Pharmacokinetics of PEGylated Gold Nanoparticles: In Vitro-In Vivo Correlation

Gold nanoparticles; Human cell lines; PharmacokineticsNanopartícules d'or; Línies cel·lulars humanes; FarmacocinèticaNanopartículas de oro; Líneas celulares humanas; FarmacocinéticaData suitable for assembling a physiologically-based pharmacokinetic (PBPK) model for nanoparticles (NPs) remain relatively scarce. Therefore, there is a trend in extrapolating the results of in vitro and in silico studies to in vivo nanoparticle hazard and risk assessment. To evaluate the reliability of such approach, a pharmacokinetic study was performed using the same polyethylene glycol-coated gold nanoparticles (PEG-AuNPs) in vitro and in vivo. As in vitro models, human cell lines TH1, A549, Hep G2, and 16HBE were employed. The in vivo PEG-AuNP biodistribution was assessed in rats. The internalization and exclusion of PEG-AuNPs in vitro were modeled as first-order rate processes with the partition coefficient describing the equilibrium distribution. The pharmacokinetic parameters were obtained by fitting the model to the in vitro data and subsequently used for PBPK simulation in vivo. Notable differences were observed in the internalized amount of Au in individual cell lines compared to the corresponding tissues in vivo, with the highest found for renal TH1 cells and kidneys. The main reason for these discrepancies is the absence of natural barriers in the in vitro conditions. Therefore, caution should be exercised when extrapolating in vitro data to predict the in vivo NP burden and response to exposure.This research was funded by the European Commission under the Horizon 2020 programme (HISENTS, Grant Agreement No. 685817 and VISION, Grant Agreement No. 857381). Financial support from the Structural Funds of EU by implementation of the project “Strategic research in SMART monitoring, treatment, and prevention against coronavirus (SARS-CoV-2)”, ITMS 2014+ code NFP313011ASS8 co-financed by the European Regional Development Fund

Hepato(Geno)toxicity assessment of nanoparticles in a HepG2 liver spheroid model

(1) In compliance with the 3Rs policy to reduce, refine and replace animal experiments, the development of advanced in vitro models is needed for nanotoxicity assessment. Cells cultivated in 3D resemble organ structures better than 2D cultures. This study aims to compare cytotoxic and genotoxic responses induced by titanium dioxide (TiO), silver (Ag) and zinc oxide (ZnO) nanoparticles (NPs) in 2D monolayer and 3D spheroid cultures of HepG2 human liver cells. (2) NPs were characterized by electron microscopy, dynamic light scattering, laser Doppler anemometry, UV-vis spectroscopy and mass spectrometry. Cytotoxicity was investigated by the alamarBlue assay and confocal microscopy in HepG2 monolayer and spheroid cultures after 24 h of NP exposure. DNA damage (strand breaks and oxidized base lesions) was measured by the comet assay. (3) Ag-NPs were aggregated at 24 h, and a substantial part of the ZnO-NPs was dissolved in culture medium. Ag-NPs induced stronger cytotoxicity in 2D cultures (EC 3.8 µg/cm 2) than in 3D cultures (EC > 30 µg/cm 2), and ZnO-NPs induced cytotoxicity to a similar extent in both models (EC 10.1-16.2 µg/cm 2). Ag- and ZnO-NPs showed a concentration-dependent genotoxic effect, but the effect was not statistically significant. TiO-NPs showed no toxicity (EC > 75 µg/cm 2). (4) This study shows that the HepG2 spheroid model is a promising advanced in vitro model for toxicity assessment of NPs

A new source of representative secondary PET nanoplastics. Obtention, characterization, and hazard evaluation

Acord transformatiu CRUE-CSICAltres ajuts: Juan de la Cierva IJC2020-2686IMicro and nanoplastics (MNPLs) are emergent environmental pollutants requiring urgent information on their potential risks to human health. One of the problems associated with the evaluation of their undesirable effects is the lack of representative samples, matching those resulting from the environmental degradation of plastic wastes. To such end, we propose an easy method to obtain polyethylene terephthalate nanoplastics from water plastic bottles (PET-NPLs) but, in principle, applicable to any other plastic goods sources. An extensive characterization indicates that the proposed process produces uniform samples of PET-NPLs of around 100 nm, as determined by using AF4 and multi-angle and dynamic light scattering methodologies. An important point to be highlighted is that to avoid the metal contamination resulting from methods using metal blades/burrs for milling, trituration, or sanding, we propose to use diamond burrs to produce metal-free samples. To visualize the toxicological profile of the produced PET-NPLs we have evaluated their ability to be internalized by cells, their cytotoxicity, their ability to induce oxidative stress, and induce DNA damage. In this preliminary approach, we have detected their cellular uptake, but without the induction of significant biological effects. Thus, no relevant increases in toxicity, reactive oxygen species (ROS) induction, or DNA damage -as detected with the comet assay- have been observed. The use of representative samples, as produced in this study, will generate relevant data in the discussion about the potential health risks associated with MNPLs exposures

Antibacterial films based on MOF composites that release iodine passively or upon triggering by near-infrared light

This work was supported by the CERCA Program/Generalitat de Catalunya.Multidrug-resistant bacteria have become a global health problem for which new prophylactic strategies are now needed, including surface-coatings for hospital spaces and medical equipment. This work reports the preparation and functional validation of a metal-organic framework (MOF) based composite for the triggered controlled release of iodine, an antimicrobial element that does not generate resistance. It comprises beads of the iodophilic MOF UiO-66 containing encapsulated gold nanorods (AuNRs) coated with a silica shell. Irradiation of the AuNRs with near-infrared light (NIR) provokes a photothermal effect and the resultant heat actively liberates the iodine. After validating the performance of this composite, it is integrated into a polymer for the development of antibacterial films. This work assesses the adsorption of iodine into these composite films, as well as its passive long-term release and active light-triggered. Finally, this work validates the antibacterial activity of the composite films in vitro against gram-positive and gram-negative bacteria. The findings will surely inform the development of new prophylactic treatments

Engineering Stöber Silica Nanoparticles : Insights into the Growth Mechanism and Development of Silica-Based Nanostructures for Multimodal Imaging

Aprofitant l'experiència del grup Inorganic Nanoparticles (ING) de l'ICN2, que té com a gran expertesa en la producció de nanopartícules col·loïdals altament monodisperses, aquesta tesi té com a objectiu fabricar una nanoestructura híbrida complexa inorgànica-orgànica utilitzant sílice com a material de suport, aplicant mètodes sintètics de química en líquid, per al desenvolupament d'un agent de contrast multifuncional amb propietats adequades per aplicar-lo en imatge mèdica. Per això s'han abordat tres objectius principals: en primer lloc, l'estudi del mecanisme de nucleació i creixement de les NPs de SiO2 per controlar amb precisió la mida de les partícules. En segon lloc, una modificació sistemàtica de la superfície i el nucli de les nanopartícules de sílice, per tal de preparar nanopartícules a base de sílice amb propietats òptiques funcionals i, en tercer lloc, explotar la funcionalitat dels híbrids de sílice preparats per al desenvolupament duna nanoestructura complexa multicapa híbrida amb capacitats dimatge multimodal.Aprovechando la experiencia del grupo Inorganic Nanoparticles (ING) del ICN2, que tiene como gran experticia en la producción de nanopartículas coloidales altamente monodispersas, esta tesis tiene como objetivo fabricar una nanoestructura híbrida compleja inorgánica-orgánica utilizando sílice como material de soporte, aplicando métodos sintéticos de química en líquido, para el desarrollo de un agente de contraste multifuncional con propiedades adecuadas para su aplicación en imagen médica. Para ello se han abordado tres objetivos principales: en primer lugar, el estudio del mecanismo de nucleación y crecimiento de las NPs de SiO2 para controlar con precisión el tamaño de las partículas. En segundo lugar, una modificación sistemática de la superficie y el núcleo de las nanopartículas de sílice, con el fin de preparar nanopartículas a base de sílice con propiedades ópticas funcionales y, en tercer lugar, explotar la funcionalidad de los híbridos de sílice preparados para el desarrollo de una nanoestructura compleja multicapa híbrida con capacidades de imagen multimodal.In this regard, taking advantage of the expertise in the group on the production of highly monodisperse colloidal nanoparticles, this thesis aims to fabricate an inorganic-organic complex hybrid nanostructure using silica as supporting material, by applying wet chemistry synthetic methods, for the development of a multifunctional contrast agent with adequate properties for their application in medical imaging. For that purpose, three main objectives have been addressed: first, the study of the mechanism of nucleation and growth of the SiO2 NPs in order to precisely control the size of the particles. Second, a systematically surface and core modification of the silica nanoparticles, in order to prepare silica-based nanoparticles with functional optical properties and third, exploiting the functionality of the prepared silica hybrids for the development of a hybrid multilayer complex nanostructure with multimodal imaging capabilitie

Engineering Stöber Silica Nanoparticles: Insights into the Growth Mechanism and Development of Silica-Based Nanostructures for Multimodal Imaging

Aprofitant l’experiència del grup Inorganic Nanoparticles (ING) de l’ICN2, que té com a gran expertesa en la producció de nanopartícules col·loïdals altament monodisperses, aquesta tesi té com a objectiu fabricar una nanoestructura híbrida complexa inorgànica-orgànica utilitzant sílice com a material de suport, aplicant mètodes sintètics de química en líquid, per al desenvolupament d’un agent de contrast multifuncional amb propietats adequades per aplicar-lo en imatge mèdica. Per això s’han abordat tres objectius principals: en primer lloc, l’estudi del mecanisme de nucleació i creixement de les NPs de SiO2 per controlar amb precisió la mida de les partícules. En segon lloc, una modificació sistemàtica de la superfície i el nucli de les nanopartícules de sílice, per tal de preparar nanopartícules a base de sílice amb propietats òptiques funcionals i, en tercer lloc, explotar la funcionalitat dels híbrids de sílice preparats per al desenvolupament duna nanoestructura complexa multicapa híbrida amb capacitats dimatge multimodal.Aprovechando la experiencia del grupo Inorganic Nanoparticles (ING) del ICN2, que tiene como gran experticia en la producción de nanopartículas coloidales altamente monodispersas, esta tesis tiene como objetivo fabricar una nanoestructura híbrida compleja inorgánica-orgánica utilizando sílice como material de soporte, aplicando métodos sintéticos de química en líquido, para el desarrollo de un agente de contraste multifuncional con propiedades adecuadas para su aplicación en imagen médica. Para ello se han abordado tres objetivos principales: en primer lugar, el estudio del mecanismo de nucleación y crecimiento de las NPs de SiO2 para controlar con precisión el tamaño de las partículas. En segundo lugar, una modificación sistemática de la superficie y el núcleo de las nanopartículas de sílice, con el fin de preparar nanopartículas a base de sílice con propiedades ópticas funcionales y, en tercer lugar, explotar la funcionalidad de los híbridos de sílice preparados para el desarrollo de una nanoestructura compleja multicapa híbrida con capacidades de imagen multimodal.In this regard, taking advantage of the expertise in the group on the production of highly monodisperse colloidal nanoparticles, this thesis aims to fabricate an inorganic-organic complex hybrid nanostructure using silica as supporting material, by applying wet chemistry synthetic methods, for the development of a multifunctional contrast agent with adequate properties for their application in medical imaging. For that purpose, three main objectives have been addressed: first, the study of the mechanism of nucleation and growth of the SiO2 NPs in order to precisely control the size of the particles. Second, a systematically surface and core modification of the silica nanoparticles, in order to prepare silica-based nanoparticles with functional optical properties and third, exploiting the functionality of the prepared silica hybrids for the development of a hybrid multilayer complex nanostructure with multimodal imaging capabilitiesUniversitat Autònoma de Barcelona. Programa de Doctorat en Químic

A new source of representative secondary PET nanoplastics. Obtention, characterization, and hazard evaluation

Micro and nanoplastics (MNPLs) are emergent environmental pollutants requiring urgent information on their potential risks to human health. One of the problems associated with the evaluation of their undesirable effects is the lack of representative samples, matching those resulting from the environmental degradation of plastic wastes. To such end, we propose an easy method to obtain polyethylene terephthalate nanoplastics from water plastic bottles (PET-NPLs) but, in principle, applicable to any other plastic goods sources. An extensive characterization indicates that the proposed process produces uniform samples of PET-NPLs of around 100 nm, as determined by using AF4 and multi-angle and dynamic light scattering methodologies. An important point to be highlighted is that to avoid the metal contamination resulting from methods using metal blades/burrs for milling, trituration, or sanding, we propose to use diamond burrs to produce metal-free samples. To visualize the toxicological profile of the produced PET-NPLs we have evaluated their ability to be internalized by cells, their cytotoxicity, their ability to induce oxidative stress, and induce DNA damage. In this preliminary approach, we have detected their cellular uptake, but without the induction of significant biological effects. Thus, no relevant increases in toxicity, reactive oxygen species (ROS) induction, or DNA damage -as detected with the comet assay- have been observed. The use of representative samples, as produced in this study, will generate relevant data in the discussion about the potential health risks associated with MNPLs exposures.A. Villacorta was supported by Ph.D. fellowships from the National Agency for Research and Development (ANID), CONICYT PFCHA / DOCTORADO BECAS CHILE / 2020 − 72210237. L. Rubio was supported by the Fondo Nacional de Innovación y Desarrollo Científico y Tecnológico (FONDOCYT) República Dominicana (Project 2018–2019-2B2–093). This project (PlasticHeal) has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 965196. L. Rubio was supported by a contract Juan de la Cierva (IJC2020-2686I/AEI/10.13039/501100011033)

Antibacterial Films Based on MOF Composites that Release Iodine Passively or Upon Triggering by Near-Infrared Light

Multidrug-resistant bacteria have become a global health problem for which new prophylactic strategies are now needed, including surface-coatings for hospital spaces and medical equipment. This work reports the preparation and functional validation of a metal-organic framework (MOF) based composite for the triggered controlled release of iodine, an antimicrobial element that does not generate resistance. It comprises beads of the iodophilic MOF UiO-66 containing encapsulated gold nanorods (AuNRs) coated with a silica shell. Irradiation of the AuNRs with near-infrared light (NIR) provokes a photothermal effect and the resultant heat actively liberates the iodine. After validating the performance of this composite, it is integrated into a polymer for the development of antibacterial films. This work assesses the adsorption of iodine into these composite films, as well as its passive long-term release and active light-triggered. Finally, this work validates the antibacterial activity of the composite films in vitro against gram-positive and gram-negative bacteria. The findings will surely inform the development of new prophylactic treatments.This work was supported by the Spanish MINECO (project RTI2018-095622-B-I00, RTI2018-099965-B-I00, AEI/FEDER, UE), the Catalan AGAUR (project 2017 SGR 238, 2017 SGR 1431), and the ERC, under the EU-FP7 (ERC-Co 615954). It was also funded by the CERCA Program/Generalitat de Catalunya. ICN2 is supported by the Severo Ochoa program from the Spanish MINECO (Grant No. SEV-2017-0706). X.H. thanks the China Scholarship Council (CSC) for scholarship support (201804910551). M.B. thanks the Polish National Agency for Academic Exchange (contract no. PPN/BEK/2018/1/00094/U/00001). O.M. acknowledges financial support from the Spanish Ministry of Science and Innovation (MICINN) by FPI fellowship, resolved by the Agencia Estatal de Investigación (AEI) with reference (BES-2017-083043)

Low Density Parity Check Code Decoder Architecture Study and Design

文探討一種錯誤更正碼的技術，低密度同位元檢查碼(Low-Density Parity- Check Code, LDPC)，其中包含碼的組成、碼的編解碼、及其遞迴解碼演算法，進而引入硬體設計的概念，分別探討完全平行式解碼架構、序列解碼架構、部份平行式解碼架構。不同的方式應用於不同的實際情況中。有quasi-cyclic半循環特性的同位元檢查矩陣有 個子矩陣，每一個子矩陣為單位矩陣或是其circulant矩陣，以上通稱為circulant 矩陣，其特點為每一個列為上一列的右移。此種矩陣可以建構出一系列的(QC_LDPC) 碼，可藉由定義每一個子矩陣的第一列的第一個一的位置，可找出適合的低密度同位元檢查碼且具有好的解碼效能。種半循環低密度同位元檢查碼亦適合部份平行式的解碼器實作，此部份平行式解碼器具有很高的彈性。此外介紹解碼器中主要的運算功能單元，諸如位元點單元及檢查點單元。部份平行式的解碼器結合完全平行式及序列式低密度同位元檢查碼解碼器優點，提供非常好硬體的方案，諸如可避免完全式解碼器大量繞線的問題，及序列式速度慢且需要大面積的記憶體，因此部份平行式的同位元檢查碼解碼器已成為現今低密度同位元檢查碼解碼器設計主流。終探討及實作部份平行式的同位元檢查碼解碼器，此架構之解碼器之同位元檢查矩陣具有特殊規律的結構，其優點為方便編碼器實作於移位暫存器。而解碼器之負責運算功能單元間的訊息的傳遞控制邏輯，可藉由簡單的累加器來產生所需要的記憶體位址，大幅降低以完全平行式設計方式所需的大量繞線。This Thesis discusses an error correction technology, Low-Density Parity Check (LDPC) code, as well as its code constructions, encoding methods and decoding algorithms.artially parallel decoder design methodology provides appropriate trade-off between hardware complexity and decoding throughput. Partially parallel decoder also combines the advantages from both the LDPC fully parallel decoder and serial decoder. Many Quasi-Cyclic LDPC codes have been studied and developed. These kinds of QC_LDPC codes not only reduce the memory addressing complexity in a decoder design but also the encoding complexity. Other compatible QC_LDPC codes have also been proposed. In this Thesis, we choose a code construction method similar to [27] to implement a partially parallel decoder suitable for the family of (3, 6)-regular LDPC codes. array of circulant sub-matrices can be used to represent the parity check matrix Hqc of a QC_LDPC code. A family of structured QC_LDPC codes can be constructed by shifting the identity sub-matrix into different circulant sub-matrices. These kinds of QC_LDPC codes are suitable for partially parallel decoder. And its construction provides flexibility in hardware design.TABLE OF CONTENTSBSTRACT iIST OF FIGURES viiIST OF TABLES ixHAPTER 1 INTRODUCTION 1.1 LDPC Code Encoding 1.2 LDPC Code Decoding 2.3 Interesting Issues in VLSI Implementation of LDPC Decoder 2.3.1 Code Constructions 2.3.2 Functional Units of Decoder 3.3.3 Decoding Algorithms 3.3.4 Toward Good Performance 3.4 Thesis Organization 4HAPTER 2 BACKGROUND INFORMATION 5.1 Low-Density Parity Check Codes 5.2 Quasi-Cyclic LDPC Codes 9.3 Quasi-Cyclic LDPC Constructions 9.3.1 Array Based LDPC Constructions 10.4 Efficient LDPC Code Encoding 10.4.1 Quasi-Cyclic LDPC Encoding 12HAPTER 3 DECODING ALGORITHMS 13.1 LDPC Code Decoding Overview 13.2 Message Passing Algorithm 15.2.1 Summary of Log -Message Passing Algorithm 17.3 Tanh Rules 18.3.1 Multitiplicative Form 19.3.2 Additive Form 20.4 Min-Sum Algorithm 23.4.1 Summary of Min-Sum Algorithm 24.5 Modified Min-Sum Algorithm 25.5.1 Summary of Modified Min-Sum Algorithm 26.6 Summary of Decoding Algorithms 26HAPTER 4 LDPC DECODER ARCHITECTURES 31.1 LDPC Decoder Architectures Overview 31.2 Partially Parallel Based LDPC Decoder Architectures 34.2.1 Partially Parallel Based LDPC Decoder Architectures Processing 36.2.2 Memory Addressing 37.3 Key Functional Units in LDPC Decoder 38.3.1 Bit-Node-Unit 39.3.2 Check-Node Unit 41.4 Partially Parallel LDPC Decoder Diagram 45.4.1 A Prototype Partially Parallel LDPC Decoder 45HAPTER 5 DECODER PROTOTYPING IMPLEMENTATION AND DISCUSSION 47.1 Prototype (3, 6) Partially Parallel LDPC Decoder Specification 47.2 Simulation Results 48.3 Evaluation 56.3.1 Finite State Machine Design 57.3.2 Synthesis Results and Discussions 59HAPTER 6 CONCLUSION AND FUTURE WORK 65.1 Conclusion 65.2 Future Work 65.2.1 Encoding Methods 66.2.2 Code Constructions 66.2.3 Functional Units 66.2.4 Decoding Process 67EFERENCE 6

Gold and titania nanoparticles accumulated in the body induce late toxic effects and alterations in transcriptional and miRNA landscape

The growing production of nanomaterials and their presence in consumer products raises fear about their impact on human health and the environment. Of particular concern are those nanomaterials that exhibit poor excretion and tend to accumulate in living organisms. Our study investigated the potential adverse biological effects of residual gold and titania nanoparticles (PEG-AuNPs and TiONPs) 28 days after a single intravenous administration in rats. To comprehensively assess the potential health hazard of these metal nanoparticles (MNP), toxicological and transcriptomic analyses were employed. The liver was the primary organ of the MNP deposition, causing a reduction in the relative liver weight compared to unexposed animals. Concurrently, changes in serum biomarkers indicative of hepatic dysfunction and hematological and immunological alternations were determined. Integrated transcriptomic analysis unveiled exposure-induced effects on the rats' lungs, liver, and kidneys. The hepatic tissue, particularly in PEG-AuNPs-exposed rats, exhibited a noteworthy prevalence of deregulated genes, with functional classification spanning lipid metabolism, cell cycle, and cell proliferation pathways. Although the number of deregulated miRNAs was relatively modest compared to mRNA expression changes, both types of MNPs deregulated miR-203a, associated with liver injury, and miR-18a-5p and miR-32-5p linked to kidney damage. This study underscores the imperative for a more exhaustive biosafety assessment of poorly soluble MNPs that tend to deposit in the body. Such investigations are crucial for delineating the potential risks of these nanomaterials and guiding the development of adequate safety measures in their production and usage