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Environmental Science & Technology Sep 2022The ozonolysis of alkenes contributes substantially to the formation of secondary organic aerosol (SOA), which are important modulators of air quality and the Earth's...
The ozonolysis of alkenes contributes substantially to the formation of secondary organic aerosol (SOA), which are important modulators of air quality and the Earth's climate. Criegee intermediates (CIs) are abundantly formed through this reaction. However, their contributions to aerosol particle chemistry remain highly uncertain. In this work, we present the first application of a novel methodology, using spin traps, which simultaneously quantifies CIs produced from the ozonolysis of volatile organic compounds in the gas and particle phases. Only the smallest CI with one carbon atom was detected in the gas phase of a β-caryophyllene ozonolysis reaction system. However, multiple particle-bound CIs were observed in β-caryophyllene SOA. The concentration of the most abundant CI isomer in the particle phase was estimated to constitute ∼0.013% of the SOA mass under atmospherically relevant conditions. We also demonstrate that the lifetime of CIs in highly viscous SOA particles is at least on the order of minutes, substantially greater than their gas-phase lifetime. The confirmation of substantial concentrations of large CIs with elongated lifetimes in SOA raises new questions regarding their influence on the chemical evolution of viscous SOA particles, where CIs may be a previously underestimated source of reactive species.
Topics: Aerosols; Alkenes; Carbon; Ozone; Polycyclic Sesquiterpenes; Volatile Organic Compounds
PubMed: 36054832
DOI: 10.1021/acs.est.2c04101 -
Food & Function Apr 2021In this study, β-carotene loaded oil-in-water emulsions were stabilized by complex interfaces composed of propylene glycol alginate (PGA), rhamnolipids (Rha), and zein...
In this study, β-carotene loaded oil-in-water emulsions were stabilized by complex interfaces composed of propylene glycol alginate (PGA), rhamnolipids (Rha), and zein colloidal particles (ZCPs). The influence of mixed biopolymer-surfactant, biopolymer-particle, surfactant-particle and biopolymer-surfactant-particle interfaces on the performance of the emulsions was investigated. The stability, microstructure, rheological properties, and in vitro gastrointestinal digestion of the emulsions were controlled by regulating the adding sequence and mass ratio of the multiple stabilizers. The droplet size of the emulsion was in the range of 14-77 μm. After encapsulation into the emulsions stabilized by the complex interfaces, the photothermal stability of β-carotene were increased by 41.53% and 21.52%, respectively. The co-existence of particles, biopolymers, and surfactants could induce competitive displacement, multilayer deposition and an interparticle network at the interface. Compared with a single PGA- or Rha-stabilized emulsion, the complex interface-stabilized emulsion reduced the release of FFA by 28.06% and 26.16%, respectively. The interfacial composition of the emulsion and the delayed lipid digestion further affected the bioaccessibility of β-carotene in the gastrointestinal tract (GIT). The mixed biopolymer-particle-surfactant interface-stabilized emulsion could be incorporated in foods, pharmaceuticals and cosmetics for excellent stability, targeted nutrient delivery and controlled lipolysis.
Topics: Biological Availability; Biopolymers; Digestion; Drug Stability; Elasticity; Emulsions; Gastrointestinal Tract; Microscopy, Electron, Scanning; Particle Size; Pepsin A; Surface-Active Agents; Viscosity; Zein; beta Carotene
PubMed: 33877248
DOI: 10.1039/d0fo02975k -
Frontiers in Bioengineering and... 2020Substrate surface characteristics such as roughness, wettability and particle density are well-known contributors of a substrate's overall osteogenic potential. These...
Substrate surface characteristics such as roughness, wettability and particle density are well-known contributors of a substrate's overall osteogenic potential. These characteristics are known to regulate cell mechanics as well as induce changes in cell stiffness, cell adhesions, and cytoskeletal structure. Pro-osteogenic particles, such as hydroxyapatite, are often incorporated into a substrate to enhance the substrates osteogenic potential. However, it is unknown which substrate characteristic is the key regulator of osteogenesis. This is partly due to the lack of understanding of how these substrate surface characteristics are transduced by cells. In this study substrates composed of polycaprolactone (PCL) and carbonated hydroxyapatite particles (HAp) were synthesized. HAp concentration was varied, and a range of surface characteristics created. The effect of each substrate characteristic on osteoblastic differentiation was then examined. We found that, of the characteristics examined, only HAp density, and indeed a specific density (85 particles/cm), significantly increased osteoblastic differentiation. Further, an increase in focal adhesion maturation and turnover was observed in cells cultured on this substrate. Moreover, β-catenin translocation from the membrane bound cell fraction to the nucleus was more rapid in cells on the 85 particle/cm substrate compared to cells on tissue culture polystyrene. Together, these data suggest that particle density is one pivotal factor in determining a substrates overall osteogenic potential. Additionally, the observed increase in osteoblastic differentiation is a at least partly the result of β-catenin translocation and transcriptional activity suggesting a β-catenin mediated mechanism by which substrate surface characteristics are transduced.
PubMed: 33490047
DOI: 10.3389/fbioe.2020.591084 -
Environment International Jun 2020Although ionizing radiation is known to have detrimental effects on red blood cells, the effect of environmental radioactivity associated with ambient particulate matter...
Although ionizing radiation is known to have detrimental effects on red blood cells, the effect of environmental radioactivity associated with ambient particulate matter (PM) is unknown. We hypothesized that exposure to ambient PM-associated beta particle radioactivity (PR) would be associated with a lower hemoglobin concentration. We studied 1.704 participants from the Normative Aging Study (NAS) over 36 years (1981-2017) who lived in Eastern, MA and the surrounding area. Exposures to PR was assessed using USEPA's RadNet monitoring network that measures gross beta radiation associated with ambient PM. Mixed effect models with a random intercept adjusting for potential confounders was used, including ambient black carbon (BC) and particulate matter ≤2.5 μm (PM) concentrations. Greater cumulative PR activities at 7-, 14-, 21- and 28-days before the hemoglobin determination were associated with lower hemoglobin concentrations. The greatest effect was for a 28-day moving average. An IQR of 0.83 × 10 Bq/m of ambient PR was associated with a 0.12 g/dL decrease in hemoglobin concentration (95%CI: -0.18 to -0.05). The effects of PR were similar when the models were adjusted for ambient BC or PM. This is the first study to demonstrate an association between environmental ionizing radiation released from particulate matter with a lower hemoglobin concentration, suggesting that ambient radiation may contribute to the development of anemia.
Topics: Aged; Air Pollutants; Air Pollution; Beta Particles; Environmental Exposure; Hemoglobins; Humans; Male; Particle Size; Particulate Matter; Radioactivity
PubMed: 32304940
DOI: 10.1016/j.envint.2020.105735 -
World Journal of Nuclear Medicine 2021Neuroendocrine neoplasms (NENs) are a very diverse group of tumors with a worldwide rise in incidence. Systemic therapy remains the mainstay treatment for unresectable... (Review)
Review
Neuroendocrine neoplasms (NENs) are a very diverse group of tumors with a worldwide rise in incidence. Systemic therapy remains the mainstay treatment for unresectable and/or metastatic NENs. Lu-DOTATATE, a radiopharmaceutical which emits beta particles, has emerged as a promising therapy for metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, limited treatment options are available particularly after the failure of Lu-DOTATATE therapy. This review aims to identify and summarize the available evidence for, and potential adverse events of, targeted alpha-particle therapy (TAT) in the treatment of metastatic NENs, specifically GEP-NENs. The MEDLINE, EMBASE, SCOPUS, and Cochrane Library databases were searched. Two articles which met the inclusion criteria were identified and included in the review. Putative radiopharmaceuticals that can be considered for metastatic NEN treatment include Actinium (Ac)-DOTATATE and Bismuth (Bi)-DOTATOC. There was evidence of partial response using both radiopharmaceutical agents without significant hematological, renal, or hepatotoxicity. Future studies should consider longer term, randomized controlled trials investigating the role of TAT, in particular, Ac-DOTATATE, in the treatment of metastatic NENs.
PubMed: 35018146
DOI: 10.4103/wjnm.wjnm_160_20 -
Clinical Cancer Research : An Official... Apr 2021Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus,...
PURPOSE
Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA ().
EXPERIMENTAL DESIGN
LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and _Hi- transgenic mice were imaged with Zr- or treated with Y- or Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [Ac]hu5A10 and [Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [Zr]hu5A10 in nonhuman primates (NHP) were determined using PET.
RESULTS
Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [Y]/[Ac]hu5A10 effectively reduced tumor burden and prolonged survival ( ≤ 0.0054). Effects of [Y]hu5A10 were more immediate than [Ac]hu5A10 (TTN, < 0.0001) but less sustained (TTP, < 0.0001). Complete responses were observed in 7 of 18 [Ac]hu5A10 and 1 of 9 mice [Y]hu5A10. Pharmacokinetics of [Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period.
CONCLUSIONS
We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.
Topics: Alpha Particles; Animals; Beta Particles; Disease Models, Animal; Electrons; Linear Energy Transfer; Macaca fascicularis; Male; Mice; Mice, Inbred BALB C; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Radioimmunotherapy; Receptors, Androgen; Tissue Distribution
PubMed: 33441295
DOI: 10.1158/1078-0432.CCR-20-3614 -
Current Medicinal Chemistry 2020Receptor-targeted image-guided Radionuclide Therapy (TRT) is increasingly recognized as a promising approach to cancer treatment. In particular, the potential for... (Review)
Review
Receptor-targeted image-guided Radionuclide Therapy (TRT) is increasingly recognized as a promising approach to cancer treatment. In particular, the potential for clinical translation of receptor-targeted alpha-particle therapy is receiving considerable attention as an approach that can improve outcomes for cancer patients. Higher Linear-energy Transfer (LET) of alpha-particles (compared to beta particles) for this purpose results in an increased incidence of double-strand DNA breaks and improved-localized cancer-cell damage. Recent clinical studies provide compelling evidence that alpha-TRT has the potential to deliver a significantly more potent anti-cancer effect compared with beta-TRT. Generator-produced 212Pb (which decays to alpha emitters 212Bi and 212Po) is a particularly promising radionuclide for receptor-targeted alpha-particle therapy. A second attractive feature that distinguishes 212Pb alpha-TRT from other available radionuclides is the possibility to employ elementallymatched isotope 203Pb as an imaging surrogate in place of the therapeutic radionuclide. As direct non-invasive measurement of alpha-particle emissions cannot be conducted using current medical scanner technology, the imaging surrogate allows for a pharmacologically-inactive determination of the pharmacokinetics and biodistribution of TRT candidate ligands in advance of treatment. Thus, elementally-matched 203Pb labeled radiopharmaceuticals can be used to identify patients who may benefit from 212Pb alpha-TRT and apply appropriate dosimetry and treatment planning in advance of the therapy. In this review, we provide a brief history on the use of these isotopes for cancer therapy; describe the decay and chemical characteristics of 203/212Pb for their use in cancer theranostics and methodologies applied for production and purification of these isotopes for radiopharmaceutical production. In addition, a medical physics and dosimetry perspective is provided that highlights the potential of 212Pb for alpha-TRT and the expected safety for 203Pb surrogate imaging. Recent and current preclinical and clinical studies are presented. The sum of the findings herein and observations presented provide evidence that the 203Pb/212Pb theranostic pair has a promising future for use in radiopharmaceutical theranostic therapies for cancer.
Topics: Bismuth; Humans; Lead Radioisotopes; Neoplasms; Precision Medicine; Radioisotopes; Radiopharmaceuticals; Tissue Distribution
PubMed: 32720598
DOI: 10.2174/0929867327999200727190423 -
Journal of Agricultural and Food... Feb 2021Novel Pickering emulsions were stabilized by complex interfaces in the presence of zein colloidal particles (ZCPs), propylene glycol alginate (PGA), and rhamnolipid...
Novel Pickering emulsions were stabilized by complex interfaces in the presence of zein colloidal particles (ZCPs), propylene glycol alginate (PGA), and rhamnolipid (Rha) for delivery of β-carotene. The influence of the particle-surfactant, particle-biopolymer, and particle-biopolymer-surfactant mixed interfaces on the physiochemical properties and digestion fate of Pickering emulsions was investigated. It is the first time that three different types of emulsifiers have been used to synergistically stabilize food Pickering emulsions for delivery of lipophilic nutraceuticals. The physicochemical stability, microstructure, rheological properties, and gastrointestinal digestion of Pickering emulsions were controlled by the addition sequence and mass ratio of multiple stabilizers, which showed the enhanced stability and delayed lipid digestion of the particle-biopolymer-surfactant-stabilized Pickering emulsions. After encapsulation into Pickering emulsions, the retention rate of β-carotene increased 2-fold under UV radiation for 8 h. The coexistence of ZCPs, PGA, and Rha could induce the competitive displacement, multilayer deposition, and interparticle network at the interface. The combination of particles, a biopolymer, and a surfactant delayed the lipolysis during gastrointestinal tract. By modulating the interfacial composition, the release rate of free fatty acids from Pickering emulsions was reduced from 19.46% to 2.83% through different mechanisms. The novel Pickering emulsion could be incorporated in foods as well as pharmaceuticals for controlled lipid digestion or targeted nutrient delivery purposes.
Topics: Alginates; Biopolymers; Digestion; Drug Compounding; Drug Stability; Emulsions; Gastrointestinal Tract; Humans; Particle Size; Rheology; Surface-Active Agents; Zein; beta Carotene
PubMed: 33512160
DOI: 10.1021/acs.jafc.0c06409 -
Molecules (Basel, Switzerland) Aug 2023Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(β)-particle-emitting radiopharmaceuticals is a new treatment paradigm for...
Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(β)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have been used strategically to enhance the tumor uptake and retention of existing PSMA-based investigational agents. Previously, we developed a series of PSMA-based, β-particle-emitting, low-molecular-weight compounds. From this series, Lu-L1 was selected as the lead agent because of its reduced off-target radiotoxicity in preclinical studies. The ligand L1 contains a PSMA-targeting Lys-Glu urea moiety with an N-bromobenzyl substituent in the ε-amino group of Lys. Here, we structurally modified Lu-L1 to improve tumor targeting using two known albumin-binding moieties, 4-(-iodophenyl) butyric acid moiety (IPBA) and ibuprofen (IBU), and evaluated the effects of linker length and composition. Six structurally related PSMA-targeting ligands (Alb-L1-Alb-L6) were synthesized based on the structure of Lu-L1. The ligands were assessed for in vitro binding affinity and were radiolabeled with Lu following standard protocols. All Lu-labeled analogs were studied in cell uptake and selected cell efficacy studies. In vivo pharmacokinetics were investigated by conducting tissue biodistribution studies for Lu-Alb-L2-Lu-Alb-L6 (2 h, 24 h, 72 h, and 192 h) in male NSG mice bearing human PSMA+ PC3 PIP and PSMA- PC3 flu xenografts. Preliminary therapeutic ratios of the agents were estimated from the area under the curve (AUC) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (s) of the ligands were in the ≤10 nM range. The long-linker-based agents, Lu-Alb-L4 and Lu-Alb-L5, displayed significantly higher tumor uptake and retention ( < 0.001) than the short-linker-bearing Lu-Alb-L2 and Lu-Alb-L3 and a long polyethylene glycol (PEG) linker-bearing agent, Lu-Alb-L6. The area under the curve (AUC) of the PSMA+ PC3 PIP tumor uptake of Lu-Alb-L4 and Lu-Alb-L5 were >4-fold higher than Lu-Alb-L2, Lu-Alb-L3, and Lu-Alb-L6, respectively. Also, the PSMA+ PIP tumor uptake (AUC) of Lu-Alb-L2 and Lu-Alb-L3 was ~1.5-fold higher than Lu-Alb-L6. However, the lowest blood AUC and kidney AUC were associated with Lu-Alb-L6 from the series. Consequently, Lu-Alb-L6 displayed the highest ratios of AUC(tumor)-to-AUC(blood) and AUC(tumor)-to-AUC(kidney) values from the series. Among the other agents, Lu-Alb-L4 demonstrated a nearly similar ratio of AUC(tumor)-to-AUC(blood) as Lu-Alb-L6. The tumor-to-blood ratio was the dose-limiting therapeutic ratio for all of the compounds. Conclusions: Lu-Alb-L4 and Lu-Alb-L6 showed high tumor uptake in PSMA+ tumors and tumor-to-blood ratios. The data suggest that linker length and composition can be modulated to generate an optimized therapeutic agent.
Topics: Humans; Male; Animals; Mice; Ligands; Tissue Distribution; Albumins; Beta Particles; Butyric Acid
PubMed: 37630410
DOI: 10.3390/molecules28166158 -
Frontiers in Immunology 2022Allergic respiratory diseases have increased dramatically due to air pollution over the past few decades. However, studies are limited on the effects of inorganic...
BACKGROUND
Allergic respiratory diseases have increased dramatically due to air pollution over the past few decades. However, studies are limited on the effects of inorganic components and particulate matter with different particle sizes in smog on allergic diseases, and the possible molecular mechanism of inducing allergies has not been thoroughly studied.
METHODS
Four common mineral elements with different particle sizes in smog particles were selected, including AlO, TiO, FeO, and SiO. We studied the relationship and molecular mechanism of smog particle composition, particle size, and allergic reactions using mast cells, immunoglobulin E (IgE)-mediated passive cutaneous anaphylaxis (PCA) model, and an ovalbumin (OVA)-induced asthmatic mouse model and , combined with transmission electron microscopy, scanning transmission X-ray microscopy analysis, and transcriptome sequencing.
RESULTS
Only 20 nm SiO particles significantly increased β-hexosaminidase release, based on dinitrophenol (DNP)-human serum albumin (HSA) stimulation, from IgE-sensitized mast cells, while other particles did not. Meanwhile, the PCA model showed that Evan's blue extravasation in mice was increased after treatment with nano-SiO particles. Nano-SiO particles exposure in the asthmatic mouse model caused an enhancement of allergic airway inflammation as manifested by OVA-specific serum IgE, airway hyperresponsiveness, lung inflammation injury, mucous cell metaplasia, cytokine expression, mast cell activation, and histamine secretion, which were significantly increased. Nano-SiO particles exposure did not affect the expression of FcϵRI or the ability of mast cells to bind IgE but synergistically activated mast cells by enhancing the mitogen-activated protein kinase (MAPK) signaling pathway, especially the phosphorylation levels of the extracellular signal-regulated kinase (ERK)1/2. The ERK inhibitors showed a significant inhibitory effect in reducing β-hexosaminidase release.
CONCLUSION
Our results indicated that nano-SiO particles stimulation might synergistically activate IgE-sensitized mast cells by enhancing the MAPK signaling pathway and that nano-SiO particles exposure could exacerbate allergic inflammation. Our experimental results provide useful information for preventing and treating allergic diseases.
Topics: Animals; Asthma; Disease Models, Animal; Humans; Hypersensitivity; Immunoglobulin E; Inflammation; Lung Injury; Mast Cells; Mice; Mitogen-Activated Protein Kinases; Silicon Dioxide; Smog; beta-N-Acetylhexosaminidases
PubMed: 35936002
DOI: 10.3389/fimmu.2022.911300