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A potential solution to decrease toxicity in colorectal cancer treatment

Cancer is one of the world’s leading causes of death, with over 18.1 million cases and 9.6 million deaths in 2018. One of the most successful drugs used in chemotherapy for the treatment of diverse severe cancers is 5-Fluorouracil (5-FU), however, one of the major problems described in clinical practice is 5-FU cell resistance.

Resarchers of the Nucleic Acids group and the Colloidal and interfacial Chemistry Group of CIBER-BBN at IQAC-CSIC have collaborated in a research to  inspect and test the ability of parallel G-quadruplexes to deliver floxuridine oligonucleotides into different types of cancer cells; finally, the internalization ability and the antiproliferative action of these oligoFdU-G-quadruplexes have been evaluated in FU-resistant cell lines.

Recently an article has been published with the research results by the Jorunal of Molecules entitled “Parallel G-quadruplex structures increase cellular uptake and cytotoxicity of 5-Fluoro-2′-deoxyuridine Oligomers in 5-Fluorouracil resistant cells”

The article describes a potential solution to decrease the toxicity of floxuridine, a known nucleoside antimetabolite used in the treatment of colorectal cancer, explains Ramón Eritja, Scientific Director of NANBIOSIS U29 from CIBER-BBN and IQAC-CSIC.

The authors used the NANBIOSIS Unit 29 Oligonucleotide Synthesis Platform (OSP) to prepare short oligonucleotides that form a tetrameric structure that is recognized by cancer cells facilitating the specific delivery to the tumor cells. Once inside of the cells, the oligonucleotides generate the active drug by nuclease degradation as a Trojan horse.

Article of reference:

Clua A, Fàbrega C, García-Chica J, Grijalvo S, Eritja R. Parallel G-quadruplex Structures Increase Cellular Uptake and Cytotoxicity of 5-Fluoro-2′-deoxyuridine Oligomers in 5-Fluorouracil Resistant Cells. Molecules. 2021; 26(6):1741. [DOI] 

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NANBIOSIS Scientific Women in the International Day of Women and Girls in Science

Today February 11 is the International Day of Women and Girls in Science, a day to raise awareness of the gender gap in science and technology.

According to the United Nations, while yet women and girls continue to be excluded from participating fully in science, science and gender equality are vital to achieve the internationally agreed development goals, including the 2030 Agenda for Sustainable Development. Thus, in recent years, the international community has made a great effort to inspire and promote the participation of women and girls in science.

NANBIOSIS wants to acknowledge  the efforts made by scientific women who struggle every day to contribute their bit to Science and highlight their essential role in nowadays research. Especially we want to recognize the work of scientists women involved in NANBIOSIS, whatever is the nature of their contribution: technical, scientific development, management, coordination, direction, etc; just to mention some examples:
Neus Ferrer and Mercedes Márquez in the Scientific Direction and Coordination of Unit 1 Protein Production Platform (PPP)
Pilar Marco and Nuria Pascual in the Management and Scientific Coordination of U2 Custom Antibody Service (CAbS) 
Miriam Royo in the Scientific Direction of U3 Synthesis of Peptides Unit
Nora Ventosa and Nathaly Segovia in the Scientific Direction and Technical Coordination of U6 Biomaterial Processing and Nanostructuring Unit
Isabel Oliveira and Teresa Galán in the Coordination of U7 Nanotecnology Unit
Rosa Villa and Gemma Gabriel in the Management and Scientific Coordination of U8 Micro – Nano Technology Unit
Gema Martínez in the Scientific Coordination of U9 Synthesis of Nanoparticles Unit
Fany Peña in the Scientific Coordination of U13 Tissue & Scaffold Characterization Unit
Mª Luisa González Martín and Margarita Hierro in the of Direction and Scientific Coordination of U16 Tissue & Scaffold Characterization Unit
Gemma Pascual and Isabel Trabado in the Coordination of the U17 Confocal Microscopy Service
Isolda Casanova in the Scientific Coordination of U18 Nanotoxicology Unit
Beatriz Moreno in the Scientific Direction of Unit 19 Clinical tests lab
Ibane Abásolo in the Scientific Coordination of Unit 20 In Vivo Experimental Platformt
Verónica Crisóstomo in the Scientific Direction of Unit 24 Medical Imaging 
Ana Paula Candiota in the Scientific Coordination of Unit 25 Biomedical Applications I 
Maria Luisa García in the Scientific Direction of U28 NanoImaging Unit from Bionand, recently incorporated to NANBIOSIS, Anna Aviñó in the Scientific Coordination of U29 Oligonucleotide Synthesis Platform (OSP) – and

Nerea Argarate in the coordination of NANBIOSIS

Thanks to all of you and your teams!

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Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles

In the frame of the collaboration of three units of NANBIOSIS, researchers of CIBER-BBN Groups proposed a strategy to simultaneously deliver anticancer drug pairs, composed by a tumor-targeted protein nanoparticle and an antiproliferative drug, with specific activ-ity for the same type of cancer.

These three units are:

The results on the investigation have been published in an article entitled “Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles”· by Acta Biomaterialia

The researchers have explored the possibility to conjugate tumor-targeted cytotoxic nanoparticles and conventional antitumoral drugs in single pharmacological entities using CXCR4-targeted self-assembling protein nanoparticles based on two potent microbial toxins, the exotoxin A from Pseudomonas aeruginosa and the diphtheria toxin from Corynebacterium diphtheriae, to which oligo-floxuridine and monomethyl auristatin E respec- tively have been chemically coupled.

The resulting multifunctional hybrid nanoconjugates, with a hydro- dynamic size of around 50 nm, are stable and internalize target cells with a biological impact. Although the chemical conjugation minimizes the cytotoxic activity of the protein partner in the complexes, the concept of drug combination proposed is fully feasible and highly promising when considering multiple drug treatments aimed to higher effectiveness or when facing the therapy of cancers with acquired resistance to classical drugs.

Thus, these results open a wide spectrum of opportunities in nanomedical oncology.

Article of reference:

Eric Voltà-Durán, Naroa Serna, Laura Sánchez-García, Anna Aviñó, Julieta M. Sánchez, Hèctor López-Laguna, Olivia Cano Garrido, Isolda Casanova, Ramón Mangues, Ramon Eritja, Esther Vázquez, Antonio Villaverde, Ugutz Unzueta Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles. Acta Biomaterialia, Volume 119, 1 January 2021, Pages 312-322), 57746-57756 https://doi.org/10.1016/j.actbio.2020.11.018 

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Nucleic Acids Chemistry, new book release by Ramon Eritja

Ramón Eritja, Scientific Director of NANBIOSIS Unit 29 Oligonucleotide Synthesis Platform (OSP) has just published a new book “Nucleic Acids Chemistry, modifications and conjugates for Biomedicine and Nanotechnology“, Anna Avinó, Scientific Coordinator of NANBIOSIS Unit 29 is also a writer of the book.

The book “Nucleic Acids Chemistry” takes the most important aspects of the methodology of oligonucleotides synthesis, that is currently expanding by the endorsement of a dozen of new medicines, such as the first medicine based on interfering RNA for the control of LDL and cholesterol in blood that will facilitate the decrease of cardiovascular illnesses.

The writing of the book has been directed by Dr. Ramon Eritja, of Centro de Investigación en Red de Nanomedicina (CIBER-BBN) and is Research Professor at Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), being its director between 2012-2017. The co-authors are Carme Fàbrega, Anna Aviñó, Santiago Grijalvo, Andreia F. Jorge, from IQAC-CSIC, Carlos González from Instituto de Química Física Rocasolano (IQFR-CSIC) and Raimundo Gargallo from University de Barcelona  The book began to be written in mid-2019, although most of the book was written during the lockdown.

In the last five years, an expansion of technologies based on DNA and RNA in diagnosis and therapeutic use has been produced, and it has been very important in the research of quick solutions to avoid the COVID pandemic and, predictably, the research group’s environment has led the development of several solutions, like biosensors for the direct detection of SARS-CoV-2.

A former PhD student of Ramon Eritja group, Dr. Ramón Güimil García, Head of Synthetic Oligonucleotides bei BioNTech, has participated in the development of the BioNTech-Pfizer mRNA vaccine. Another doctor, Brendan Manning, formed member of the group, has participated in the development of a diagnosis kit named Sherlock, which uses the CRISPR-Caspasa system for the detection of the virus that causes COVID.

Dr Erija completed his doctoral thesis at the University of Barcelona directed by Dr. Ernest Giralt on the subject of peptide synthesis. In 1984 he carried out his first postdoc with Dr. Itakura at the Beckman Research Institute of City of Hope in Los Angeles where the production of the first synthetic genes was carried out, highlighting the production of synthetic insulin that, with the name of humulin, solved the problems generated from the use of swine insulin. In 1986 she completed the second postdoc with Dr. Caruthers at the University of Colorado at Boulder. In this laboratory, phosphoramidites were developed, which are the reagents used today for the production of synthetic DNA and RNA. Upon his return to Barcelona, ​​he joined the CSIC Research and Development Center where he organized the first research group in our country focused on oligonucleotide synthesis. In 1984 he moved to the European Molecular Biology Laboratory (EMBL) in Heidelberg (Germany) to direct for 5 years one of the most prestigious groups in DNA and RNA Chemistry in Europe. Upon his return to Barcelona, ​​he was part of the Barcelona Institute for Biomedical Research (IRB Barcelona) and was recognized as a group of excellence by the CIBER-BBN. In 2012 he moved to the IQAC-CSIC to occupy the direction of the institute until 2017.

Refernce:

Nucleic Acids Chemistry – Modifications and Conjugates for Biomedicine and Nanotechnology Edited by: Ramon Eritja. De Gruyter | 2021 DOI: https://doi.org/10.1515/9783110639537

The book can be purchased here: link

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Non-viral mediated gene therapy in human cystic fibrosis airway epithelial cells recovers chloride channel functionality

Researchers of CIBER-BBN Units of NANBIOSIS: U29 Oligonucleotide Synthesis Platform (OSP) at IQAC_CSIC, led by Prof. Ramón Eritja and U10 Drug Formulation, at UPV-EHU, led by Prof José Luis Pedraz, are coauthors of an article published by International Journal of Pharmaceutics.

Gene therapy strategies based on non-viral vectors are currently considered as a promising therapeutic option for the treatment of cystic fibrosis (CF), being liposomes the most commonly used gene carriers. Niosomes offer a powerful alternative to liposomes due to their higher stability and lower cytotoxicity, provided by their non-ionic surfactant and helper components. In this work, a three-formulation screening is performed, in terms of physicochemical and biological behavior, in CF patient derived airway epithelial cells. The most efficient niosome formulation reaches 28% of EGFP expressing live cells and follows caveolae-mediated endocytosis. Transfection with therapeutic cystic fibrosis transmembrane conductance regulator (CFTR) gene results in 5-fold increase of CFTR protein expression in transfected versus non-transfected cells, which leads to 1.5-fold increment of the chloride channel functionality. These findings highlight the relevance of niosome-based systems as an encouraging non-viral gene therapy platform with potential therapeutic benefits for CF.

The article acknowledges U10 Drug Formulation, for the intellectual and technical assistance

Article or reference:

Non-viral mediated gene therapy in human cystic fibrosis airway epithelial cells recovers chloride channel functionality-Sainz-Ramos, M., Villate-Beitia, I., Gallego, I., A.L. Qtaish, N., Lopez-Mendez, T.B., Eritja, R., Grijalvo, S., Puras, G., Pedraz, J.L. International Journal of Pharmaceutics, 588, art. no. 119757, 2020. https://doi.org/10.1016/j.ijpharm.2020.119757

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Three Nanbiosis units work in the development of new sensors for the better detection of the fungus P. jirovecii, responsible for Pneumocystis pneumonia

Researchers from the CIBER-BBN have succeeded in developing detection systems for Pneumocystis jirovecii, an atypical fungus responsible for very serious pneumonia in immunosuppressed patients. These results, published in the journal Nanomaterials, are the result of collaboration between the CIBER-BBN groups led by Laura Lechuga, Ramon Eritja and Ramón Martínez Máñez, and the CIBERESP group led by Enrique J. Calderón.

The researchers acknowledge the paricipation of three NANBIOSIS units of CIBER-BBN:

The detection of the fungus in patients, who may be asymptomatic carriers until they develop pneumonia, is currently carried out using the PCR technique, requiring several hours, adequate facilities and qualified personnel to detect it. Now, the application of Nanotechnology has allowed the development of more sensitive and efficient biosensors to detect specific sequences corresponding to pathogens responsible for infectious diseases in a shorter time and without the need for large infrastructures.

In this case, a specific sequence corresponding to the gene belonging to the ribosomal subunit (mtLSU rRNA) of the P. jirovecii fungus has been detected using hairpin-shaped capture probes. These specific probes, as pointed out by Dr. Aviñó, a researcher at CIBER-BBN at the IQAC-CSIC, “are more efficient and are capable of recognizing a specific genomic sequence of the fungus and forming very stable triplex structures that can be detected on different platforms. biosensor “.

Laura Lechuga’s team at ICN2, through the use of an optical biosensor based on SPR technology, has detected in real time and without the use of markers, P. jirovecii in bronchoalveolar lavages and nasopharyngeal aspirates with a detection limit of nM level and in just a few minutes.

Likewise, the group led by Ramón Martínez-Máñez, scientific director of CIBER-BBN and principal investigator of the IQMA-IDM group at the Universitat Politècnica de València, has used the strategy of molecular gates composed of an anodic albumin matrix to develop a sensor capable of to efficiently detect real P. jirovecii samples without previous amplification steps in as little as one hour.

“These advances in the diagnosis of PCP have great potential for the development of highly sensitive point-of-care devices using direct patient samples and applicable in a wide variety of settings,” says the CIBERESP group leader. Enrique J. Calderón from the Virgen del Rocío University Hospital in Seville.

The researchers also emphasize that these techniques are very selective and can discriminate patients with other respiratory diseases derived from other microorganisms, thus allowing a more reliable diagnosis of infectious diseases.

Articles of reference:

Calvo-Lozano, O., Aviñó, A., Friaza, V., Medina-Escuela, A., S Huertas, C., Calderón, E. J., Eritja, E., Lechuga, L. M. (2020). Fast and accurate pneumocystis pneumonia diagnosis in human samples using a label-free plasmonic biosensor. Nanomaterials, 10(6), 1246. https://doi.org/10.3390/nano10061246

Pla, L., Santiago-Felipe, S., Aviñó, A., Eritja, R., Ruiz-Gaitán, A., Pemán, J., Friaza, V., Calderón, E.J. Martínez-Máñez, R., Aznar E. (2020). Triplex hybridization-based nanosystem for the rapid screening of Pneumocystis pneumonia in clinical samples. Journal of Fungi, 6(4), 292. https://doi.org/10.3390/jof6040292

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Closer to understand the regulation of SMARCA4 expression

Researchers of NANBIOSIS U29 Oligonucleotide Synthesis Platform (OSP) from CIBERBBN at @IQAC_CSIC, led by Prof. Ramón Eritja, are the authors of an article published by Int J Biol Macromol. 2020, entitled “Influence of pH and a porphyrin ligand on the stability of a G-quadruplex structure within a duplex segment near the promoter region of theSMARCA4 gene”. Prof Eritja hightlighs the contribution to this work by Dr. Raimundo Gargallo from the University of Barcelona.

The manuscript described the structural analysis of the promoter region of the SMARCA4 gene involved in ovarian cancer. This promoter region has an exceptionally long G-rich sequence. In this work we observed the formation of a singular G-quadruplex structure in equilibrium with an i-motif that can be modulated by changes in the pH and by the addition of external G-quadruplex ligands such as porphyrins. The NANBIOSIS Unit U29 provided synthetic versions of the DNA promoter region for the structural analysis.

In a previous work, the formation of G-quadruplex structures in a 44-nucleotide long sequence found near the promoter region of the SMARCA4 gene was reported. The central 25 nucleotides were able to fold into an antiparallel G-quadruplex structure, the stability of which was pH-dependent. In the present work, the effect of the presence of lateral nucleotides and the complementary cytosine-rich strand on the stability of this G-quadruplex has been characterized. Moreover, the role of the model ligand TMPyP4 has been studied. Spectroscopic and separation techniques, as well as multivariate data analysis methods, have been used with these purposes. The results have shown that stability of the G-quadruplex as a function of pH or temperature is greatly reduced in the presence of the lateral nucleotides. The influence of the complementary strand does not prevent the formation of the G-quadruplex. Moreover, attempts to modulate the equilibria by an external ligand led us to determine the influence of the TMPyP4 porphyrin on these complex equilibria. This study could eventually help to understand the regulation of SMARCA4 expression.

Article of reference:

Influence of pH and a porphyrin ligand on the stability of a G-quadruplex structure within a duplex segment near the promoter region of the SMARCA4 gene. Alba Navarro Sanae Benabou RamonEritja RaimundoGargallo. International Journal of Biological Macromolecules. Volume 159, 15 September 2020, Pages 383-393. https://doi.org/10.1016/j.ijbiomac.2020.05.062

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How to take advantage of the body’s natural processes to create innovative therapies?

During the month of October took place the Spanish Society of atherosclerosis (SEA 2020) Virtual meetings, promoted by Novartis. Prof. Ramon Eritja, Scientific Director of NANBIOSIS U29 Oligonucleotide Synthesis Platform (OSP) (from CIBERBBN at IQAC_CSIC), was the guess speaker in the session “Innovation and future therapeutic strategies in dyslipidemia” giving the conference entitled “How to take advantage of the body’s natural processes to create innovative therapies“, in the telematic congress of the Spanish society of atherosclerosis (SEA 2020) in the session “Innovation and future therapeutic strategies in dyslipidemia”.

Dr. Ramon Eritja, explained the mechanism of action of some new drugs based on small DNA or RNA fragments and especially the mechanism of action of Inclisiran (Leqvio®). This new medicine developed by Novartis received a positive report from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for the treatment of familial hypercholesteria. It is the first time that this type of medicine has received a positive report for the treatment of a very prevalent disease that is one of the causes of cardiovascular diseases.

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NANBIOSIS researchers featured in the 15th Edition of Spanish Researchers Ranking

The 15th edition of the Webometrics Ranking of World Universities has been published, ranking researchers in Spain as well as Spaniards doing research abroad. A total of 11 Directors of NANBIOSIS units appear on the most recent list, featured on the top 2000. The list is ordered by the h-index, a metric that calculates research impact based on a correlation of papers published and number of citations, and then by number of citations. The result is a list of whose’s publications have had more impact online.

NANBIOSIS researchers featured are Fernando Albericio (#207), scientific director of U3 Synthesis of Peptides Unit, Ramón Martínez Máñez (#342) U26 NMR: Biomedical Applications II, Jaume Veciana (#459) U6 Biomaterial Processing and Nanostructuring Unit, José Luis Pedraz (#906) U10 Drug Formulation unit, Jesús Santamaría (#912) U9 Synthesis of Nanoparticles Unit, Ramón Eritja (#1022) U29 Oligonucleotide Synthesis Platform (OSP), Pablo Laguna (#1153) U27 High Performance Computing, Antoni Villaverde (#1249) U1 Protein Production Platform (PPP), Laura Lechuga (#1511) U4 Biodeposition and Biodetection Unit M.Pilar Marco (#1517), U2 Custom Antibody Service (CAbS), and Josep Samitier (#1836) U7 Nanotechnology Unit.

This list reflects on the impact online publication can have as a tool to share knowledge. 

For further information: here

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NANBIOSIS U2, U3 & U29 participate in the POC4CoV project to develop diagnostic technologies for SARS-COV-2

The Spanish Higher Council for Scientific Research (CSIC) will finance the project Point-of-care tests for the rapid detection of SARS-CoV-2 (POC4CoV), whose objective is to have effective diagnostic technologies for Covid-19. The Institute of Microelectronics of Barcelona (IMB-CNM-CSIC), the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC) and the Institute of Materials Science of Aragon (ICMA) participate in it.

The POC4CoV project aims to develop Point-of-Care (POC) devices for the in vitro diagnosis of SARS-COV-2 infection quickly and reliably, thanks to the use of multiplexed systems and the use of particular biomolecular probes. To do this, POC technological platforms will be used in combination with specific capture biomolecules and nanobiotechnological probes (enzyme bioconjugates and biofunctional plasmonic and magnetic nanoparticles), which will allow the simultaneous detection of different biomarkers (viral RNA and antigens, IgM and IgG) related to Covid-19 disease. The biomolecular complexes will be collected at specific points on the devices where the electrochemical or optical signals will be recorded.

The developed POC platforms will undergo analytical and clinical validation in a clinical setting.

Three units of NANBIOSIS (form CIBER-BBN and IQAC-CSIC) will will take an active participation in the project.

NANBIOSIS Unit 2 Custom Antibody Service (CAbS), will produce antibodies against the Spike protein and other virus proteins, trying to maximize the recognition of those epitopes that differentiate SARS-CoV-2 from other Coronaviruses

NANBIOSIS Unit 3 Synthesis of Peptides Unit will synthesize peptidic sequences that will allow to identify towards which epitopes the immune response is directed, which will allow to develop more specific diagnostic methods.

NANBIOSIS Unit 29 Oligonucleotide Synthesis Platform (OSP) has designed probes with oligonucleotide sequences that will allow the capture of viral RNA through the formation of high affinity triplex complexes

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