Micro- and Nanoplastics Breach the Blood–Brain Barrier (BBB): Biomolecular Corona’s Role Revealed

Humans are continuously exposed to polymeric materials such as in textiles, car tires and packaging. Unfortunately, their break down products pollute our environment, leading to widespread contamination with micro- and nanoplastics (MNPs). The blood–brain barrier (BBB) is an important biological barrier that protects the brain from harmful substances. In our study we performed short term uptake studies in mice with orally administered polystyrene micro-/nanoparticles (9.55 µm, 1.14 µm, 0.293 µm). We show that nanometer sized particles—but not bigger particles—reach the brain within only 2 h after gavage. To understand the transport mechanism, we performed coarse-grained molecular dynamics simulations on the interaction of DOPC bilayers with a polystyrene nanoparticle in the presence and absence of various coronae. We found that the composition of the biomolecular corona surrounding the plastic particles was critical for passage through the BBB. Cholesterol molecules enhanced the uptake of these contaminants into the membrane of the BBB, whereas the protein model inhibited it. These opposing effects could explain the passive transport of the particles into the brain

Evaluation of a novel integrin antagonist AV-398 in melanoma cells

Das maligne Melanom ist eine sehr aggressive Krebsart, die bereits sehr früh metastasieren kann. Während der Tumorentwicklung wird im Melanom wie auch in einigen anderen Arten von Tumoren der Integrinrezeptor V3 verstärkt exprimiert, ein Prozess der mit einem erhöhten Invasionspotential der Zellen einhergeht. Ebenso weisen aktivierte Endothelzellen in den neu gebildeten Tumor-assoziierten (Blut-) Gefäßen dieses Integrin verstärkt auf. Eine spezifische Blockade dieses Oberflächenrezeptors scheint daher ein vielversprechender Ansatzpunkt für die Krebstherapie zu sein, da diese Therapie gleichermaßen maligne Krebszellen sowie neu gebildete Gefäße betrifft. Dadurch wird sowohl das Tumorwachstum als auch die Metastasierung verhindert bzw. eingeschränkt. In dieser Doktorarbeit werden die Wirkmechanismen eines neuen nieder-molekularen Integrinantagonisten, AV-398, für die Anwendung im malignen Melanom untersucht. AV-398 zeigte starke antiproliferative wie auch Apoptose-induzierende Effekte, und zwar bereits bei Applikation von niedrigen mikromolaren Dosen, sowohl in 2D als auch in komplexeren, und typischerweise therapieresistenteren, 3D Zellkulturmodellen. Auch wurden die Zellmigration und Zellinvasion in demselben Konzentrationsbereich reduziert. Die Behandlung mit AV-398 zeigte einen zeit- und dosisabhängigen Anstieg von abgelösten (nicht adhärenten) Zellen, sowie eine charakteristisch veränderte Morphologie der noch adhärenten Zellen. Weitere detaillierte Studien zu den zugrundeliegenden Wirkmechanismen legten sowohl eine Aktivierung von Anoikis in den nicht-adhärenten Zellen (bereits nach 4h Behandlung), sowie die Entstehung von mitotischen Defekten in den adhärenten Zellen nahe, welche zeitlich akkumulierten und veränderte Zellkernstrukturen aufwiesen. Darüber hinaus zeigten diese Populationen Anzeichen einer Blockade des Zellzyklus, sowie die Induktion von Zelltod nach 24h. Zusammenfassend lässt sich sagen, dass AV-398 eine effektive Wirkung auf Melanomzellen in vitro aufweist, die hauptsächlich durch die Induktion von Apoptose (Anoikis) vermittelt wird, als auch die Zellmigration und -invasion effektiv inhibiert. Daher wäre AV-398 auch eine vielversprechende neue Substanz für die Krebstherapie.Melanoma is a very aggressive type of tumor that is able to metastasize in a very early stage of the disease. During malignant progression, melanoma and other tumors show elevated expression of integrin V3, which renders cells more invasive. Also, activated endothelial cells of angiogenic vessels express high levels of this integrin. Therefore, blockage of this surface receptor seems to be a promising attempt to specifically target malignant cells and inhibit further tumor growth and metastasis via antiangiogenic mechanisms. In this thesis, the mechanism of action of a novel small molecule integrin antagonistic drug, AV-398, was evaluated with respect to its application in melanoma. AV-398 exerted strong anti-cancer effects together with inhibition of migration and invasion in the low micromolar range, both in 2D and more complex 3D spheroid models. AV-398 treatment increased time- and dose-dependently the amount of floating cell fractions and markedly changed the morphology of non-detached cells. More detailed studies on the underlying cytotoxic mechanism of action revealed the induction of anoikis in floating cells as early as 4h after the start of treatment. Additionally, cells acquired mitotic defects, resulting in the accumulation of cells with abnormal nuclear structures in the adherent fraction, which showed cell cycle arrest and induction of apoptosis from 24h onwards. Taken together, this data shows that AV-398 is effective in melanoma cells in vitro, depicting both cytotoxic and anti-migratory/anti-invasive action. Therefore, AV-398 might also be a valuable drug candidate for further clinical development as an anti-cancer drug.submitted by Verena KopatzAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Diss., 2018(VLID)329750

Nanoparticle-Mediated Drug Delivery of Doxorubicin Induces a Differentiated Clonogenic Inactivation in 3D Tumor Spheroids In Vitro

Involvement of 3D tumor cell models in the in vitro biological testing of novel nanotechnology-based strategies for cancer management can provide in-depth information on the real behavior of tumor cells in complex biomimetic architectures. Here, we used polyethylene glycol-encapsulated iron oxide nanoparticles for the controlled delivery of a doxorubicin chemotherapeutic substance (IONPDOX), and to enhance cytotoxicity of photon radiation therapy. The biological effects of nanoparticles and 150 kV X-rays were evaluated on both 2D and 3D cell models of normal human keratinocytes (HaCaT) and tumor cells—human cervical adenocarcinoma (HeLa) and human squamous carcinoma (FaDu)—through cell survival. In all 2D cell models, nanoparticles were similarly internalized in a peri-nuclear pattern, but resulted in different survival capabilities following radiation treatment. IONP on normal keratinocytes showed a protective effect, but a cytotoxic effect for cancer cells. In 3D tumor cell models, IONPDOX were able to penetrate the cell spheroids towards the hypoxic areas. However, IONPDOX and 150 kV X-rays led to a dose-modifying factor DMFSF=0.1 = 1.09 ± 0.1 (200 µg/mL IONPDOX) in HeLa spheroids, but to a radioprotective effect in FaDu spheroids. Results show that the proposed treatment is promising in the management of cervical adenocarcinoma

Micro- and Nanoplastics Breach the Blood–Brain Barrier (BBB): Biomolecular Corona’s Role Revealed

Humans are continuously exposed to polymeric materials such as in textiles, car tires and packaging. Unfortunately, their break down products pollute our environment, leading to widespread contamination with micro- and nanoplastics (MNPs). The blood–brain barrier (BBB) is an important biological barrier that protects the brain from harmful substances. In our study we performed short term uptake studies in mice with orally administered polystyrene micro-/nanoparticles (9.55 µm, 1.14 µm, 0.293 µm). We show that nanometer sized particles—but not bigger particles—reach the brain within only 2 h after gavage. To understand the transport mechanism, we performed coarse-grained molecular dynamics simulations on the interaction of DOPC bilayers with a polystyrene nanoparticle in the presence and absence of various coronae. We found that the composition of the biomolecular corona surrounding the plastic particles was critical for passage through the BBB. Cholesterol molecules enhanced the uptake of these contaminants into the membrane of the BBB, whereas the protein model inhibited it. These opposing effects could explain the passive transport of the particles into the brain

Systematic, evolution and genetic of bears

Bears have fascinated people since ancient times. The relationship between bears and humans dates back thousands of years, during which time we have also competed with bears for shelter and food. In modern times, bears have come under pressure through encroachment on their habitats, climate change, and illegal trade in their body parts, including the Asian bile bear market. The IUCN lists six bears as vulnerable or endangered, and even the least concern species, such as the brown bear, are at risk of extirpation in certain countries. The poaching and international trade of these most threatened populations are prohibited, but still ongoing. Covering all bears species worldwide, this beautifully illustrated volume brings together the contributions of 200 international bear experts on the ecology, conservation status, and management of the Ursidae family. It reveals the fascinating long history of interactions between humans and bears and the threats affecting these charismatic species

Unveiling Nanoparticles: Recent Approaches in Studying the Internalization Pattern of Iron Oxide Nanoparticles in Mono- and Multicellular Biological Structures

Nanoparticle (NP)-based solutions for oncotherapy promise an improved efficiency of the anticancer response, as well as higher comfort for the patient. The current advancements in cancer treatment based on nanotechnology exploit the ability of these systems to pass biological barriers to target the tumor cell, as well as tumor cell organelles. In particular, iron oxide NPs are being clinically employed in oncological management due to this ability. When designing an efficient anti-cancer therapy based on NPs, it is important to know and to modulate the phenomena which take place during the interaction of the NPs with the tumor cells, as well as the normal tissues. In this regard, our review is focused on highlighting different approaches to studying the internalization patterns of iron oxide NPs in simple and complex 2D and 3D in vitro cell models, as well as in living tissues, in order to investigate the functionality of an NP-based treatment