News U26

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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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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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.

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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