Harnessing nanoparticles to improve toxicity after head and neck radiation

doi:10.1016/j.nano.2011.12.011

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 8, Issue 7, October 2012, Pages 1223-1231

https://doi.org/10.1016/j.nano.2011.12.011 Get rights and content

Abstract

This article reports the evaluation of cerium oxide (CeO₂) nanoparticles' ability to decrease xerostomia and radiation-induced dermatitis in mice after head and neck radiation. Mice were irradiated using an IC160 x-ray system. Two cohorts were included: (A) No-radiation and (B) 30 Gy/6 fractions, and were randomized into three groups: (1) saline, (2) 15 nM CeO₂ and (3) 15 μM CeO₂. Stimulated salivary flow and radiation-induced dermatitis were evaluated post radiation. Stimulated sialometry demonstrated improved salivary production in all CeO₂ groups in comparison with controls (flow: 204 vs. 115 μL/10 minutes, P = 0.0002). One week post radiation, G-III dermatitis decreased in the 15 μM group in comparison with controls (10% versus 100% incidence, respectively). There was decreased skin hyperpigmentation at 12 weeks in the 15-μM group in comparison with 15-nM and non-CeO₂ groups (50%, 70%, and 90% G-II, respectively). This study suggests that CeO₂ may be radioprotective for salivary production and reduces G-III dermatitis and skin hyperpigmentation incidence. CeO₂ as radioprotectant may be a feasible concept during radiotherapy.

From the Clinical Editor

This study demonstrates in a mouse model that cerium oxide (CeO₂) nanoparticles may provide an important mechanism in preventing radiation induced xerostomia, a common complication of head and neck radiation treatments.

Graphical Abstract

Radiation effects in the absence and presence of CeO2. Figure A: Sialometry 6 weeks after radiation suggests a dose-dependent decrease in salivary function. Figure B: Effects of CeO2 on salivary protection after radiation exposure. Results demonstrate a difference in saliva production between radiation-only controls and mice receiving radiation plus CeO2. Figure C: Effects of nanoceria on skin hyperpigmentation. Mice treated with 15 nM CeO2 nanoparticles (NPs) demonstrated a lower incidence of Grade II (33.33%) and a higher incidence of Grade I (66.67%) hyperpigmentation. Mice treated with 15 µM CeO2 NPs had an equal incidence of Grade I and II hyperpigmentation.

Section snippets

CeO₂ NPs synthesis and characterization

The CeO₂ NPs were synthesized using a microemulsion process as previously described.13, 25 Synthesized CeO₂ was examined by high-resolution transmission electron microscopy (HRTEM) and dynamic light scattering (DLS) to determine individual particle and agglomerate size.¹³ The physiochemical properties of the synthesized NPs are illustrated in Figure 1.

Animals

Female athymic nude mice (NCI-nu) were purchased from the Animal Production Area of the National Cancer Institute Frederick Cancer Research and

Validation of a radiation-induced xerostomia model

Athymic nude mice were exposed to different doses of single-fraction radiation (12.5 Gy, 15 Gy, 17.5 Gy, or 20 Gy) and sialometry analysis was performed (Figure 2). Our results indicate a dose-dependent decrease in salivary function, which is consistent with clinical observations reported on human patients undergoing radiotherapy to the head and neck (Figure 2).1, 2, 4. We observed the greatest decrease in stimulated salivary flow after 15 Gy – 17.5 Gy of single-fraction radiation. To simulate

Discussion

Radiation-induced xerostomia, dermatitis, fibrosis, and mucositis are common and often severe complications of radiotherapy for head and neck cancer.1, 3, 6 One strategy to reduce normal tissue toxicity in this population of patients is the use of radiation protectors. The development of agents that can be employed to protect normal cells from the pernicious effects of radiation has been an active area of study since the 1950s. In an effort to combat these effects, several free-radical

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A review on biomedical and dental applications of cerium oxide nanoparticles ― Unearthing the potential of this rare earth metal
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Nanotechnology deals with particles ranging from 1 to 100 nm in size called as nanoparticles. These nano particles exhibit unique properties which find an application in many industries and medical fields. A growing body of evidence points out the newer developing technologies adopted in the field of medicine in terms of target therapies, imaging systems, drug deliveries, etc. is through the incorporation of nanoparticles. Cerium oxide nanoparticles have gained attention in the last decade due to exceptional properties such as redox activity, biofilm inhibition, antibacterial activity, anti-inflammatory activity, etc. The method of synthesis of cerium oxide nanoparticles plays a pivotal role in its application. It exhibits redox properties and catalytic activity and thus has found its use in biomedical applications. Nanoparticles are incorporated into dental materials such as restorative cements/sealants, adhesives, and denture systems to improve their properties. Among the various metal oxide nanoparticles, cerium oxide nanoparticles (CeO₂NPs) are known to exhibit lower toxicity to mammalian cells and possess unique antibacterial mechanism. In addition, they exhibit potent properties such as antitumor, anti-inflammatory, antibacterial activities, and functions as an immunosensor. CeO₂NPs have excellent scavenging properties for reactive oxygen species, which is why they are being considered for therapeutic purposes. In this review, various methods of synthesis of CeO₂NPs are discussed. Several factors that determine the particle size and morphology of these materials are important for biomedical and dental applications. Emphasis is given to preparation methods and variables such as calcination temperature, which have a profound effect on particle size and morphology. This article also presents various applications of CeO₂NPs in the biomedical and dental fields.
The characterization of purified citrate-coated cerium oxide nanoparticles prepared via hydrothermal synthesis
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Citation Excerpt :
Interest has recently sparked for nanoceria use in biomedical applications [14],[15]. The therapeutic potential of nanoceria includes treating/addressing cancer [16],[17], radiation-induced damage [18],[19], cardiac dysfunction [20],[21], neurodegenerative diseases [22],[23], retinal degeneration [24],[25], and wounds [26] to name a few. For nanoceria particles to be effective in biomedical applications, small size with little variance, and high colloidal stability are instrumental for positive, meaningful outcomes.
Cerium oxide nanoparticles were synthesized using a hydrothermal approach with citric acid as a stabilizing agent. Citric acid adsorption onto the nanoceria particle surface can cease particle formation and create a stable dispersion for an extended shelf life. The product was dialyzed immediately following the synthesis to remove unreacted cerium that could contribute to biological effects. Nanoparticle characterization results are expected to help identify the surface citrate bonding structure.
Many characterization techniques were utilized to determine size, morphology, surface properties, and citrate complexation on the nanoceria particle surface. These included transmission electron microscopy, electron energy loss spectroscopy, dynamic light scattering, x-ray diffraction, thermogravimetric analysis, Fourier-transform infrared spectroscopy, Raman spectroscopy, UV–Vis absorption spectroscopy, zeta potential, and ¹³C solid-state nuclear magnetic resonance spectroscopy.
Primary particles were hexagonal, determined to be 4.2 nm in diameter. The hydrodynamic diameter of the dialyzed product was 10.8 nm. Each agglomerate was estimated to contain an average of 5.7 particles. The citrate coating contained 2.8 citrate molecules/nm², corresponding to an approximate citrate monolayer. Citrate complexation with the nanoceria surface includes the central carboxyl geminal to the hydroxyl and perhaps one of its terminal carboxyl groups.
An overview on recent in vivo biological application of cerium oxide nanoparticles
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However, the recent use of nanomaterials alone or in combination with traditional radio-protectants has overcome these problems as a higher in vivo cytoprotection was observed compared to the traditional radio-protectants [96]. Some in vitro reports have demonstrated the efficacy of CNPs to protect biological tissues against radiation-induced damage [102–106]. In addition, the in vivo application of CNPs for radiation-induced pneumonitis and lung injury have been reported by few earlier studies [107–109].
Cerium oxide nanoparticles (CNPs) possess a great potential as therapeutic agents due to their ability to self-regenerate by reversibly switching between two valences +3 and +4. This article reviews recent articles dealing with in vivo studies of CNPs towards Alzheimer's disease, obesity, liver inflammation, cancer, sepsis, amyotrophic lateral sclerosis, acute kidney injury, radiation-induced tissue damage, hepatic ischemia reperfusion injury, retinal diseases and constipation. In vivo anti-cancer studies revealed the effectiveness of CNPs to reduce tumor growth and angiogenesis in melanoma, ovarian, breast and retinoblastoma cancer cell-induced mice, with their conjugation with folic acid, doxorubicin, CPM, or CXC receptor-4 antagonist ligand eliciting higher efficiency. After conjugation with triphenylphosphonium or magnetite nanoparticles, CNPs were shown to combat Alzheimer's disease by reducing amyloid-β, glial fibrillary acidic protein, inflammatory and oxidative stress markers in mice. By improving muscle function and longevity, the citrate/EDTA-stabilized CNPs could ameliorate amyotrophic lateral sclerosis. Also, they could effectively reduce obesity in mice by scavenging ROS and reducing adipogenesis, triglyceride synthesis, GAPDH enzyme activity, leptin and insulin levels. In CCl₄-induced rats, stress signaling pathways due to inflammatory cytokines, liver enzymes, oxidative and endoplasmic reticulum messengers could be attenuated by CNPs. Commercial CNPs showed protective effects on rats with hepatic ischemia reperfusion and peritonitis-induced hepatic/cardiac injuries by decreasing oxidative stress and hepatic/cardiac inflammation. The same CNPs could improve kidney function by diminishing renal superoxide, hyperglycemia and tubular damage in peritonitis-induced acute kidney injury in rats. Radiation-induced lung and testicular tissue damage could be alleviated in mice, with the former showing improvement in pulmonary distress and bronchoconstriction and the latter exhibiting restoration in spermatogenesis rate and spermatid/spermatocyte number. Through enhancement of gastrointestinal motility, the CNPs could alleviate constipation in both young and old rats. They could also protect rat from light-induced retinal damage by slowing down neurodegenerative process and microglial activation.
Simulated biological fluid exposure changes nanoceria's surface properties but not its biological response
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Nanoscale cerium dioxide (nanoceria) has industrial applications, capitalizing on its catalytic, abrasive, and energy storage properties. It auto-catalytically cycles between Ce³⁺ and Ce⁴⁺, giving it pro-and anti-oxidative properties. The latter mediates beneficial effects in models of diseases that have oxidative stress/inflammation components. Engineered nanoparticles become coated after body fluid exposure, creating a corona, which can greatly influence their fate and effects. Very little has been reported about nanoceria surface changes and biological effects after pulmonary or gastrointestinal fluid exposure. The study objective was to address the hypothesis that simulated biological fluid (SBF) exposure changes nanoceria’s surface properties and biological activity. This was investigated by measuring the physicochemical properties of nanoceria with a citric acid coating (size; morphology; crystal structure; surface elemental composition, charge, and functional groups; and weight) before and after exposure to simulated lung, gastric, and intestinal fluids. SBF-exposed nanoceria biological effect was assessed as A549 or Caco-2 cell resazurin metabolism and mitochondrial oxygen consumption rate. SBF exposure resulted in loss or overcoating of nanoceria’s surface citrate, greater nanoceria agglomeration, deposition of some SBF components on nanoceria’s surface, and small changes in its zeta potential. The engineered nanoceria and SBF-exposed nanoceria produced no statistically significant changes in cell viability or cellular oxygen consumption rates.
Biodistribution and PET imaging of 89-zirconium labeled cerium oxide nanoparticles synthesized with several surface coatings
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Cerium oxide nanoparticles (CONPs) have unique surface chemistry allowing catalyst-like antioxidant properties, and are being investigated for several disease indications in medicine. Studies have utilized surface modified CONPs toward this application, but have been lacking in comprehensive biodistribution and pharmacokinetic data and a direct comparison to uncoated CONPs. We developed an enhanced single-pot synthesis of several coated CONPs and an efficient intrinsic core labeling of CONPs with the clinical PET isotope, zirconium-89, allowing detailed PET imaging and ex vivo biodistribution. All coated [⁸⁹Zr]-CONPs showed benefit in terms of biodistribution compared to uncoated [⁸⁹Zr]-CONPs, while retaining the intrinsic antioxidant properties. Among these, poly(acrylic acid) coated CONPs demonstrated excellent candidacy for clinical implementation due to their enhanced renal clearance and low reticuloendothelial system uptake. This work also demonstrates the value of intrinsic core labeling and PET imaging for evaluation of nanoparticle constructs to better inform future studies towards clinical use.
Protection effect of cerium oxide nanoparticles against radiation-induced acute lung injuries in rats
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Citation Excerpt :
They used 15 nM CNP, 15 and 18 Gy whole-thorax radiation and they compared CNP with their Amifostine group and found out that CNP decreased fibrosis and collagen deposition in comparison with the radiation and Amifostine group.22 In another study by Madero et al., 2012, H&E staining in irradiated head and neck region cells also showed the preservation of cells in comparison with the radiation alone group which had a vast lymphocyte and macrophage invasion and morphological damage.26 Our experimental design including the radiation dose, molarity, and size of CNP, was somewhat similar to the above-mentioned studies.
Radiation therapy is one of the most common tools for treating cancer. The aim is to deliver adequate doses of radiation to kill cancer cells and the most challenging part during this procedure is to protect normal cells from radiation. One strategy is to use a radioprotector to spare normal tissues from ionizing radiation effects. Researchers have pursued cerium oxide nanoparticles as a therapeutic agent, due to its diverse characteristics, which include antioxidant properties, making it a potential radioprotector.
One hundred rats were divided into five groups of A) control group, intraperitoneal (IP) saline injection was done twice a week; B) bi-weekly IP injection of 14.5 nM (0.00001 mg/kg) CNP for two weeks; C) a single whole thorax radiation dose of 18 Gy; D) a single whole thorax radiation dose of 18 Gy + bi-weekly injection of 14.5 nM CNP for two weeks after radiation; E) bi-weekly IP injection of 14.5 nM CNP for two weeks prior to radiation + a single whole thorax radiation dose of 18 Gy. Thirty days after irradiation, 7 rats from each group were anesthetized and their lungs extracted for histopathological examination.
Statistical analyses revealed that CNP significantly decreased the incidence of tissue collapse and neutrophile aggregation in rats receiving CNP before radiation in comparison with the radiation group.
The results suggested the possibility of using CNP as a future radioprotector due to its ability to protect normal cells against radiation-induced damage.

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: The authors report no conflicts of interest in the conduct of this research. Partial support from the NSF CBET 1007495 grant (to Seal) to carry out the design and synthesis of nanoparticles is acknowledged.

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Research ArticleHarnessing nanoparticles to improve toxicity after head and neck radiation

Abstract

From the Clinical Editor

Graphical Abstract

Section snippets

CeO2 NPs synthesis and characterization

Animals

Validation of a radiation-induced xerostomia model

Discussion

Int J Radiat Oncol Biol, Phys

Intern J Radiat Oncol, Biol, Phys

Int J Radiat Oncol Biol Phys

Eur J Cancer

Radiother Oncol

Nanomedicine