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Nanbiosis

NANBIOSIS in the NEW BOOK of the Unique Science and Technology Infrastructures (ICTS)

We are pleased to inform that the new book of Unique Scientific and Technical Infrastructures (ICTS) has been published by the Spanish Ministery of Sciencie and Innovation with the collaborations of the ICTS. You can download it download it here.

The Spanish Map of Unique Science and Technology Infrastructures (ICTS, in Spanish) , goups biomedical technologies, cleanrooms, supercomputers, advanced lasers, telescopes, underground laboratories, synchrotrons, particle accelerators, biological reserves, solar, oceanic and hydraulic platforms, oceanographic research ships, and polar bases in Antarctica. A total of 29 ICTS, made up of 64 infraestructures, allow for ambitious research projects that attract first-rate talent and enhance the technological and innovative industry capacities.

As Diana Morant, Spanish Minister of Science and Innovation says in its prelude “The Unique Science and Technology Infrastructures (ICTS), are crucial for the current country project around science and innovation that we are building together: administrations, research and technology centers, companies and society. I encourage you to go through the pages of this book and discover avant-garde facilities that represent the excellent scientific and technological capabilities that exist today in Spain.

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7th Annual Meeting of the Unique Science and Technology Infrastructures in Spain

On September 7, the annual meeting of the directors of the 29 Singular Scientific and Technical Infrastructures (ICTS) of Spain took place in Seville.

The event was organized in five round tables:

Table 1 Development of in-house technology in ICTs and its transfer
Table 2 ICTS response to crisis situations: the COVID19 pandemic and the La Palma volcano eruption
Table 3 Digital Continuum: data management and processing in ICTS
Table 4 Provision of shared ICT Services: connectivity and cybersecurity, implementation of open science in the cloud
Table 5 Stimulation of scientific vocations and social interest in ICTS
Table 6 National and international cooperation between ICTS

The Scientific Director of NANBIOSIS, Jaume Veciana, spoke at Table 5 dedicated to “Stimulation of scientific vocations and social interest in Unique Science and Technology Infrastructures (ICTS)” in which also participated the ICTS Center for Pulsed Lasers, the Astronomical Center Hispanic in Andalusia (CAHA), the National Center for Research on Human Evolution (CENIEH), the Spanish Institute of Oceanography (IEO), the Great Telescope of the CANARY ISLANDS and the Spanish Supercomputing Network (RES).

The meeting was attended by the Minister of Science and Innovation, Diana Morant, who recalled that she remembered that the 29 ICTS contribute to providing solutions from science to present and future challenges and, in addition, are a lever of opportunities throughout the Spanish territory. In total, more than 2,300 people work in these facilities, which have an annual budget of more than 250 million euros.

The minister also highlighted that the reform of the Science, Technology and Innovation Law of September 5, 2022, regulates the for the first time. ICTS Map

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Philipps-Universität Marburg (Germany) -NANBIOSIS U25 collaboration on the study of tumour microenvironment (TME) changes in Glioblastoma

The scientific coordinator of NANBIOSIS U25 “RNM: Biomedical Application I”, Ana Paula Candiota, was recently awarded with a mobility fellowship from CIBER-BBN for a scientific exchange visit to Philipps-Universität Marburg, in Marburg, Germany.


This scientific stage was motivated for a sustained collaboration between the research groups (GABRMN, in charge of U25 and Neurosurgery Lab group in Marburg), regarding the study of tumour microenvironment (TME) changes in Glioblastoma and possible relationship with the noninvasive MRSI-based biomarkers. Both groups have applied together to different funding calls including ERA-NET Transcan and Pathfinder Open, and Marburg group has hosted a predoctoral stage from a GABRMN PhD student.

The University of Marburg is the university with the longest tradition in Hesse, founded in 1527. With thirteen Leibniz Prize winners, the University of Marburg is one of the leading research institutions in the State of Hesse. Related to the Medicine Faculty of the Philipps University of Marburg is the Uniklinikum Giessend Und Marburg (UKGM), in which the Neurosurgery Lab, lead by Prof. Jörg-Walter Bartsch, is located. This group is hosting Dr. Candiota stage until September 9th.

The main objectives of this short stage are to strength the scientific collaboration, to finish pending work related to TME GL261 glioblastoma, to get familiarized with some approaches used in Marburg and not mastered by GABRMN, and finally to give a talk to group and clinical members, highlighting the potential of U25 and the translational characteristics of the common projects held by both institutions.

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The University of Valencia among the 300 best universities in the world, hosting NANBIOSIS U26 of CIBER-BBN on RNM for Biomedical Applications

The Academic Ranking of World Universities (ARWU), known as Shanghai Ranking, which was made public on August 15, places the University of Valencia among the elite of the 300 best universities in the world and the second of the Spanish universities.

This indicator organizes up to 20,000 university centers worldwide,
based on transparent methodology and objective third-party data. ARWU is regarded as one of the three most influential and widely observed university rankings

The NANBIOSIS U26 NMR: Biomedical Applications II created by CIBER-BBN is hosted by the University of Valencia is led by Prof. Ramón Martínez Ma´ñez and Prof Salvador Gil Grau and has a laboratory with a NMR (14T) for acquiring unique metabolic profiles of biofluids, cell lines and tissues

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Two NANBIOSIS Units of CIBER-BBN at UAB, one of the 300 best universities in the world, according the Shanghai Ranking

The Academic Ranking of World Universities (ARWU), known as Shanghai Ranking, which was made public on August 15, places the Autonomous University of Barcelona among the elite of the 300 best universities in the world.

This indicator organizes up to 20,000 university centers worldwide,
based on transparent methodology and objective third-party data. ARWU is regarded as one of the three most influential and widely observed university rankings

Two of NANBIOSIS Units created by UAB and CIBER-BBN are part of this university:

U1 Protein Production Platform (PPP), led by Toni Villaverde, Neus Ferrer and Mercedes Marquez, offer an “tailored” service for the design, production and purification of recombinant proteins using both prokaryotic and eukaryotic expression systems

U25 NMR: Biomedical Applications I, led by Carles Arús and Ana Paula Candiota, with a recognized research track record in the use of NMR as a tool for biomedical applications, and more especifically to identify biomarkers of different pathologies, the main objective of this unit is the acquisition, processing and/or interpretation of Nuclear Magnetic Resonance data

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1st Nanomedicine Forum of CIBER-BBN/NANBIOSIS and CSIC Nanomed Conection

During the days 30 of June and 1st of July took place in Barcelona, in the auditorium of the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), the 1st Forum on Nanomedicine gathering scientists from the CSIC net Nanomed Conection and from the CIBER-BBN and its ICTS NANBIOSIS.

This forum brought toguether researchers from the most eminent national research centers in nanomedicine, that during the two days meeting presented their works and findings and discussed the impact of nanomedicine in the fields of drug delivery, diagnosis and therapy.

The workshop was open by the Director of IQAC-CSIC,  Jesús Joglar, the  Scientific Coordinator of Nanomed Conection, Fernando Herranz, and the Scientific Director of CIBER-BBN, Ramón Martínez Máñez.

18 research groups gave their talks distributed in four sessions:

  • Nanobiotechnological solutions for diagnosis and therapy
  • Drug delivery nanosystems
  • Applications for oncology 
  • Nanomedicine & other frontier applications

The presentations aroused great interest and futher debate among the attendees present in the auditorium (around 50) and the on line participants (The event was also broadcast online previous registration with more than 125 registrations received).

The videos of the presentations will be soon available in the NANBIOSIS youtube channel.

Here we highlight the eight talks by researchers from NANBIOSIS units:

The first session of Nanobiotechnological solutions for diagnosis and therapy,  started  with the talk by Montserrat Rodríguez from Nb4D group NANBIOSIS U2 CAbS, from CIBER-BBN and IQAC-CSIC, entitled “Targeting aromatic amino acid metabolism for the early diagnosis of neurological diseases”, presenting their results on in vitro samples, on thermal power characterization experiments to study the thermal efficiency of non-sinusoidal stimulation and on efficiency characterization experiments in cell cultures with cancer cell liness.

Also in this session chaired by Miriam Royo, Scientific Coordinator of NANBIOSIS U3 Synthesis of Peptides Unit of  CIBER-BBN and IQAC-CSIC,  took place an interesting and passionate talk by Ramón Eritja, Scientific Director of NANBIOSIS U29 Oligonucleotide Synthesis Platform (OSP)

In the last years, interest in therapeutic applications of oligonucleotides has increased enormously, especially after the development of messenger RNA vaccines in response to the COVID-19 pandemic. In this way, metabolic diseases such as dyslipidemia and hereditary diseases such as Duchenne muscular dystrophy have been successfully addressed. The NANBIOSIS  Oligonucleotide Synthesis Platform (OSP) focuses on the design, synthesis and characterization of modified oligonucleotides, in order to enhance the therapeutic properties of the oligonucleotides and to improve the control of gene expression. Ramon Eritja presented their most recent results in the development of new conjugates with antiproliferative activity and in the design of DNA probes for the detection of viral genomes.

 

In the session of “Nanomedicine and other frontiers applications”, chaired by María del Puerto Morales Herrero (ICMM-CSIC), Elena Martínez Fraiz,  from the Nanobioengineering group of CIBER-BBN and IBEC running NANBIOSIS Unit 7 of Nanotechnology, presented  a nanostructured surface able to produce multivalent effects of surface-bound ephrinB1 ligands on the dynamics of oligomerization of EphB2 receptors  whic can benefit applications such as the design of new bioactive materials and drug-delivery systems.

The session of Drug delivery nanosystems, chaired by Ramón Martínez Máñez, began with the talk by Vanessa Díaz Riascos, presesnting the in vivo efficacy, biodistribution and toxicity testing of nanomedicines at NANBIOSIS U20 FVPR, of CIBER-BBN and VHIR, explaining how their texting expertise and their in vivo and ex vivo fluorescence imaging techniques facilitate a rapid and efficient preclinical development of candidates, reducing considerably the time and costs of conventional developments.


Santiago Grijalvo Torrijo, from NANBIOSIS U12 Nanostructured liquid characterization unit expoke about Nano-emulsion-derived polymeric carriers for biomedical applications also discussing the impact of the protein corona on colloidal stability, antioxidant activities, cytotoxicity and cellular uptake of drug-loaded nanoparticles.

Antoni Llopis Lorente, (NANBIOSIS U26 NMR: Biomedical Applications II), expoke about Gated silica nanoparticles for controlled release. Chemical communication, based on the exchange of molecules as messengers, allows different entities to share information, cooperate and orchestrate collective behaviors. Communication using chemical messengers (such as neurotransmitters, hormones and pheromones) is the main way of communication across the natural world; yet engineering chemical communication between micro/nanosystems is a key emergent topic in micro/nanotechnology, biomimicry and related areas. Santiago explainined recent progress by their group in the development of engineered particles for chemical communication and nanomedicine applications.

And closing the session, Mariana Köber (Nanomol Group –NANBIOSIS U6 of Biomaterial Processing and Nanostructuring Unit  from CIBER-BBN and ICMAB-CSIC) gave a talk on Quatsomes as versatile nanovesicles for biomedical applications.

In the session of Applications for Oncology, Pilar Martín Duque from NFP group – NANBIOSIS U9 Synthesis of Nanoparticles Unit of CIBER-BBN and INMA-CSIC, gave a very interesting talk explained their approach and recent progress on the search of trojan horses for an improved theragnosis of cancer.

Here we want to thank the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC) for hosting this event and for the help in its preparation and development.

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Metal-free contrast agents: novel approaches

The joint expertise of CIBER-BBN Nanomol Group – NANBIOSIS U6 from at ICMAB-CSIC (José Vidal and Vega Lloveras) and NANBIOSIS U25 at UAB (Ana Paula Candiota), led to a recently published article in the prestigious journal Biomacromolecules

Brain tumours such as Glioblastomas are a challenge in the clinics and proper diagnosis and follow-up are crucial for patient outcome. Contrast agents are usually administered to patients for assessing blood brain barrier integrity and quantitation of enhancing areas are part of the clinical criteria for estimating response/relapse. However, most contrast agents currently used in clinics are based in metal elements such as Gadolinium and are not exempt of risks. In addition, due to the renal excretion route, administering such agents to some patients is contraindicated. Our work explored the potential of organic radicals anchored to dendrimers to act as contrast agents for glioblastoma studies, proposing a metal-free alternative for contrast enhanced glioblastoma studies. The article describes details of synthesis and characterization of these agents, as well as in vivo, ex vivo and in vivo magnetic resonance studies. The orthotopic immunocompetent GL261 glioblastoma murine model was used for in vivo and ex vivo studies. The novel contrast agent proved to be non-harmful for wild type mice and produced sustained and long lasting contrast in tumour-bearing mice, even in much lower doses in comparison with gadolinium administration.

The diagnosis and follow-up of high-grade brain tumours such as glioblastomas relies mostly in MRI, and contrast agents currently used are based on Gadolinium, which is not exempt of risks. The resarchers’ approach explores organic radicals anchored to dendrimers as a metal-free alternative to produce contrast enhancement in MRI, safer than Gadolinium-based compounds, and with translational potential.

Article of reference:
Zhang S, Lloveras V, Lope-Piedrafita S, Calero-Pérez P, Wu S, Candiota AP, Vidal-Gancedo J. Metal-Free Radical Dendrimers as MRI Contrast Agents fof Glioblastoma Diagnosis: Ex Vivo and In Vivo Approaches. Biomacromolecules. 2022 Jun 24. doi: 10.1021/acs.biomac.2c00088.

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How engineered protein helps Nanomedicine againts Cancer

The use of protein nanoparticles as biomaterials have been rising in recent years due to their characteristics: high biocompatibility, structural versatility, biodegradability and plasticity of design. We can later incorporate peptide ligands for specific targeting as fusion proteins and use these nanoparticles for targeted nanomedicine.

However, not all proteins can be used as scaffolds for targeted drug delivery, as they need to meet certain criteria. First, it is crucial that the proteins used as a scaffold allow site-specific drug conjugation. The stability and proteolysis resistance of these proteins is also important to remain assembled during the bloodstream circulation. In addition, the scaffolds must be biologically neutral, meaning that they should not interact with other human proteins that interfere with their capacity to reach and specifically deliver their cargo. The lack of immunogenicity of these proteins is also desired to avoid immune system recognition. And, ideally, the proteins used as a scaffold should not have post-translational modifications to ensure that they fold equally in both prokaryotic and eukaryotic cell factories for production.

The scaffolds that have all these properties have a better chance to both achieve a proper biodistribution and to successfully deliver their cargo molecules into the target cells. The Green Fluorescent Protein (GFP) satisfy most of the desired characteristics for a scaffold. Moreover, its intrinsic fluorescence allows the tracking of the protein distribution and intracellular localization both in vitro and in vivo.

The use of GFP as a protein scaffold for targeted drug delivery has been extensively studied in our group. We have been able to deliver cytotoxic drugs through our patented platform for targeted delivery. This platform consists of a cationic peptide ligand (T22) and a hexa-histidine peptide that act as self-assembling tags. T22 is a CXCR4 ligand that enables a targeted delivery to CXCR4+ cells, a receptor that is overexpressed in metastatic cancer cells. We have demonstrated previously in an in vivo model that more than the 85% of the administered product was accumulated in the tumor and that we could efficiently conjugate Floxuridine (a genotoxic antimetabolite) to our T22-GFP-H6 nanoparticles, resulting in a strong anti-metastatic activity.

Despite these very promising results, GFP is an exogenous protein from Aequorea victoria and, consequently, triggers an immune response, which limits its clinical use. Thus, we needed to find a human protein that matches the exceptional properties of GFP as a protein scaffold. Fortunately, a non-fluorescent GFP-like protein has been described in humans and it corresponds to one of the three globular domains of Nidogen, a structural protein that binds to collagen IV, laminin and perlecan with high affinity. The globular domain G2 has a beta-barrel structure with a central alpha-helix that folds very similarly to the GFP, despite that these proteins share very low sequence identity. Notably, this domain does not have post-translational modifications that could interfere with its production and folding in prokaryotic cells.

However, perlecan and collagen IV binding sites have been reported within this G2 domain. Therefore, we needed to selectively mutate these binding sites in order to assure the biological neutrality of the nanoparticles. After a thorough structural analysis, we incorporated four different mutations to engineer a biologically neutral product that was named HSNBT. There were no differences detected between the wild-type G2 domain and the engineered HSNBT protein regarding the predicted structural epitopes, which suggested that the introduced mutations would not generate immunogenicity.

In order to validate the new scaffold, we used the above-mentioned patented platform with T22 and the hexa-histidine tag, replacing GFP for the new HSNBT scaffold. First, we characterized the resulting nanoparticles and we determined, both by Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM), that they had a size of around 10 nanometers. Then, we observed that the T22-HSNBT-H6 nanoparticles were internalized effectively by CXCR4+ cells. This specificity was corroborated when we used a CXCR4 antagonist (AMD) and we saw a notable decrease of their internalization. Then, we successfully conjugated floxuridine to the nanoparticles (T22-HSNBT-H6-FdU) through the free lysine-amino groups of the protein and we demonstrated that the nanoconjugates had a potent cytotoxic effect in CXCR4+ cells.

Once we have validated these nanoconjugates in vitro, we tested them in a colorectal cancer mouse model. Notably, we saw an important tumor growth inhibition after several doses of these nanoconjugates. The inhibitory effect was slightly higher when using the new scaffold than with GFP. We also saw a significant increase in cell death bodies and caspase-3 activation in the tumor after the treatment with the nanoconjugates. Again, the effect was more potent with HSNBT as a scaffold than with GFP. Remarkably, the treatment did not result in any histological toxicity and there were no differences between the weight of the treated mice when compared to the untreated mice.

This technology is protected by 3 patents: The ligand to enter CXCR4+ cells (WO2012/095527), the nanoconjugates (EP17382461.6) and the human scaffold protein HSNBT, (EP19383201), all three licensed to Nanoligent SL.

All in all, these results confirm that the G2 domain of nidogen can be used as a protein scaffold for targeted drug delivery. Its performance both in vitro and in vivo not only matches the observed with GFP, but it is even more efficient than GFP when conjugated with floxuridine. Therefore, the engineered HSNBT protein shows a very exciting potential to be used in the development of protein-based nanomedicines.  

By Carlos Martínez Torró (NANBIOSIS U1 PPP)

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U16-S07. Evaluation of the adhesion capacities and formation of biolayers of microorganisms on materials. Evaluation of bactericidal and/or bacteriostatic responses of materials. OUTSTANDING

Description:

Evaluation of the adhesion of microorganisms to surfaces, including the evaluation of their viability. Adhesion can be studied under flow or static and at different contact times. Study of biolayers formed on materials after different growth times. Evaluation of bactericidal and/or bacteriostatic responses using viability kits or plate growth.


Applications:

Testing of materials with anti-infective objectives. Testing of compounds with antibacterial purpose.

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U16-E07. Equipment for microbiology tests on materials. OUTSTANDING

Description: It is the set of precise elements to carry out microbiological tests with materials. Includes laminar flow adhesion chambers, Robbin devices, shaker and drip bioreactors, fluorescence microscopes, plate readers, ovens, autoclaves, etc.

Technical specifications: Allows quantifications on different types of systems. Depending on the specific conditions, it is possible to evaluate behavior in extensive solid materials or in suspension.

Applications: The services that can be provided with this equipment are:
Evaluation of the adhesion capacities and formation of biolayers of microorganisms on materials. Evaluation of bactericidal and/or bacteriostatic responses of materials.

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