficial effects of cerium oxide nanoparticles to counteract the degeneration processes in the retina.

Superoxide dismutase mimetic nanoceria restrains cerulein induced acute pancreatitis.

Aim: The present study was carried out to assess the effect of nanoceria (NC) on pancreatic inflammation caused by cerulein. Methods: NC was characterized and in vitro studies were carried out in murine macrophages. The in vivo effects were tested on cerulein-induced pancreatitis. Results:In vitro treatment with NC remarkably protected macrophages from lipopolysaccharide-induced inflammation and oxidative stress as evident from the results of 2',7'-dichlorofluorescin diacetate, JC-1 and MitoSox staining. In vivo treatment with NC showed potent superoxide dismutase and catalase mimetic activity, antipancreatitis activity and improved histology. Furthermore, it reduced the expression of p65-NF-κB and acetylation of histone H3 at lysine K14, K56 and K79 residues. Conclusion: We for the first time, demonstrate that NC may be a promising candidate for the therapy of pancreatitis.

Protective Effect of Nanoceria on Cisplatin-Induced Nephrotoxicity by Amelioration of Oxidative Stress and Pro-inflammatory Mechanisms.

Cisplatin (CP) is one of the most important anticancer compounds with its therapeutic usefulness in diverse types of solid cancer. However, its use is limited due to nephrotoxicity induced by it. Oxidative stress is an effective participant which contributes actively to pathogenesis of CP-induced nephrotoxicity. Nanoparticle form of a rare earth metal cerium, also known as nanoceria (NC), has come up as a potential antioxidant and anti-inflammatory agent. In the present study, administration of CP in Swiss mice resulted in reduction of body weight, increased oxidative stress and pro-inflammatory cytokine levels including IL-6 and TNF-α along with alteration in normal histological architecture of kidney. On the contrary, NC (0.2 and 2 mg/kg i.p.) ameliorated nephrotoxicity of CP which was evident by reduction in levels of renal injury markers in plasma, i.e., creatinine and blood urea nitrogen. NC ameliorated oxidative stress by showing a reduction in levels of malondialdehyde and increased levels of endogenous antioxidants reduced glutathione and catalase. Further, NC treatment also reduced the levels of pro-inflammatory cytokines. Furthermore, protective effect of NC was also corroborated by histopathological studies wherein, kidneys from CP group showed altered tissue structure after acute as well as chronic exposure of CP while the tissues from treated groups showed absence of alterations in kidney histology. The results from present study suggested that oxidative stress and pro-inflammatory cytokines play a central role in pathogenesis of CP-induced nephrotoxicity and NC provides protection from CP-induced nephrotoxicity due to its antioxidant and anti-inflammatory properties.

Multifunctional antioxidant nanoliposome-mediated delivery of PTEN plasmids restore the expression of tumor suppressor protein and induce apoptosis in prostate cancer cells.

Prostate cancer is the second leading cause of cancer death in men and about one in nine will be diagnosed in his lifetime. Loss of PTEN has been considered as one of the major factors leading to the origin of prostate cancer through modulating PI3K/AKT signaling pathways. In this study, we have prepared a multifunctional antioxidant nanoliposome containing PTEN plasmid and cerium oxide nanoparticles (CeNPs). The efficient delivery of PTEN plasmid to human prostate cancer cells (PC-3) leads to restoration of the expression of lost PTEN protein in the cell cytoplasm. The delivered superoxide dismutase (SOD)-mimetic CeNPs were also found to decrease the cytoplasmic free radical levels in prostate cancer cells. The above two activities induced DNA fragmentation and micronucleus formation in prostate cancer cells. Furthermore, it was also found that these multifunctional antioxidant nanoliposomes inhibit the PI3K/AKT signaling pathway to negatively regulate the cell viability of prostate cancer cells. The mRNA expression pattern of other relevant proteins predominantly involved in cancer cell proliferation and apoptosis suggested that the high PTEN expression could control the synthesis of oncogenic proteins. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3152-3164, 2018.

Cerium oxide nanoparticles: In pursuit of liver protection against doxorubicin-induced injury in rats.

Doxorubicin (DOX) is considered as a backbone in several chemotherapeutic regimens. Nevertheless, the reported systemic toxicity usually hampers its broad application. Interestingly, Cerium oxide nanoparticles (CeONPs) depicted promising regenerative antioxidant and hepatoprotective potentials against multiple oxidative stress-induced pathologies. Thus, the aim of the present study was to determine either CeONPs would display hepatoprotective properties once concomitantly administered with DOX or not. Male Sprague Dawley rats were divided into four groups (n = 10) in a two weeks study: Control (received saline, IP injection thrice a week), CeO (0.5 mg/kg, IP injection once a week), DOX (2.5 mg/kg, IP injections thrice a week) and DOX + CeO (received both treatments). Hepatic toxicity was assessed by histological and ultrastructural studies. In addition, serum transaminases (ALT, AST) and malondialdehyde (MDA), an oxidative stress marker, were evaluated. CeONPs were not only proved to be safe at the proposed dose, but also their concomitant administration with DOX managed to mitigate DOX-induced hepatic insult on both histological and biochemical aspects. Such hepatoprotective behavior was referred to the noticed antioxidant action CeONPs as highlighted by the significant difference in MDA levels.

Cellular internalization and antioxidant activity of cerium oxide nanoparticles in human monocytic leukemia cells.

Overproduction of free radicals contributes to oxidative stress and inflammation leading to various disease conditions. Cerium oxide nanoparticles (nanoceria) have been shown to scavenge free radicals and have the potential for being used as a therapeutic agent in disease conditions. Therefore, in the present study, human monocytic leukemia cells (THP-1) were used as a model to evaluate the uptake and free radical scavenging activity of nanoceria. Our data showed a significant (P<0.05) increase in the internalization of nanoceria in a concentration-dependent (10-100 µg/mL) manner in THP-1 cells. Although no cytotoxicity was observed at these concentrations, nanoceria significantly (P<0.05) reduced the amount of reactive oxygen species. This was evident by a significant (P<0.05) decrease in the 2,7-dichlorofluorescein diacetate fluorescence observed in flow cytometry and fluorescence microscopy. The present study shows that nanoceria have therapeutic potential in diseases such as cancer.

Regulating Near-Infrared Photodynamic Properties of Semiconducting Polymer Nanotheranostics for Optimized Cancer Therapy.

Development of optical nanotheranostics for the capability of photodynamic therapy (PDT) provides opportunities for advanced cancer therapy. However, most nanotheranostic systems fail to regulate their generation levels of reactive oxygen species (ROS) according to the disease microenvironment, which can potentially limit their therapeutic selectivity and increase the risk of damage to normal tissues. We herein report the development of hybrid semiconducting polymer nanoparticles (SPNs) with self-regulated near-infrared (NIR) photodynamic properties for optimized cancer therapy. The SPNs comprise a binary component nanostructure: a NIR-absorbing semiconducting polymer acts as the NIR fluorescent PDT agent, while nanoceria serves as the smart intraparticle regular to decrease and increase ROS generation at physiologically neutral and pathologically acidic environments, respectively. As compared with nondoped SPNs, the NIR fluorescence imaging ability of nanoceria-doped SPNs is similar due to the optically inactive nature of nanoceria; however, the self-regulated photodynamic properties of nanoceria-doped SPN not only result in dramatically reduced nonspecific damage to normal tissue under NIR laser irradiation but also lead to significantly enhanced photodynamic efficacy for cancer therapy in a murine mouse model. This study thus provides a simple yet effective hybrid approach to modulate the phototherapeutic performance of organic photosensitizers.