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New fluorescent organic nanoparticles to see the invisible

A new nanomaterial for bioimaging has been developed by researchers at NANBIOSIS Unit 6 Biomaterial Processing and Nanostructuring Unit from the Nanomol group from ICMAB-CSIC and CIBER-BBN . The researchars are also members of the TECNIO technology transfer network ACCIÓ-Generalitat de Catalunya, together with the New Jersey Institute of Technology (NJIT, USA) and the University of Parma (UNIPR, Italy). The results of the study are the result of the TECNIOspring PLUS project co-financed by ACCIÓ and the European Commission.

It is true that it is very difficult to understand what happens in our bodies if we are unable to visualise it. For example, we currently know that tumour cells have the capacity to grow without control thanks to various microscopic techniques that have allowed us to enlarge them to such an extent that we have been able to see each cell perfectly. The design of microscopes and the optical and electronic engineering behind them has advanced very rapidly in recent years. In fact, the 2014 Nobel Prize in Chemistry was awarded to researchers Eric Betzig, William E. Moerner and Stefan Hell, for the development of super-resolution fluorescence microscopy. These advances have made it possible to see even what is inside cells, reaching the nanometer scale with high resolution.

Now, what happens when we are not able to see what we are looking for? This is where fluorescent probes come into play, molecules that provide a signal: they emit light at a certain wavelength once they are excited. These probes must meet a series of requirements, among which are: they must have a high luminosity or brightness, be totally biocompatible, and have high photo-stability and high dispersibility in physiological media.

The Nanomol group has developed new fluorescent probes, specifically fluorescent organic nanoparticles (FONs). These new FONs are based on Quatsomes (QSs), nanovesicules produced by the same group through a green technology (Delos-susp, Nanomol Technologies SL), which are charged with fluorophores or fluorescent molecules – specifically two types of carbocyanins. The nanoparticles have an average diameter of 120 nm and have demonstrated good biocompatibility and high stability, both over time and once exposed to high power laser irradiation.

Characterization of nanovesicles was made at the ICTS “NANBIOSIS”, more specifically by the Unit 6 Biomaterial Processing and Nanostructuring Unit of CIBER-BBN.

“The brightness achieved is especially relevant: these new fluorescent nanoparticles are about 100 times brighter than other commercial fluorescent nanoparticles, such as Quantum Dots, thus allowing the acquisition of high quality images” explains Judit Morla-Folch, postdoctoral researcher of the Nanomol group at the ICMAB and first author of the study, published in the journal ACS Appl. Mater. Interfaces.

In addition, these nanoparticles have another singularity, and that is that they experience Förster resonance energy transfer, usually abbreviated as FRET. This phenomenon allows for improved image acquisition as it significantly reduces self-absorption and therefore background noise during bioimage acquisition. In addition, the FRET effect allows the integrity of the nanoparticle to be monitored, a great advantage for biomedical applications where it is necessary to know when the nanovesicle remains as a whole or it disintegrates.

In summary, the fluorescent organic nanoparticles (FONs) developed by the Nanomol group of the ICMAB-CSIC in collaboration with the NJIT (USA) and the UNIPR (Italy) constitute a promising platform for bioimaging and for the design of medical diagnostic kits.

Cover Figure: The new fluorescent organic nanoparticles allow to improve the visualization of cells and tissues under the microscope.

Reference article:

Dye-Loaded Quatsomes Exhibiting FRET as Nanoprobes for Bioimaging
Judit Morla-Folch, Guillem Vargas-Nadal, Tinghan Zhao, Cristina Sissa, Antonio Ardizzone, Siarhei Kurhuzenkau, Mariana Köber, Mehrun Uddin, Anna Painelli, Jaume Veciana, Kevin D. Belfield, and Nora Ventosa
ACS Appl. Mater. Interfaces 2020, 12, 18, 20253–20262
DOI: 10.1021/acsami.0c03040

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Peptide‐Capped Mesoporous Nanoparticles: Toward a more Efficient Internalization of Alendronate.

Osteoporosis is an illness which appears when the osteoblast/osteoclast activities are unbalanced taking place bone resorption (caused by osteoclasts) in higher extension than bone formation (induced by osteoblasts). Alendronate is one of the most used drugs for osteoporosis treatment despite its scarce bioavailability. In an attempt to improve it, gated mesoporous silica nanoparticles, for the controlled release of alendronate, have been synthesized and characterized. These hybrid nanoparticles include labelled alendronate inside the porous, those porous are capped with a peptide designed to be selectively cleaved by cathepsin K enzyme (overexpressed in osteoclasts).

Two CIBER-BBN units of the ICTS NANBIOSIS were implied in the research: the peptide was prepared by U3 Synthesis of Peptides Unit and substances were characterized at U26 NMR: Biomedical Applications II Unit at University of Valencia.

The nanoparticles were internalized by RAW 264.7 macrophages (which could differentiate in osteoclasts) and were able to release its entrapped cargo in the presence of cathepsin K added in the macrophage lysates. From the set with aminopropyl functionalized silica, loaded with nitrobenzofurazan labelled alendronate and capped with the same peptide, 4.2% of the total alendronate amount in contact with the cells is liberated inside them and could produce its therapeutic effect.

Article of reference:

Elena Añón, Ana M. Costero, Pedro Amorós, Jamal El Haskouri, Ramón Martínez‐Mánez, Margarita Parra, Salvador Gil, Pablo Gaviña, M. Carmen Terencio, María Alfonso. Peptide-Capped. Mesoporous Nanoparticles: Toward a more Efficient Internalization of  Alendronate. Chemistry Europe, March 2020

https://doi.org/10.1002/slct.202000417

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A recombinant SARS-CoV-2 vaccine

NANBIOSIS Protein Production Platform (PPP) Unit 1 (of CIBER-BBN and Autonomous University of Barcelona) is involved in a micro-patronage project for the development of a vaccine for COVID 19.

NANBIOSIS Unit 1 is directly involved in the initial part of the Virus Like Particles and Proteins expression and purification project of SARS-COV-2

Most vaccines used today are based on either attenuated forms of the original pathogen, or are inactivated vaccines, in which the pathogen has undergone physical or chemical treatments to eliminate its infectivity. The project proposes to use a new vaccine strategy based on recombinant proteins in imitation of viruses (virus-like particles or VLPs). The same strategy with which, for example, papillomavirus and hepatitis B virus vaccines have been created.

VLPs contain recombinant structural proteins, obtained by the introduction and expression of a gene in cultured cells, that form nanostructures similar to viral particles but do not contain their genetic information and, therefore, are not infectious. These particles are capable of arousing a strong immune response as they form a three-dimensional structure where the virus epitopes are exposed, but they are very safe.

VACCINE PROTOTYPE:

Design
First, we will design the genes that encode the structural proteins of the virus. At this point, the different sequences of the virus genome deposited in public databases must be analyzed and compared in detail. In this way, we can select the most representative sequence. On the other hand, we will carry out some control tests to detect the different fragments of the proteins where the response of the immune system is concentrated, the so-called antigens.
These studies will be carried out using bioinformatics tools by the Computational Biology Group of dr. Xavier Daura from the UAB Institute of Biotechnology and Biomedicine (IBB).

Production and purification
To carry out these productions, we need to use cultured cell lines in which we introduce the genes that encode the virus’s proteins and establish optimal obtaining conditions, without the need to use highly biological containment laboratories. Once produced, we will carry out a purification process and they can be validated.

This block will be carried out in parallel by the research group led by Dr. Francesc Godia from the Department of Chemical, Biological and Environmental Engineering, and Dr. Neus Ferrer from the Department of Genetics and Microbiology and member of the Nanobiotechnology Group led by Dr Antoni Villaverde, attached to the IBB and the CIBER-BBN. In addition, we will have the help of UAB research-scientific-technical services, such as the Microscopy Service (SM), and the Proteomics and Structural Biology Service (sePBioEs) and a unique scientific-technical infrastructure called NANBIOSIS.

Validation with patient serum and cell models
Once the proteins are purified, it is necessary to validate the vaccine formulations with patient serum. In other words, it must be demonstrated that the patient sera of the COVID-19 are linked to the vaccine proposals developed. This task will be coordinated by dr. Eduard José Cunilleras from the UAB Department of Animal Medicine and Surgery in collaboration with doctors from the Parc Taulí, Germans Trias, Vall d’Hebron and Santa Creu i Sant Pau hospitals, and the help of the scientific-technical service to support the research of the Crop, Antibody and Cytometry Service (SCAC) of the UAB.

TESTS ON ANIMALS

Any product to be administered to humans must first go through a preclinical phase in animal models. All trials, when they reach this stage, must be approved by the Ethics Committee on Animal and Human Experimentation. The safety and efficacy of the vaccine are tested in these models.

During vaccination trials we will monitor the weight of the animals and their general condition. The presence of antibodies in the blood of vaccinated animals will be evaluated in cell cultures. The serum of the vaccinated animals will be incubated with the SAR-CoV-2 and we will proceed to the infection of cell cultures. If the antibodies are capable of reducing the infectivity of the virus, then we will move on to the final part of this stage, which will consist of infecting the vaccinated animals with the virus to see if they are protected from infection. A group of unvaccinated animals will also be infected and we will compare the results with another group of unvaccinated and uninfected animals. The vaccine should give similar results to the last group of animals.

Further information about the project and FAQs about donations: https://micromecenatge.uab.cat/vacunacoronavirus

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A project to develop rapid and early diagnostic tests of Covid-19 to reduce false negatives

The Journal Heraldo de Aragón has published an article highlighting the participation of Aragonese researchers in projects to fight Covid-19 Pandemic. Pilar Martín Duque, researcher from NANBIOSIS U9 Synthesis of Nanoparticles Unit, is leading a project financed by the Covid-19 Fund, launched by the Carlos III Health Institute (ISCIII). Thanks to this project, rapid and early diagnostic tests of Covid-19 are being developed to reduce false negatives.

To read the article: https://www.heraldo.es/branded/la-tecnologia-y-la-innovacion-claves-vitales-para-el-desarrollo-sostenible/

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“We need a drastic change in the organization and management of science”

The Jorunal “Redacción Médica” has created an espace call Covid-19 Lessons to gather critical evaluations and recommendations of the most relevant personalities in the health sector, so that the National Health System and the professional and business ecosystem that surrounds it can draw conclusions and face future similar challenges with greater guarantees.

Laura M. Lechuga, Scientific Director of NANBIOSIS U4, from CIBER-BBN at ICN2-CSIC, coordinates CONVAT, one of the projects selected by the European Commission to advance in the knowledge about the Coronavirus, adds her perspective to the document Covid-19 Lessons: “We need a drastic change in the organization and management of science“

According to prof. Lechuga, ·one of the main successes in this crisis has been the intense and excellent dedication of a large part of the international scientific community who, from a multidisciplinary perspective, has tried to contribute their talent and training to make great strides in the knowledge of this new SARS-CoV-2 virus; this crisis has driven this collaboration exponentially. “The rapid mobilization of funds and resources available to scientists has also been (and continues to be) impressive during this crisis. The pandemic has placed before the eyes of all humanity that the greatest values of our society lie in knowledge, training, science and research to face a problem of these dimensions that unfortunately may be repeated in the future.“

As main errors, Laura Lechuga highlights the disconnection between the scientific and political world. “The scientits had contributed its knowledge and rigorous studies to warn of the dangers that lie in wait for us, but it is clear that until now the connection between scientific advice and government policies is extremely weak, not only in our country. country but also internationally”

Possibly, at the national level, our scientific system could have given a faster response if it had been much more robust and competitive and had not been so weakened due to the numerous cuts suffered since the previous crisis and the lack of replacement of researchers. Our research environment, although it is nourished by a lot of talent, is not so much in its own development resources, infrastructures and technologies, so its contribution is being more limited.

There is no doubt that we need a decided investment in science both in terms of human and material resources, and a drastic change in the organization and management of science, which causes our scientists to invest most of their valuable time in requests for funding, resources human and cumbersome administrative justifications, which have little to do with scientific research“.

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New therapy for triple negative breast cancer is successfully tested in preclinical animals

Researchers CIBER-BBN and NANBIOSIS Unit 26, the Príncipe Felipe Research Center (CIPF), the Universitat Politècnica de València (UPV) and the Institut de Recerca Biomèdica (IRB) of Barcelona manage to inhibit tumor growth, reduce metastasis and decrease the toxicity of the antitumor drug Navitoclax in preclinical animal models of triple negative breast cancer (TNBC).

These types of TNBC tumors do not express any of the three receptors involved in most breast cancers (estrogen, progesterone, and HER2), so the most common treatments such as hormone therapy are not viable in these patients.

This new study, led by Mar Orzáez, principal investigator of the CIPF Peptides and Proteins Laboratory and Ramón Martínez Máñez, scientific director of CIBER-BBN, NANBIOSIS Unit 26, member of the CIPF-UPV Joint Unit in Mechanisms of disease and Nanomedicine and researcher at the Interuniversity Institute of Research on Molecular Recognition and Technological Development (IDM) at UPV, shows that a combined treatment of a senescence inducer and a senolytic nanoparticle, selectively removes senescent cells, delays tumor growth and reduces metastasis in a mouse model of aggressive breast cancer.

Until now, the application of senescence inducers represents a successful treatment strategy in patients with breast cancer, although the accumulation of senescent cells in the body can sometimes promote tumor recurrence.

Cell senescence or aging takes place in both physiological and pathological situations. When a cell goes into senescence, it stops dividing and releases substances that cause inflammation.

When an uncontrolled accumulation of these senescent cells occurs, the excess of inflammatory factors can end up damaging healthy cells, thereby contributing to aging, the appearance of pathologies such as diabetes, neurodegenerative diseases or promoting the development of tumors and promoting metastasis.

With this new approach, after the induction of senescence, the cells are eliminated by treatment with a senolytic nanoparticle, and a new therapeutic opportunity opens up to improve the results in patients with breast cancer and a new combined treatment is proposed that may be relevant to other senescence-inducing chemotherapeutic drugs.

The results, published in the Journal of Controlled Release (JCR), offer new therapeutic approaches to advance in later phases and clinical trials and allow different tumor types to be addressed.

Orzáez and Máñez have pointed out that “the induction of senescence in tumors represents an advance in the treatment of cancer, which may be even greater in combination with this type of senolytic treatments that eliminate senescent cells and help reduce metastasis.”

Manuel Serrano from the Institut de Recerca Biomèdica (IRB) in Barcelona has also collaborated in the study.

Article of reference:

Irene Galiana, Beatriz Lozano-Torres, Mónica Sancho, María Alfonso, Andrea Bernardos, Viviana Bisbal, Manuel Serrano, Ramón Martínez-Máñez, Mar Orzáez, Preclinical antitumor efficacy of senescence-inducing chemotherapy combined with a nanoSenolytic, Journal of Controlled Release, Volume 323 https://doi.org/10.1016/j.jconrel.2020.04.045

Sourse of information: CIBER-BBN

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Scientific trends with the participation of NANBIOSIS expertise

Within the series of virtual conferences organized during the months of May, June and July by the Extremaduran office, two researchers of NANBIOSIS are invited speakers: Laura M. Lechuga Gómez, NANBIOSIS Unit 4 Biodeposition and Biodetection Unit (form CIBER-BBN and ICN2-CSIC); and María Coronada Fernández Calderón NANBIOSIS U16 Surface Characterization and Calorimetry Unit (from CIBER-BBN and University of Extremadura)who will talk about technologies at the service of health.

The cycle ’90 minutes for Science, for innovation to bring society closer to the latest scientific trends, starts next Wednesday, May 27, at 5:00 p.m. It will deal with topics such as biomedical research and its influence on the improvement of early diagnosis of diseases (the director of the Department of Immunology and Oncology of the CSIC National Biotechnology Center, Ana Cuenda Méndez, will offer a conference on the role of proteins in inflammatory, infectious and cancer processes, and the engineer in Molecular Biotechnology and principal investigator in the Laboratory of Medical Biotechnology of the Austral University of Chile, Alejandro Rojas-Fernández, will address the generation of nano-antibodies against emerging viruses, such as COVID19), ethics in the face of the challenges of artificial intelligence.

Registration, open and free, can now be formalized on the website of the Office for Innovation.

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NAV-GAL, a new senolytic drug against cancer, on spanish TV

The work carried out by the team of researchers of CIBER-BBN and Politecnic University of Valencia, led by, Ramón Martínez Máñez, Scientific Director of NANBIOSIS U26 NMR: Biomedical Applications II, is highlighted by the Spanish TV.

This team has developed a new drug against lung cancer that, along with other therapies, eliminates cells that have been bottled prematurely without harming healthy ones. The drug has been successfully administered in mice, now it comes the challenge of finding a way to administer it without damaging the patient’s healthy organs, and they propose inserting it into a capsule that would be released only in the intestine, thus preventing it from passing through the stomach even if it was administered orally.

This new drug called Nav-Gal , is part of the drugs called “senolytics”, those that are capable of killing only cancer cells.





Further information here
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“Molecular probes and gated materials in biomedical applications and communication between nanoparticles” by Ramón Martínez

Next June 8, 2020, 12 pm, Ramón Martínez Máñez, Scientific Director of CIBER-BBN and NANBIOSIS U26, give an on line seminar, hosted by Jaume Veciana and Anna Roig will from ICMAB-CSIC.

The development of optical molecular probes and probes based on gated nanoparticles has been an area of interest during the last decades. Optical probes are able to transform chemical information in the environment into a suitable optical signal, usually a change in colour of fluorescence. Moreover, gated materials have also been widely used for the development of drug delivery systems.

Some examples of optical probes and gated materials for sensing and controlled delivery in biomedical applications will be described. From another point of view, the talk will also describe how nanoparticles are able to communicate each to another via the exchange of chemical messengers. Communication between nanodevices may find applications in different areas and a number of future new results are envisioned in this research field.

The development of optical molecular probes and probes based on gated nanoparticles has been an area of interest during the last decades. Optical probes are able to transform chemical information in the environment into a suitable optical signal, usually a change in colour of fluorescence. Moreover, gated materials have also been widely used for the development of drug delivery systems.

Register HERE to attend the seminar via Zoom. 

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CoNVaT, the ‘Nanotrap’ for the coronavirus – highlighted by BBVA Fundation

Prof. Laura M. Lechuga, Scientific Director of NANBIOSIS Unit 4 Biodeposition and Biodetection Unit (from CIBER-BBN and ICN2-CSCIC) was awarded with the Physics, Innovation and Technology Award of the Royal Spanish Physics Society (RSEF) and the BBVA Foundation 2016.

BBVA Foundation has dedicated an article to explain the  EU CoNVaT project, led by Laura Lechuga, whose objective is to obtain a diagnostic test for COVID-19 from the first day of infection, fast but highly sensitive, and which does not require a laboratory or qualified personnel. A test made with extremely sophisticated technology, and at the same time low cost, applicable to future waves of the epidemic. It is financed with more than two million euros by the European Union with a duration of one year.

The test is a biosensor that uses nanophotonics, and it will be used in two devices: one will detect virus proteins, the other, its genetic material. The heart of the device, and what gives it its main advantage over other existing diagnostic tests, is a chip that implements one of the most sensitive measurement techniques in physics: photonic interferometry. It is based on the idea that a beam of light undergoes small but measurable changes when it intersects an object. On the CoNVaT project chip, changes in the light beam will alert to the presence of the virus in the sample.

The test that will detect virus proteins is what is technically called an ‘antigen test’. It can be carried out in health centers or at sampling points, by non-specialized staff, and will give results in less than thirty minutes. Saliva samples will surely be used, although researchers are still studying it.

“The technique is so sensitive that it will be able to detect the presence of the virus from the first day of infection,” explains Lechuga. “And it will not only tell if the virus is or not, but also in what quantity. This is important because it gives an idea of ​​how advanced the infection is. ”

‘Nanotrap’ for the coronavirus

The device will occupy what a shoe box, but at its core, where the measurement takes place, everything happens on a nanometric scale, that is, to dimensions of millionths of millimeters. It is, in essence, a nanotrap for proteins. Researchers attach proteins designed in the laboratory specifically to trap certain proteins in the virus envelope to the chip; both fit as a key and lock, so that the proteins fixed on the chip are actually hooks of the highest specificity – they only capture the virus’s proteins.

Channels a few nanometers thick have also been engraved on the chip: light passes through them. These guides form a circuit with a single input, but which forks, so that only one of the branches passes through the protein trap. When both light beams meet again, it is observed that the one that has interacted with the proteins has undergone modifications, and it is the analysis of these changes that reveals the presence of the virus, and in what quantity.

The device to detect genetic material of the virus -RNA- is based on the same principle, but it should be done in the laboratory. Lettuce explains that its purpose will be above all to confirm the result of the first. It will be faster than the PCR currently used – less than half an hour versus several hours – and it does not need specialized technicians – something indispensable with PCR.

Biology is the most difficult

“In this type of device, the biological part is by far the most complex,” explains Lechuga. Anchor the proteins to the chip at the correct angle, stabilize them to resist movement, keep them in a liquid medium … “they are thirty steps”.

It is a very sophisticated technology but already validated in the clinic. The ICN2 Biosensors and Bioanalytical Applications Group led by Lechuga has developed, among others, nano-biosensors that detect colon cancer early in blood samples, and also for tuberculosis and sepsis cases. “One of the reasons we have achieved the ConVAT project is that we have experience with clinical samples, which is really a completely different world than the laboratory.”

The group advances fast. They started working about three weeks ago and have just received from their French collaborators proteins that match those of the virus. Patient validation, when the device is completed, will be handled by the group in Italy.

The objective, at the end of the project, is for a company to take care of scaling the technology to bring it to the market at an affordable price. “Especially in a situation like the current one, we work with the idea that our work can reach everyone, as soon as possible,” says Lechuga.

Further information in Spanish in the original article by MÓNICA G. SALOMONE BBVA Foundation

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