Nanoparticles In Organs Research Articles

BIOGENIC AND ANTHROPOGENIC MAGNETIC NANOPARTICLES IN THE PHLOEM SIEVE TUBES OF PLANTS

The samples of leaves and roots of Nicotiana tabacum, the stems and tubers of Solanum tuberosum and the stems of pea Pisum sativum were examined by scanning probe microscopy in atomic force and magnetic force modes after cultivation without and with addition of magnetite nanoparticles in soil. Chains of both biogenic and anthropogenic magnetic nanoparticles are detected in the wall of the phloem sieve tubes i.e., the vascular tissue of plants. Such a localization of biogenic magnetic nanoparticles supports the idea that the chains of magnetic nanoparticles in different organs of plants have common metabolic functions. Stray gradient magnetic fields about several thousand Oe, which are created by chains of both biogenic and anthropogenic magnetic nanoparticles, can significantly affect the metabolic processes through the influence on mass transfer of vesicles, granules, organelles and other components. In view of the results of this investigation, both BMNs and anthropogenic magnetite nanoparticles chains can significantly affect the processes of mass transfer of vesicles, organelles, structural elements of the membrane and others components because they create stray magnetic fields and gradient magnetic forces.

Revealing the In Situ Behavior of Aggregation-Induced Emission Nanoparticles and Their Biometabolic Effects via Mass Spectrometry Imaging.

Simultaneous imaging of exogenous nanomaterials and endogenous metabolites in situ remains challenging and is beneficial for a systemic understanding of the biological behavior of nanomaterials at the molecular level. Here, combined with label-free mass spectrometry imaging, visualization and quantification of the aggregation-induced emission nanoparticles (NPs) in tissue were realized as well as related endogenous spatial metabolic changes simultaneously. Our approach enables us to identify the heterogeneous deposition and clearance behavior of nanoparticles in organs. The accumulation of nanoparticles in normal tissues results in distinct endogenous metabolic changes such as oxidative stress as indicated by glutathione depletion. The low passive delivery efficiency of nanoparticles to tumor foci suggested that the enrichment of NPs in tumors did not benefit from the abundant tumor vessels. Moreover, spatial-selective metabolic changes upon NPs mediated photodynamic therapy was identified, which enables understanding of the NPs induced apoptosis in the process of cancer therapy. This strategy allows us to simultaneously detect exogenous nanomaterials and endogenous metabolites in situ, hence to decipher spatial selective metabolic changes in drug delivery and cancer therapy processes.

Effects of Particle Geometry for PLGA-Based Nanoparticles: Preparation and In Vitro/In Vivo Evaluation.

The physicochemical properties (size, shape, zeta potential, porosity, elasticity, etc.) of nanocarriers influence their biological behavior directly, which may result in alterations of the therapeutic outcome. Understanding the effect of shape on the cellular interaction and biodistribution of intravenously injected particles could have fundamental importance for the rational design of drug delivery systems. In the present study, spherical, rod and elliptical disk-shaped PLGA nanoparticles were developed for examining systematically their behavior in vitro and in vivo. An important finding is that the release of the encapsulated human serum albumin (HSA) was significantly higher in spherical particles compared to rod and elliptical disks, indicating that the shape can make a difference. Safety studies showed that the toxicity of PLGA nanoparticles is not shape dependent in the studied concentration range. This study has pioneering findings on comparing spherical, rod and elliptical disk-shaped PLGA nanoparticles in terms of particle size, particle size distribution, colloidal stability, morphology, drug encapsulation, drug release, safety of nanoparticles, cellular uptake and biodistribution. Nude mice bearing non-small cell lung cancer were treated with 3 differently shaped nanoparticles, and the accumulation of nanoparticles in tumor tissue and other organs was not statistically different (p > 0.05). It was found that PLGA nanoparticles with 1.00, 4.0 ± 0.5, 7.5 ± 0.5 aspect ratios did not differ on total tumor accumulation in non-small cell lung cancer.

Bio-distribution of Carbon Nanoparticles Studied by Photoacoustic Measurements

Carbon-based nanomaterials are promising for a wide range of biomedical applications, i.e. drug delivery, therapy, and imaging including photoacoustic tomography, where they can serve as contrast agents, biocompatibility and biodistribution of which should be assessed before clinical setting. In this paper, localization of carbon flurooxide nanoparticles, carbon nanodots from β-alanine, carbon nanodots from urea and citric acid and glucose-ethylenediamine nanoparticles (NPs) in organs of Wistar rats were studied by photoacoustic measurements after 24 h of their intravenous injection. 16 ns light pulse from a Q-switched Nd:YAG laser with 1064 nm wavelength was used as an excitation source. The laser-induced photoacoustic signals were recorded with a ring piezoelectric detector. Light absorption by carbon NPs resulted in noticeable enhancement of the photoacoustic amplitude in the tissues where the NPs were accumulated. The NPs were preferably accumulated in liver, kidneys and spleen, and to a lesser extent in heart and gastrocnemius muscles. Together with remarkable fluorescent properties of the studied carbon nanomaterials, their photoacoustic responses allow their application for bi-modal fluorescence-photoacoustic bio-imaging.

In silico-моделирование в оптимизации алгоритмов фармакокинетических исследований [25MG2+] порфирин-фуллереновых наночастиц

The search for effective pharmacophores to treat ischemic stroke is precipitated by the prevalence and high mortality of the condition. Optimization of preclinical scenarios for promising neuroprotectants by mathematical modeling using up-to-date computational platforms is a well-defined and urgent task. This study aimed to develop a drug-oriented model represented by an ordinary differential equation system to study pharmacokinetics of 25Mg2+-releasing porphyrin-fullerene nanocationite PMC16 in silico using MATLAB and adjust computating model's adequatness using in vivo rat model. The developed five-compartment model predicts the distribution of nanoparticles in organs and tissues (e.g. the brain, the heart and the liver) for the purpose of experimental parameters optimization. The in silico produced pharmacokinetic curves show good agreement with the data obtained using in vivo rat model of ischemic stroke. The in silico and in vivo results indicate that PMC16 nanoparticles effectively cross the blood-brain barrier.

Distributions of mercury and selenium in rats ingesting mercury selenide nanoparticles

Mercury (Hg) is one of the most toxic environmental pollutants, and is biocondensed via the food chain. Selenium (Se) is an essential element that possesses an antagonistic property towards Hg in vivo. The antagonistic property is explained by the assumption that Hg and Se directly interact to form HgSe nanoparticles (HgSe NPs) in organs. It is presumed that the toxic effects of HgSe NPs are lower than that of ionic Hg; however, no precise evaluation has been conducted so far. In the present study, we evaluated the distribution of HgSe NPs ingested in Se-deficient rats. The recovery of serum selenoproteins from a deficient level was not observed in rats orally administered HgSe NPs. In addition, the excretion of Hg and Se via urine was not observed. Interestingly, the biosynthesis of selenoproteins and urinary selenometabolites would have required the production of selenide through the degradation of HgSe NPs. Therefore, it seems that selenide and Hg are not released from HgSe NPs in vivo. The administration of HgSe NPs did not increase Hg and Se concentrations in organs, and almost all HgSe NPs were recovered in feces, indicating no or low bioaccessibility of HgSe NPs even in Se-deficient rats. These results suggest that HgSe NPs are biologically inert and do not become a secondary environmental pollutant of Hg.

Observation of targeted gold nanoparticles in nasopharyngeal tumour nude mice model through dual-energy computed tomography.

This study was performed to specify the efficiency of imaging nanoparticle concentration as contrast media in dual‐energy computed tomography (DECT). Gold nanoparticles (AuNPs) and gold nanoparticles‐conjugated folic acid through cysteamine (FA‐Cya‐AuNPs) were both considered as contrast agents. Characterization of NPs was performed using Dynamic Light Scattering (DLS) and zeta potential. The hemocompatibility of NPs was confirmed by different blood parameters such as white blood cell, red cell distribution width, hemoglobin, lymphocytes counts and haemolysis assay. DECT algorithm was confirmed using calibration phantom at different concentrations of NPs and tube potentials (80 and 140 kVp). Then, DECT was used to quantify the concentration of both AuNPs and FA‐Cys‐AuNPs in human nasopharyngeal cancer cells. Mice were injected with non‐targeted AuNPs and targeted AuNps at a concentration of 3 × 103 μg/ml. Then, they were scanned with different tube potentials. The concentration of nanoparticles in the various organs of nude mice was measured through DECT imaging and inductively coupled plasma mass spectrometry (ICP‐MS) analysis. The results of DECT images were compared with ICP‐MS analysis and indicated that they were approximately similar. In sum, FA‐Cys‐AuNPs can be a proper candidate for targeted contrast media in DECT molecular scanning of human nasopharyngeal tumours.

Evaluation of tissue-clearing techniques for intraorgan imaging of distribution of polymeric nanoparticles as drug carriers

Objective The development of drug delivery systems using nanocarriers requires intraorgan imaging techniques for evaluating the distribution of nanocarriers. In this study, we evaluated the tissue-clearing techniques for the imaging of polymeric nanoparticles, a nanocarrier, in the liver used as a model of pigment-rich organ in mice. Significance The intraorgan imaging method of polymeric nanoparticles was examined without sectioning of organ samples for evaluating the delivery efficiency in preclinical studies. Methods DiI-loaded polymeric nanoparticles and fluorescence-tagged tomato lectin for fluorescence labeling of liver general structures were intravenously administered to mice. Tissue-clearing treatment of the mouse liver was performed using ClearT2, ScaleSQ(0), clearing agent comprising fructose, urea, and glycerol for imaging (FUnGI), clear unobstructed brain/body imaging cocktails and computational analysis (CUBIC), and modified CUBIC techniques. Intraorgan fluorescence imaging in the liver was performed by confocal laser microscopy. Results ClearT2 treatment exhibited insufficient clearing capability in the mouse liver. Although CUBIC treatment exhibited the best clearing capability, the CUBIC caused DiI leakage. ScaleSQ(0), FUnGI, and modified CUBIC treatments exhibited better clearing capability than ClearT2 technique while preserving the DiI. In the fluorescence imaging, the CUBIC and modified CUBIC exhibited deeper visualization than with the ScaleSQ(0) and FUnGI; however, the CUBIC led to a change in DiI distribution. The modified CUBIC enabled the deepest visualization while preserving the distribution of DiI. Conclusion The intraorgan imaging method was established using modified CUBIC technique by the intravenous administration of fluorescence-tagged tomato lectin for evaluating the distribution of polymeric nanoparticles in mouse pigment-rich organs.

Mixed Amphiphilic Polymeric Nanoparticles of Chitosan, Poly(vinyl alcohol) and Poly(methyl methacrylate) for Intranasal Drug Delivery: A Preliminary In Vivo Study.

Intranasal (i.n.) administration became an alternative strategy to bypass the blood–brain barrier and improve drug bioavailability in the brain. The main goal of this work was to preliminarily study the biodistribution of mixed amphiphilic mucoadhesive nanoparticles made of chitosan-g-poly(methyl methacrylate) and poly(vinyl alcohol)-g-poly(methyl methacrylate) and ionotropically crosslinked with sodium tripolyphosphate in the brain after intravenous (i.v.) and i.n. administration to Hsd:ICR mice. After i.v. administration, the highest nanoparticle accumulation was detected in the liver, among other peripheral organs. After i.n. administration of a 10-times smaller nanoparticle dose, the accumulation of the nanoparticles in off-target organs was much lower than after i.v. injection. In particular, the accumulation of the nanoparticles in the liver was 20 times lower than by i.v. When brains were analyzed separately, intravenously administered nanoparticles accumulated mainly in the “top” brain, reaching a maximum after 1 h. Conversely, in i.n. administration, nanoparticles were detected in the “bottom” brain and the head (maximum reached after 2 h) owing to their retention in the nasal mucosa and could serve as a reservoir from which the drug is released and transported to the brain over time. Overall, results indicate that i.n. nanoparticles reach similar brain bioavailability, though with a 10-fold smaller dose, and accumulate in off-target organs to a more limited extent and only after redistribution through the systemic circulation. At the same time, both administration routes seem to lead to differential accumulation in brain regions, and thus, they could be beneficial in the treatment of different medical conditions.

Evaluation of the Biodistribution of Magnetoliposomes in a Tumor and Organs of Mice by Electron Paramagnetic Resonance Spectroscopy

Electron paramagnetic resonance spectroscopy has been applied for the first time to study the bio-distribution of magnetoliposomes formed with magnetite nanoparticles (Fe3O4) in tumors and organs of Lewis carcinoma-bearing mice in the absence and presence of an external magnetic field. The animals of the experimental group were subjected to an external magnetic field (0.6 T) in the tumor area after intravenous injection of magnetoliposomes at a dose of 7.56 Fe/kg. Analysis of the electron-spin resonance spectra of mouse organs and tissue samples showed that exposure to a magnetic field resulted in a two-fold increase in Fe3O4 accumulation within the tumor (p < 0.05) compared to the control; this makes it possible to recommend the obtained magnetoliposomes for use as a magnetically controlled carriers for targeted delivery of antitumor agents. A high concentration of superparamagnetic magnetite nanoparticles was detected in the liver in the absence and presence of an external magnetic field. The differences in the accumulation of Fe3O4 in the lungs and liver in the presence of a magnetic field were statistically insignificant.

Trophoblast-Targeted Nanomedicine Modulates Placental sFLT1 for Preeclampsia Treatment.

The overexpressed soluble fms-like tyrosine kinase 1 (sFLT-1) in placenta is considered to be a potential therapeutic target for preeclampsia (PE). How to achieve efficient intervention of sFLT1 expression in the placenta is an urgent problem to be solved. PEG-PLA nanoparticle generated by double-emulsion methods is a novel siRNA delivery system. Synthetic placental CSA binding peptide (P-CSA-BP) is effective for targeting lipid-polymer nanoparticle to the placenta. We conjugated P-CSA-BP to the surface of PEG-PLA nanoparticle to create a novel placenta specific sFLT1 siRNA delivery system for the therapy of PE. Nanoparticles were synthesized using double emulsion method and characterized by dynamic light scattering and transmission electron microscopy (TEM). RT-PCR was employed to evaluate mRNA level and protein level was analyzed by ELISA kit. The tissue distribution of nanoparticles was observed through ex vivo images. The concentrations of nanoparticles in organs were measured using high-performance liquid chromatography. T-NPsisFLT1 had higher efficiency than NPsisFLT1 in accumulating in HTR-8/SVneo cells and significantly decreased the expression of sFLT1. Intravenously administered T-NPsisFLT1 specifically accumulated in placentas of mice. sFLT1 mRNA level in placenta and protein level in serum were declined by T-NPsisFLT1. T-NPsisFLT1 shown no obvious toxic effect on both mother and fetus. The utility of T-NPsisFLT1 nanoparticles as a sFLT1 siRNA placenta specific delivery system significantly silenced sFLT1 in mice and is safe for both mother and fetus. This nanoparticle is a novel potential therapeutic strategy for PE.

Bio-distribution of Gold Nanoparticles in Tumor Mass and Different Organs in Implanted Mice with Mammary Adenocarcinoma AM3 (in vivo study)

Nanoparticles has many properties, especially in treatment of medical field, but the controversy continues about their cytotoxicity. Hence, this research was conducted to estimate the concentration of gold nanoparticles (GNPs) in tumor and other organs such as kidney, liver, and spleen after injection GNPs by two routes, intratumor and intraperitoneal to compare between two methods in mice implanted with mammary adenocarcinoma for 28 days. Atomic Absorption Spectroscopy was used to measure the GNPs concentrations. The results revealed that the GNPs concentrations were significantly (P≤0.05) increased (3.75±1.75, 2.42 ±0.31 ppm) in kidney tissue after intratumor and intraperitoneal administration, respectively, when compared to the other organs (liver and spleen), followed by tumor mass (2.66±0.01, 1.09 ±0.06 ppm) in tissue. While the concentrations of GNPs in spleen and liver were (1.40 ±0.33, 0.726 ±0.01) and (0.602 ±0.03, 0.517 ±0.02) after intratumor and intraperitoneal administration respectively. Also, the experiment showed that the injection by intratumor was more efficient than intraperitonial method for tumor treatment, so, the nanoparticles were cleared by responsible lymphoid organs of body.

Biodistribution, Clearance And Morphological Alterations Of Intravenously Administered Iron Oxide Nanoparticles In Male Wistar Rats.

IntroductionNanoparticles are used worldwide because of their unique properties, with large-scale application in various fields, such as medicine, cosmetics and industries. In view of their widespread use, the potential adverse effects of nanoparticles have become a significant cause for concern, in terms of not only human health and safety but also the environment. The present investigation focused on establishing the bioaccumulation patterns and ultrastructural changes induced by retained iron oxide nanoparticles (IONPs) in various target organs of rats.MethodsTwenty-four male Wistar rats were randomly divided into four groups. Experimental animals were intravenously administered different doses of IONPs (7.5 mg/kg, 15 mg/kg and 30 mg/kg) once in a week for 4 weeks. Urine and feces samples were collected on a daily basis to assess nanoparticle clearance and analyzed via atomic absorption spectroscopy (AAS). At the end of the experiment, rats were euthanized and different organs, including spleen, liver, kidney, lung, heart, testis and brain, were dissected. Bioaccumulation of iron in organs and ultrastructural changes induced by IONPs were determined.ResultsThe maximal concentration of iron was detected in spleen and minimal concentration in the brain. The level of iron accumulation in organs was as follows: spleen>blood>liver>kidney>lung>heart>testis>brain. The excretion profile in urine revealed maximum excretion on the day following administration that was maintained until day 28, whereas the iron content in feces remained high during the first three days after injection. A similar pattern was observed throughout the duration of the experiment. Ultrastructural alterations were detected in spleen, kidney, lung, heart, testis, brain and liver, indicative of cellular damage induced by accumulating nanoparticles in these organs.ConclusionIntravenous administration of IONPs results in ultrastructural changes and dose-dependent bioaccumulation in different organs of rats.

Transition of Nanoparticles Fе3O4 and Al in a Simplified Aquatic Food Chain

This article presents the results of experiments on the transitions of Fe3O4 nanoparticles (20–30 nm) and Al (18 nm) from one organism to another, making up a simple food chain (plant–mollusk–fish). In experiments, mollusks (Melonopsis praemorsa) feed on the leaves of plant (Elodea canadensis) after being contaminated with Al or Fe3O4 nanoparticles. Nanoparticles were detected using TEM analysis in the cells of the mollusk’s organs. Then the fish (Oncorhynchus mykiss) were fed with mollusks. The distribution and localization of nanoparticles in fish organs has been determined. Experimental results showed that nanoparticles can pass from one organism to another in the food chain. Nanoparticles accumulate mainly in the liver of mollusks and fish.

Elemental imaging using laser-induced breakdown spectroscopy: latest medical applications

Multi-elemental imaging of soft tissues using Laser-induced breakdown spectroscopy, also known as LIBS, allows for the direct visualization of the distribution of endogenous or exogenous elements within tissues. LIBS was used to image the kinetics of metal nanoparticles in elimination organs, but also the physiological distribution of biological elements in situ and the topography of chemicals or metals in exposed human tissues. Based on our experience and recent literature in the field of imaging the elemental content of animal and human specimens, this review describes the principle and characteristics of the instrument, technical considerations for setting up experiments with LIBS, its advantages, limitations and possibilities for pre-clinical and medical applications.

Toxicopathological and immunological studies on different concentrations of chitosan-coated silver nanoparticles in rats.

BackgroundMuch consideration has been paid to the toxicological assessment of nanoparticles prior to clinical and biological applications. While in vitro studies have been expanding continually, in vivo investigations of nanoparticles have not developed a cohesive structure. This study aimed to assess the acute toxicity of different concentrations of chitosan-coated silver nanoparticles (Ch-AgNPs) in main organs, including liver, kidneys, and spleen.Materials and methodsTwenty-eight male albino rats were used and divided into 4 groups (n=7). Group 1 was kept as a negative control group. Groups 2, 3, and 4 were treated intraperitoneally with Ch-AgNPs each day for 14 days at doses of 50, 25, and 10 mg/kg body weight (bwt) respectively. Histopathological, morphometric and immunohistochemical studies were performed as well as oxidative stress evaluations, and specific functional examinations for each organ were elucidated.ResultsIt was revealed that Ch-AgNPs induced dose-dependent toxicity, and the repeated dosing of rats with 50 mg/kg Ch-AgNPs induced severe toxicities. Histopathological examination showed congestion, hemorrhage, cellular degeneration, apoptosis and necrosis in hepatic and renal tissue as well as lymphocytic depletion with increasing tangible macrophages in the spleen. The highest levels of malondialdehyde, alanine aminotransferase, aspartate aminotransferase (MDA, ALT, AST) and the lowest levels of reduced glutathione, immunoglobulin G, M and total protein (GSH, IgG, IgM, TP) were observed in this group. On the other hand, repeated dosing with 25 mg/kg induced mild to moderate disturbance in the previous parameters, while there was no significant difference in results of pathological examination and biochemical tests between the control group and those treated with 10 mg/kg bwt Ch-AgNPs.ConclusionChitosan-coated silver nanoparticles induce dose-dependent adverse effects on rats.

Abstract 1947: Modelling of lipid-based nanoparticle pharmacokinetics and tumor accumulation using preclinical models of ovarian cancer

Abstract Background: The development of lipid-based nanoparticles for the delivery of drugs, imaging agents, ect. to solid tumors continues to yield promising candidates for clinical testing. However, concerns have been raised over the poor translation of preclinical datasets with nanoparticle-enabled therapies into clinical outcomes. In an effort to support the utility of preclinical tumors models for predicting nanoparticle accumulation, we have created a multi-compartmental pharmacokinetic model for lipid-based nanoparticles using experimental data in two prevalent xenograft models of ovarian cancer. Methods: Two ovarian cancer xenograft models, SK-OV-3 and OV-90, were orthotopically established in a single ovary of athymic nude mice. Once the tumors had reached a volume of 0.5-0.7 mm2, the mice were intra-venously administered equivalent doses of radio-labelled nanoparticles, either porphyrin-lipid-containing PEGylated nanovesicles (Porphysomes) and PEGylated liposomes. At six timepoints post administration (6, 12, 18, 24, 36, and 48 hours) a full necropsy was preformed, and the organs measured for radio-activity. The concentrations of nanoparticles in tumors and major organs were calculated and plotted versus time. A multi-compartmental pharmacokinetic model was constructed using the time-dependent concentration of nanoparticles for either xenograft model. Results: The pathology of the orthotopic SK-OV-3 and OV-90 models were remarkably different in their vascular-permeability and cellular density, and these differences contributed to diverging nanoparticle biokinetics. Porphysome accumulation (%I.D./g), exposure (A.U.C.), and delivery efficiency (%) were significantly greater in the SK-OV-3 tumors compared with control organs (e.g., healthy ovary, muscle, etc.). Liposomes, however, did not exhibit this trend in SK-OV-3 tumors. In the OV-90 tumors, both nanoparticles exhibited increased but statistically insignificant accumulation and exposure compared with control organs. Only Porphysomes demonstrated improved delivery efficiency in the OV-90 tumors. Modelling the pharmacokinetics of the nanoparticles in a multi-compartmental model revealed distinctive kinetic parameters specific to each nanoparticle type and tumor pathology. In particular, differences were observed in the clearance rates of Porphysomes and liposomes, providing a possible explanation for their dissimilar tumor accumulations and exposures. Conclusions: Differences in the accumulation of lipid-based nanoparticles in preclinical models of ovarian cancer appear most sensitive to vascular permeability and cellular density of the xenograft. Adjusting for xenograft-dependent kinetic parameters, the Porphysome demonstrated improved but statistically insignificant tumor exposure and delivery efficiency compared with liposomes. Citation Format: Michael S. Valic, Wenlei Jiang, Lili Ding, Juan Chen, Stéphanie Lheureux, Amit M. Oza, Gang Zheng. Modelling of lipid-based nanoparticle pharmacokinetics and tumor accumulation using preclinical models of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1947.

Abstract 1953: HER2 functionalized nanoparticles are safe and specific for in vivo HER2+ breast tumor cell detection

Abstract Superparamagnetic Relaxometry (SPMR) is a highly sensitive in vivo detection technology that can localize and quantify superparamagnetic iron oxide (Fe3O4) nanoparticles when bound to tumor cells. Nanoparticles that reach and bind to the target cells are measureable by superconducting quantum interference device (SQUID) magnetometers (MRX instrument developed in house), while unbound nanoparticles such as those freely circulating in the bloodstream are not detected and bone and normal tissue do not produce any magnetic signal. In this study we demonstrate that anti-HER2 antibody conjugated nanoparticles exhibit great specificity and selectivity towards HER2+ tumor cells, and are safe (non-toxic) in preclinical models. Anti-HER2 antibody conjugated nanoparticles consist of a 25nm Fe3O4 core covered by a polymer shell with PEG and antibody conjugated on the surface. The overall size of particles is 70-80nm with PDI &amp;lt;0.1 as measured by DLS. Each particle has between 3-5 antibody molecules covalently attached to the surface with PEGylation to reduce opsonization. Our results have shown that our antibody conjugated nanoparticles can distinguish high, medium and low HER2+ expression cell lines, such as BT474 (3+), ZR75 (2+), MCF7(0/1+) in an in vitro cell based assay. Furthermore, positive signal can be competed out by pre-incubation with free HER2 antibody. In additional, negative cell lines, such as MCF10 produce undetectable SPMR signal, demonstrating good sensitivity, specificity and selectivity. Incubation with PBMC indicates that the nanoparticles do not produce an SPMR signal, suggesting minimum non-specific interaction with lymphocytes. Extensive in vivo studies using xenograph tumor mouse models have shown the nanoparticles can selectively distinguish between MCF7 vs BT474 dual implanted tumors. In addition, as a control, we used PEG only nanoparticles and showed they do not generate measurable signal in tumor. Results are corroborated using other orthogonal detection methods, such as IHC and ICP-MS. The safety profile of the nanoparticles has been demonstrated by analyzing nanoparticle accumulation in organs when injected at 20mg/kg dose via intravenous, intraperitoneal and subcutaneous delivery routes. All major organs except liver do not generate measurable MRX signal at multiple time points post injection, indicating no significant accumulation of nanoparticles in major organs. A full GLP toxicity study using rats is being conducted to demonstrate the safety of the anti-HER2 antibody conjugated nanoparticle prior to first-in-human use. Together, these results suggest that our HER2 nanoparticles are safe; can provide targeted and specific delivery to cancerous tissue in vivo and generate measurable signal on our MRX detection instrument. These studies lay out ground work for our future human clinical study for breast cancer detection. Citation Format: Marie Zhang, Jose Vargas, Antimone Dewing, Farideh Bischoff, Kelsey Mathieu, John Hazle. HER2 functionalized nanoparticles are safe and specific for in vivo HER2+ breast tumor cell detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1953.

Three-Dimensional Quantitative Co-Mapping of Pulmonary Morphology and Nanoparticle Distribution with Cellular Resolution in Nondissected Murine Lungs.

Deciphering biodistribution, biokinetics, and biological effects of nanoparticles (NPs) in entire organs with cellular resolution remains largely elusive due to the lack of effective imaging tools. Here, light sheet fluorescence microscopy in combination with optical tissue clearing was validated for concomitant three-dimensional mapping of lung morphology and NP biodistribution with cellular resolution in nondissected ex vivo murine lungs. Tissue autofluorescence allowed for label-free, quantitative morphometry of the entire bronchial tree, acinar structure, and blood vessels. Co-registration of fluorescent NPs with lung morphology revealed significant differences in pulmonary NP distribution depending on the means of application (intratracheal instillation and ventilator-assisted aerosol inhalation under anesthetized conditions). Inhalation exhibited a more homogeneous NP distribution in conducting airways and acini indicated by a central-to-peripheral (C/P) NP deposition ratio of unity (0.98 ± 0.13) as compared to a 2-fold enhanced central deposition (C/P = 1.98 ± 0.37) for instillation. After inhalation most NPs were observed in the proximal part of the acini as predicted by computational fluid dynamics simulations. At cellular resolution patchy NP deposition was visualized in bronchioles and acini, but more pronounced for instillation. Excellent linearity of the fluorescence intensity-dose response curve allowed for accurate NP dosimetry and revealed ca. 5% of the inhaled aerosol was deposited in the lungs. This single-modality imaging technique allows for quantitative co-registration of tissue architecture and NP biodistribution, which could accelerate elucidation of NP biokinetics and bioactivity within intact tissues, facilitating both nanotoxicology studies and the development of nanomedicines.

Long-circulating and target-specific distributions of cyanine 5.5-labeled hyaluronic acid nanoparticles in mouse organs during 28 days after a single administration

Long-circulating and target-specific distributions of cyanine 5.5-labeled hyaluronic acid nanoparticles in mouse organs during 28 days after a single administration