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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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A new compound removes senescent cells and reduces toxicity in cancer treatment

  • Scientists of NANBIOSIS unit 26 NMR: Biomedical Applications II, (of CIBER-BBN and the Universitat Politècnica de València), together with researchers from the Principe Felipe Research Center and the University of Cambridge confirm the therapeutic potential of using a new conjugated drug, Nav-Gal, in combination with chemotherapy

  • Nav-Gal selectively removes tumourigenic senescent cells without attacking healthy cells and reduces the toxicity of platelets

The accumulation of senescent cells plays a significant role in cancer pathogenesis and other diseases. However, senolytic drugs (intended to remove senescent cells) present significant toxicity, which limits their therapeutic benefits.

Now, a new international study involving researchers at CIBER-BBN, the Universitat Politècnica de València (UPV) and the Principe Felipe Research Center, in collaboration with the University of Cambridge, have just proved the efficiency of a new conjugated drug, Nav-Gal, which selectively removes senescent cells, minimising the effect on healthy cells and reducing toxicity through this therapy. The use of this drug in combination with chemotherapy could be confirmed as a promising strategy in treating cancer. The auspicious results of this study have been published in the journal Aging Cell.

Senescent cells: the target

Senescence is a response to cell damage and stress characterised by the arrest of the cell cycle. When aging, cells permanently stop dividing, thus preventing the propagation of damaged and dysfunctional cells. However, eventually, a massive quantity of senescent cells accumulate in tissues, resulting in the onset and progression of multiple disorders, including diabetes, cardiovascular diseases, lung fibrosis, neurological disorders or cancer. Moreover, in the case of cancer, several chemotherapies result in cell senescence, and this accumulation of senescent cells due to the treatments has been related to tumourigenesis, associated with metastasis and the recurrence of tumours in different types of cancer. That is why the search for new drugs that remove senescent cells induced by cancer treatments is a key question in order to guarantee the total eradication of the tumour and prevent them from recurring.

On this front, senolytic drugs (compounds that kill senescent cells using several mechanisms) are a promising therapeutic alternative in oncology and for treating other diseases related to the accumulation of senescent cells. However, today senolytics present a low specificity because they also damage healthy cells, and have significant toxicities, which reduce their therapeutic benefits.

Reducing toxicity and preventing “collateral damages”

In this new study, published in Aging Cell, researchers at CIBER-BBN, the Universitat Politècnica de València (UPV) and the Principe Felipe Research Center, in collaboration with researchers from CRUK, at the University of Cambridge, worked on the design of a second-generation senolytic, which is more specific and less toxic. They focused on Navitoclax, a drug validated in preclinical models that proved to have a high capacity to destroy senescent cells, modifying it with acetylated-galactose.

The new compound, called Nav-Gal, results in a drug with selective, wide-ranging senolytic activity, which induces the death of senescent cells while preserving the activity of healthy cells.

“To summarize, we suggest the galactose conjugation with certain drugs as a versatile methodology to develop second-generation prodrugs with high senolytic activity and reduced toxicity,” explains Ramón Martínez Máñez, member of the Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM) of the Universitat Politècnica de València, Scientific Director of CIBER-BBN and one of the study’s coordinators.

The researchers tested this drug in combination with chemotherapy (cisplatin) in human lung cancer cells, proving that treatment with cisplatin and Nav-Gal results in the eradication of senescent lung cancer cells and significantly reducing tumour growth. “This study provides evidence of the potential clinical application of combining senescence-induction chemotherapies with senotherapies in cancer,” explains Daniel Muñoz Espín from the CRUK Early Detection Programme of the University of Cambridge. Moreover, the compound Nav-Gal reduced platelet toxicity and the thrombopenia (reduction of the platelet circulation in bloodstream) caused by the previous drug, Navitoclax.

Reference article:

Galacto‐conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13142

About CIBER-BBN

CIBER (Consorcio Centro de Investigación Biomédica en Red, M.P.) belongs to the Institute of Health Carlos III of the Spanish Ministry of Science and Innovation, and it is also funded by the European Regional Development Fund (ERDF). The CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) is made up of 46 research groups, selected for their renowned international scientific prestige, that mainly work within three scientific programmes: Bioengineering and Biomedical Imaging, Biomaterials and Tissue Engineering, and Nanomedicine. Its research work is oriented toward the development of prevention, diagnosis and monitoring systems as well as technologies for specific therapies such as Regenerative Medicine and Nanotherapies.

Further information

CIBER Communication Department

comunicacion@ciberisciii.es / 91 171 8119

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NANBIOSIS research to fight cancer

Twenty years ago, the 4 February was declared World Cancer Day with the global challenge of cancer would not be forgotten. Since then, huge progress has been made to understand, prevent, diagnose, and treat cancer.

NANBIOSIS as an ICTS (Singular Scientific and Technical infrastructures) for biomedical research plays a very important role in the fight against cancer. Some examples of the work carried out during the last year, are bellow:

Unit 20 of NANBIOSIS  at VHIR, works in several proyects reletaed to cancer as  H2020-NoCanTher: magnetic nanoparticles against pancreatic cancer through the use of hyperthermia combined with conventional treatment. H2020-Target-4-Cancer: nanotherapy based on polymeric micelles directed against specific receptors of tumor stem cells in colorectal cancer. H2020-DiamStar: nanodiamonds directed against leukemia for the potentiation of chemotherapy. FET-OPEN EvoNano: in silico and tumor-tumor models for the prediction of PK / PD and tumor efficacy of antitumor nanomedicines against tumor stem cells.

The activities of U1 of Protein Production Platform (PPP) are also strongly committed with several projects devoted to develop new, more selective and more efficient antitumoral drugs, with antimetastatic effects.
oordinated action between units U1 of Protein Production Platform (PPP),
U18 of Nanotoxicology and U29 of Nucleic Acid Synthesis, shows promising results in development of nanopharmaceuticals with a high degree of efficacy for the treatment of metastases in colon cancer

Unit 6 of NANBIOSIS Biomaterial Processing and Nanostructuring Unit  is also working on a joined initiative between CIBER-BBN and CIBER-ONC to improve the current ex vivo immune cell expansion systems to help introduce immunotherapies such as the adoptive cell therapies, which have shown complete remissions of terminal cancer patients, to the clinics overcoming the limitation of having enough therapeutic cells with novel Nanobiomaterials. Researchers of Unit 6 and researchers of Laboratory of Translational Research in Child and Adolescent Cancer from the Vall d’Hebron Research Institute (VHIR), are working on a project financed by the Spanish Government and CIBER-BBN, for the development of a new nanomedicine for the treatment of high-risk neuroblastoma, one of the most frequent childhood cancers.

In our unit U26. NMR: Biomedical Applications II,  several studies for cancer biomarker discovery are being carried out. NMR studies on biofluids for the design of novel strategies for diagnosis support, easily transferable into the clinical practice, are being developed in biofluids in the context of cancer. Urine is one of the most easily obtainable biofluid and is a non-invasive source of biomarkers. Among these studies, we can mention the good discrimination achieved between urine from bladder cancer patients before surgery (cancer) and urine after surgery (free of cancer) and in the follow up of the disease, to monitor relapses

Some of the results of these researchs have been published in scientific magazines of high impact as for exemple;

Integrative Metabolomic and Transcriptomic Analysis for the Study of Bladder Cancer Alba Loras, Cristian Suárez-Cabrera, M. Carmen Martínez-Bisbal, Guillermo Quintás , Jesús M. Paramio, Ramón Martínez-Máñez,
Salvador Gil and José Luis Ruiz-Cerdá. Cancers 2019, 11, 686; doi:10.3390/cancers11050686

Nanostructured toxins for the selective destruction of drug-resistant human CXCR4+ colorectal cancer stem cells Naroa Serna, Patricia Álamo, Prashanthi Rameshef, Daria Vinokurovaef, LauraSánchez-García, Ugutz Unzueta, Alberto Gallardo, María  Virtudes Céspedes, Esther Vázquez, Antonio Villaverde, Ramón Mangues, Jan Paul Medema. . Journal of Controlled Release.  Volume 320, 96-104, 2020 https://doi.org/10.1016/j.jconrel.2020.01.019

Controlling self-assembling and tumor cell-targeting of protein-only nanoparticles through modular protein engineering Voltà-Durán, E., Cano-Garrido, O., Serna, N. et al. C. Sci. China Mater.63, 147–156 (2020). https://doi.org/10.1007/s40843-019-9582-9

Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci, María Virtudes Céspedes  Olivia Cano‐Garrido  Patricia Álamo  Rita Sala  Alberto Gallardo  Naroa Serna  Aïda Falgàs  Eric Voltà‐Durán  Isolda Casanova  Alejandro Sánchez‐Chardi  Hèctor López‐Laguna  Laura Sánchez‐García  Julieta M. Sánchez  Ugutz Unzueta  Esther Vázquez  Ramón Mangues  Antonio Villaverde . Advanced Materiasls Número de artículo: 1907348 , Dec. 2019 https://doi.org/10.1002/adma.201907348

Artificial Inclusion Bodies for Clinical Development Julieta M. Sánchez  Hèctor López‐Laguna  Patricia Álamo  Naroa Serna  Alejandro Sánchez‐Chardi  Verónica Nolan  Olivia Cano‐Garrido  Isolda Casanova  Ugutz Unzueta  Esther Vazquez  Ramon Mangues  Antonio Villaverde, Advanced Science. 2019 https://doi.org/10.1002/advs.201902420

Nanostructured Nucleolin-Binding Peptide for Intracellular Drug Delivery in Triple-Negative Breast Cancer Stem Cells Mireia Pesarrodona, Laura Sánchez-García, Joaquin Seras-Franzoso, Alejandro Sánchez-Chardi, Ricardo Baltá-Foix, Patricia Cámara-Sánchez, Petra Gener,  José Juan Jara, Daniel Pulido, Naroa Serna, Simó Schwartz Jr. Miriam Royo, Antonio Villaverde, Ibane Abasolo, Esther Vazquez ACS Applied Materials & Interfaces DOI: 10.1021/acsami.9b15803  

Nanostructure Empowers Active Tumor Targeting in Ligand‐Based Molecular Delivery López‐Laguna, H., Sala, R., Sánchez, J. M., Álamo, P., Unzueta, U., Sánchez‐Chardi, A., Serna, N., Sánchez‐García, L., Voltà‐Durán, E., Mangues, R., Villaverde, A., Vázquez, E., . Part. Part. Syst. Charact. 2019, 36, 1900304. https://doi.org/10.1002/ppsc.201900304

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A new fluorescent probe for NO

Nitric oxide is a component of the pollutant nitrogen oxides (NOx) responsible of different environmental negative effects. However, due to its physiological effects, NO has been used in different therapeutic applications. Thus, the inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that finds its best applications in pediatrics, by transiently improving oxygenation in respiratory failure and persistent pulmonary hypertension. The initial recommended concentration of iNO in these treatments is 20 ppm. Higher concentrations do not increase its effectiveness and are associated with a higher incidence of methemoglobinemia and formation of nitrogen dioxide. In consequence the control of iNO concentration is of great interest.

Silvia Rodríguez-Nuévalos, Margarita Parra. Samuel Ceballos, Salvador Gil and Ana M.Costero, researchers of CIBER-BBN, Politecnic University of Valencia and University of Valencia were interested in detecting nitric oxide by different protocols and decided to study the Aggregation Induced Emission (AIE) phenomena as a possible transduction mechanism for detecting nitric oxide, compatible with aqueous media.

To sum up, a new probe capable of selectively detecting nitric oxide was prepared and evaluated. The probe is a tetraphenylethylene derivative and the transduction mechanism is really based on the Aggregation Induced Emission (AIE) phenomena. The click reaction catalyzed by NO modifies the steric volume of the TPE substituents inducing clear changes in the fluorescence emission. A limit of detection of 15 ppm has been determined and the linearity range appears between 20 and 80 ppm suggesting that the probe could be useful to control the use of iNO. Other gases such as NO2, CO2, CO and SO2 do not induce appreciable changes in the measure range. The probe works properly in MeOH:H2O media.

NMR spectra were registered at the Unit 26 of ICTS “NANBIOSIS”: NMR: Biomedical Applications II of ICBER-BBN at the Universitat of Valencia led by Ramón Martínez Máñez and Salvador Gil Grau.

Article of reference:

Silvia Rodríguez-Nuévalos, Margarita Parra. Samuel Ceballos, Salvador Gil, Ana M.Costero. A nitric oxide induced “click” reaction to trigger the aggregation induced emission (AIE) phenomena of a tetraphenyl ethylene derivative: A new fluorescent probe for NO. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY A-CHEMISTRY.  Vol: 388. 2020  https://doi.org/10.1016/j.jphotochem.2019.112132

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Not always what closes best opens better: mesoporous nanoparticles capped with organic gates

Researchers of NANBIOSIS Unit 26 NMR: Biomedical Applications II have recently published an article in the scientific journal Science and Technology of Advanced Materials,

Four types of calcined MCM-41 silica nanoparticles, loaded with dyes and capped with different gating ensembles are prepared and characterized. N1 and N2 nanoparticles are loaded with rhodamine 6G and capped with bulky poly(ethylene glycol) derivatives bearing ester groups (1 and 2). N3-N4 nanoparticles are loaded with sulforhodamine B and capped with self-immolative derivatives bearing ester moieties. In the absence of esterase enzyme negligible cargo release from N1, N3 and N4 nanoparticles is observed whereas a remarkable release for N2 is obtained most likely due to the formation of an irregular coating on the outer surface of the nanoparticles. In contrast, a marked delivery is found in N1, N3, and N4 in the presence of esterase enzyme. The delivery rate is related to the hydrophilic/hydrophobic character of the coating shell. The use of hydrophilic poly(ethylene glycol) derivatives as gating ensembles on N1 and N2 enables an easy access of esterase to the ester moieties with subsequent fast cargo release. On the other hand, the presence of a hydrophobic monolayer on N3 and N4 partially hinders esterase enzyme access to the ester groups and the rate of cargo release was decreased.

Aricle of reference:

Elena Añón, Ana M. Costero, Pablo Gaviña, Margarita Parra, Jamal El Haskouri, Pedro Amorós, Ramón Martínez-Máñez & Félix Sancenón (2019) Not always what closes best opens better: mesoporous nanoparticles capped with organic gates, Science and Technology of Advanced Materials, 20:1, 699-709, DOI: 10.1080/14686996.2019.1627173

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Nanomedicine: how to get drugs to the place where they have to act.

At the beginning of June, the Jury of the Rei Jaume I 2018 Awards, formed by Nobel Prize winners, businessmen and scientists, met in Valencia to choose the winners.

Today has taken place the ceremony of delivery of the 30th edition of the awards presided over by King Felipe VI. Among the six winners, in the category of New Technologies was Ramón Martínez Mañez, Scientific Director of the CIBER-BBN and Unit 26 of NANBIOSIS.

Coinciding with its thirtieth anniversary, the Rei Jaume Foundation has produced a series of videos of interviews with the winners. In this video, Ramón Martínez Mañez, Scientific Director of Unit 26 of NANBIOSIS, who has received the Rei Jaume I Award for New Technologies, talks about the two major areas in which he works and other topics such as the recognition of science and the need to recover the talent of researchers who go out of Spain and a better connection between research and the company. Some of his answers are the following:

One of our lines of research is in the field of sensors: systems based on nanotechnology for the detection of substances such as the presence of pathogens that may be harmful to health. The other major area is nanomedicines for the controlled release of drugs, one of the fundamental ideas of nanomedicine is how to get drugs to the place where they have to act.

Recognition in science is obtained if your works are cited, having social recognition is much more difficult.

We are a good country in science but we are a country in the second division in the transfer of science to the companies, it is needed more investment so that the products end up coming to the market or so that more research is done in collaboration with companies in Spain.

It is good to leave Spain, not necessarily to succeed but to see how they work in other places. The problem that exists today is that it is very difficult to return to Spain and this is a pity because there are very well educated and very good people who stay abroad.

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The revolution of nanomedicine by Ramón Martínez Mañez

Ramón Martínez Mañez, Scientific Director of Unit 26 of NANBIOSIS NMR: Biomedical Applications II, will be next Monday, November 5 at 7 pm at the Headquarters of Alicante City (San Fernando, 40), where he will impart the conference “The scientific revolution of Nanomedicine,”

The professor of Inorganic Chemistry of the UA and director of the Nanotechnology laboratory, Javier García Martínez, will present the meeting, organized by the Fundación Premios Rey Jaume I and the UA, with the collaboration of the Valencian Agency and Innovation and the Classroom of Science and the Technology of the University of Alicante.

Ramón Martínez-Máñez, director of the Institute for Research in Molecular Recognition and Technological Development (IDM) and scientific director of the Center for Biomedical Research in Networks in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) has been recently awarded King Jaume I of New Technology 2018. The jury of the King Jaume I awarded for New Technologies valued the “exceptional contributions” by Ramón Martínez-Máñez in the development of nanosensors with application in food technology and medicine, as well as “the high scientific quality and social impact of his work “and, for these reasons, he was awarded this award in June 2018. He is also a scholar of the American Chemical Society and the Royal Spanish Society of Chemistry. He was awarded in 2016 by the latter with the prize for Excellence Research

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Ramón Martínez Máñez Master class on Nanomedicine at the Act of the Academic Opening year 2018-2019  of Spanish university

On September 25, the Polytechnic University of Valencia hosted the Solemn Act of the new Academic Opening year 2018-2019  of Spanish universities, coinciding with the commemoration of its 50th anniversary. This institutional act was chaired by S.M. King Felipe VI, the Minister of Science, Innovation and Universities, Pedro Duque, and the President of the Generalitat Valenciana, Ximo Puig, among many other authorities.

Ramón Martínez Máñez, has been in charge of teaching the master class of the new academic year. Ramón Martínez is professor of the Department of Chemistry of the UPV and director of the Interuniversity Research Institute of Molecular Recognition and Technological Development, besides Scientific Director of CIBER-BBN and Scientific Director of NANBIOSIS U26 NMR: Biomedical Applications II

In the master class, Martínez Máñez explained that nanomedicine aims to “identify diseases in their early stages at the cellular and molecular level through the use of nanodevices and contrast systems” in order to “provide an early diagnosis and, therefore, improve the prognosis of the disease“. Ramón Martínez Mañez, Rei Jaume I Award for New Technologies 2018 has underlined that, nanomedicine “is already a well-established area of ​​knowledge that seeks to apply the continuous advances of nanotechnology to medicine” and that “there are numerous studies that demonstrate its great capacity for the development of new diagnostic devices, new systems for the controlled release of drugs and materials suitable for the development of tissues.  In fact, as indicated “there are already in the market biomedical solutions based on nanotechnology such as nanoformulated drugs.” For the professor of the UPV, “we do not know what is the future of medicine, but without a doubt nanotechnology will play an important role in its development and, although we do not know who will carry out these advances, undoubtedly, the research developed in the university it will play a fundamental role “.

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Nano-carrier to release drugs into damaged cells

Senescent cells are damaged cells that do not perform their normal roles anymore but that are not dead –hence they are commonly known as zombi cells. These cells interfere with the functioning of the tissue in which they accumulate. Senescence is a cell program that is triggered by many types of damage and senescent cells are present in many diseases. They accumulate in diverse types of tissues during aging, thus contributing to the progressive deterioration associated to aging. Eliminating these zombi cells is one of the challenges facing science today.

In the Cellular Plasticity and Disease lab headed by the ICREA researcher Manuel Serrano at the Institute for Research in Biomedicine (IRB Barcelona) and supported by “la Caixa” Banking Foundation, the researchers devise strategies to eliminate senescent cells. In a study published in EMBO Molecular Medicine, they present a proof of principle of a drug delivery system with selectivity for tissues that harbour senescent cells.

In collaboration with a team headed by Ramón Martínez-Máñez, Scientific Diirector of NANBIOSIS Unit 26 NMR: Biomedical Applications II ,  the IRB Barcelona scientists have exploited a particular hallmark of senescent cells in order to design a delivery system that specifically targets them. They have demonstrated its efficacy in cells in vitro and in two experimental mouse models, namely pulmonary fibrosis and cancer. These diseases are characterized by the presence of damaged cells, and in the case of cancer this is particularly true after treatment with chemotherapy.

In these models, the senescent cells take up the carrier more efficiently than other cells and once inside the cell the casing of the carrier degrades to release the drug cargo. When the nano-vehicles contained cytotoxic compounds, the senescent cells were killed and this resulted in therapeutic improvements in mice with pulmonary fibrosis or with cancer.

“This nano-carrier may pave the way for new therapeutic approaches for serious conditions, such as pulmonary fibrosis or to eliminate chemotherapy-induced senescent cells,” explains Manuel Serrano. Another outcome of this study is that these nano-carriers could be used for diagnostic tests of senescence as they can transport a fluorescent compound or marker.

This study, performed by IRB Barcelona in collaboration with the Universidad Politécnica de Valencia, CNIO, the University of Cambridge, CIBER-BBN, and the company Pfizer in the US, is a step towards achieving the capacity to eliminate senescent cells. Developing tools to specifically eliminate senescent cells is currently a central goal for many pharmaceutical companies, among them the one set up by Manuel Serrano himself together with Ramón Martínez-Máñez and José Ramón Murguia, Senolytic Therapeutics, which is located at the Barcelona Science Park and in Boston.

The study has been funded by “la Caixa” Banking Foundation, the Botín Foundation, the European Research Council, CRUK Cambridge Centre Early Detection Programme, the Ministry of Economy and Competitiveness/ERDFs and the Catalan Governmen

Daniel Muñoz‐Espín, Miguel Rovira, Irene Galiana, Cristina Giménez, Beatriz Lozano‐Torres, Marta Paez‐Ribes, Susana Llanos, Selim Chaib, Maribel Muñoz‐Martín, Alvaro C Ucero, Guillermo Garaulet, Francisca Mulero, Stephen G Dann, Todd VanArsdale, David J Shields, Andrea Bernardos, José Ramón Murguía, Ramón Martínez‐Máñez, Manuel Serrano A versatile drug delivery system targeting senescent cells EMBO Molecular Medicine (2018) DOI 10.15252/emmm.201809355

Image: The figure shows two views, frontal and lateral, of the image obtained by CT of the lungs of a mouse with fibrosis (grey areas) before and after receiving nano-therapy directed at senescent cells. (Guillem Garaulet and Francisca Mulero, CNIO)

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