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Posts Taged drug-delivery

Identification of a novel nanotherapy active in cancer cells resistant to chemotherapy

Researchers of the Nanotoxicology Unit (u18-nanotoxicology-unit) led by Ramon Mangues and Isolda Casanova at the Research Institute of the Hospital de Sant Pau and the Protein Production Platform (u1-protein-production-platform-ppp), led by Antonio Villaverde and Neus Ferrer Miralles of the Institute of Biotechnology and Biomedicine at the Autonomous University of Barcelona, both belonging to the ICTS NANBIOSIS (nanbiosis.es) of the CIBER-BBN, have participated in the production of a novel Nanotoxin capable of selectively killing cancer cells which became resistant to chemotherapy. Development of cancer resistance frequently associates with the overexpression of the CXCR4 receptor.

It is known that chemotherapy kills cancer cells, mainly, by induction of apoptosis, after damaging the cell DNA; therefore, to survive resistant cancer cells develop anti-apoptotic mechanisms. In contrast, a Nanotoxin that has incorporated the exotoxin of Corynebacterium diphtheriae and a targeted ligand that selectively internalizes in CXCR4+ cancer cells, exploits a mechanism of cell death alternative to apoptosis, thus, effectively killing resistant cancer cells in a colorectal cancer model.  The new mechanism is the induction of a blockade of protein translation, by inhibition of the elongation factor 2, which renders sensitive to therapy cancer cells resistant to chemotherapy.

The described work opens a new avenue for the exploration of antitumor activity in cancer that relapses after current therapy, an unmet medical need in oncology, and therefore, it could have an important impact in cancer patient well being.


Naroa Serna, Patricia Álamo, Prashanthi Ramesh, Daria Vinokurova, Laura Sánchez-García, Ugutz Unzueta, Alberto Gallardo, María Virtudes Céspedes, Esther Vázquez, Antonio Villaverde, Ramón Mangues, Jan Paul Medema. Nanostructured toxins for the selective destruction of drug-resistant human CXCR4 + colorectal cancer stem cells. doi: 10.1016/j.jconrel.2020.01.019.

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New patented peptide to allows the faster internalization of drugs within cells and the design of more effective therapeutic nanoconjugates

Researchers of NANBIOSIS Unit 20 In vivo Experimental Platform of CIBER-BBN and Vall d’Hebron Research Institute (VHIR) have patented a peptide that, in comparison to the current standard treatment, is much faster, internalizes much more, and does not cause any toxicity.

The membrane of a cell is an effective barrier that hinders the targeted delivery of molecules, such as therapeutic compounds. During the last years, several strategies have been developed to get the molecules into the cell interior but, in general, the methods developed still show a low efficacy and / or toxicity. “The use of therapeutic nanoconjugates such as nanomedicines facilitates the transport and delivery of drugs in target cells, but often with less efficiency than we would like,” says Dr Simó Schwart Jr, head of the Scientific Director of NANBIOSIS Unit 20 and the CIBBIM-Nanomedicine group: Direction i Alliberament Farmacològic del Vall d’Hebron Research Institute (VHIR)/CIBER-BBN.

Given the need to get more drugs or proteins into cells, one of the alternatives to be able to increase the amount that enters their interior more quickly is what is known as Cell penetrating peptides or cellular internalizing peptides, small sequences of amino acids that have the ability to interact with the plasma membranes of cells and, as a result of this interaction, make it easier to internalize the cargo they carry. An example of application would be when an internalizing peptide binds to a therapeutic nanoconjugate, achieving a greater capacity for the nanoconjugate to enter the cell interior and, therefore, to release the drugs it carries into the cells.

Until now, one of the most important internalizing peptides used has been known as TAT. Now, a team of researchers led by Dr. Schwartz Jr, has discovered a sequence common to a family of peptides that significantly outperforms the TAT results and facilitates the cellular internalization of nanoconjugates in a very significant way. These peptides are derived from a membrane protein called CD300 which has a very high capacity to interact with sphingomyelin, a lipid found in all plasma membranes and also in intracellular organelles. “The peptides in our patent”, explains Dr. Simó Schwartz Jr, “are derived from an extracellular part of CD300, which has a high capacity to bind sphingomyelin. Compared to the current standard treatment, TAT, CD300f7 is much faster, internalizes much more, and does not cause any toxicity. The use of these peptides in nanomedicine therefore facilitates and increases the internalization process of all the cargo they carry. This means that we are able to introduce drugs into cells in less time and in greater quantities ”. The results of this discovery not only allow for faster internalization within the cell, but also open the door to designing much more effective therapeutic nanoconjugates.

Souce of information: VHIR news

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New nanocarrier for bio-imaging and drug-delivery applications

Researchers of CIBER-BBN and NANBIOSIS-ICTS (U6 Biomaterial Processing and Nanostructuring Unit at ICMAB-CSIC and U18 Nanotoxicology Unit at  Hospital de la Santa Creu i Sant Pau have developed a new nanocarrier for bio-imaging and drug-delivery applications

The new nanovesicle formulation is based on the quatsome architecture – which stands out due to the high colloidal stability and homogeneity in size – and has now been shown to be suitable for in vivo dosing.

Quatsomes are new non-liposomal lipid-based nanovesicles that have been developed by Nanomol group in recent years, and have been shown to be highly homogeneous and stable in different media for years. This colloidal stability involves important advantages for the development of pharmaceutical formulations and for guaranteeing the final product quality. Quatsomes are a promising nanocarrier for bio-imaging and drug-delivery applications, suitable for the encapsulation of both hydrophilic and hydrophobic molecules, easily functionalized with elements that favor the directionality towards therapeutic targets.

To facilitate their use in in vivo applications, Nanomol group has now developed a new Quatsome formulation, composed of cholesterol and myristalkonium chloride (MKC), the C14 homolog of benzalkonium chloride (BAK), the latter being extensively used as antimicrobial preservative in many ophthalmic and parenteral formulations on the EU and USA market. These novel MKC-Quatsomes have been synthesized in different media that are suitable for parenteral administration, in which they showed to be stable for at least 18 months. Moreover, vesicles remained stable in human serum for at least 24 hours.

In collaboration with the Oncogenesis and Antitumour Drug group of the Biomedical Research Institute of the Hospital de la Santa Creu i Sant Pau, these MKC-Quatsomes were tested in live mice bearing xenografted colorectal tumors. After intravenous injection of fluorescently labelled MKC-Quatsomes, biodistribution assays showed nanovesicle accumulation in tumors, liver, spleen, and kidneys, but not in any other organ. Importantly, MKC-Quatsomes were well-tolerated at the administered doses, and no histological alterations or toxicity was found in any of these organs. These new results suggest the applicability of quatsomes in therapeutic approaches that require systemic delivery.

NANOMOL group, Coordinator of NANBIOSIS U6 at ICMAB-CSIC and the Oncogenesis and Antitumor Drug group, coordinator NANBIOSIS U18 at Biomedical Research Institute (Hospital de la Santa Creu i Sant Pau) are members of Biomedical Research Networking center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) and have a wide expertise and recognized excellence in the synthesis, processing and study of molecular and polymeric materials and the study of their biomedical properties. NANOMOL is also a member of the technology transfer network TECNIO. ‘

Article of reference:

MKC-Quatsomes. A stable nanovesicle platform for bio-imaging and drug-delivery applications co-authored by Guillem Vargas-Nadal et al., Nanomedicine: Nanotechnology, Biology and Medicine, 24 (2020) 102136. https://doi.org/10.1016/j.nano.2019.102136

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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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Switching cell penetrating and CXCR4-binding activities of nanoscale-organized arginine-rich peptides

Scientists of Units 1 and 18 of NANBIOSIS are coathors of the article  “Switching cell penetrating and CXCR4-binding activities of nanoscale-organized arginine-rich peptides” published by Nanomedicine: Nanotechnology, Biology and Medicine

Arginine-rich protein motifs have been described as potent cell-penetrating peptides (CPPs) but also as rather specific ligands of the cell surface chemokine receptor CXCR4, involved in the infection by the human immunodeficiency virus (HIV).

Polyarginines are commonly used to functionalize nanoscale vehicles for gene therapy and drug delivery, aimed to enhance cell penetrability of the therapeutic cargo. However, under which conditions these peptides do act as either unspecific or specific ligands is unknown. The authors have here explored the cell penetrability of differently charged polyarginines in two alternative presentations, namely as unassembled fusion proteins or assembled in multimeric protein nanoparticles. By this, they have observed that arginine-rich peptides switch between receptor-mediated and receptor-independent mechanisms of cell penetration. The relative weight of these activities is determined by the electrostatic charge of the construct and the oligomerizationstatus of the nanoscale material, both regulatable by conventional protein engineering approaches

Protein production has been partially performed by the ICTS “NANBIOSIS”, more specifically by the U1. Protein Production Platform (PPP), whereas the in vivo biodistribution assays were performed in the NANBIOSIS U18. Nanotoxicology Unit,

Article of reference:

Marianna Teixeira de Pinho FavaroNaroa SernaLaura Sánchez-GarcíaRafael Cubarsi, Mónica Roldán, Alejandro Sánchez-Chardi, Ugutz Unzueta, Ramón ManguesNeus Ferrer-MirallesAdriano Rodrigues Azzoni, Esther Vázquez, Antonio VillaverdeSwitching cell penetrating and CXCR4-binding activities of nanoscale-organized arginine-rich peptides Nanomedicine: Nanotechnology, Biology and Medicine Volume 14, Issue 6, August 2018, Pages 1777-1786 



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Yesterday took place in Barcelona, at Barcelona School of Management, Universitat Pompeu Fabra, a meeting of resarch groups and units of NANBIOSIS and CIBER-BBN and companies in the third B2B Forum organized by NANBIOSIS, in this case together with NANOMED SPAIN.

Thirteen companies and twelve groups from CIBER-BBN and CCMIJU (ten of them coordinating NANBIOSIS units) got together to explain, through short presentations of ten minutes, those lines of their work aimed at finding synergies and potential collaborations in the area of Nanomedicine apllications in drug delivery and targeting. There was also a talk by a  representative of CDTI (Spanish National Center for Industrial and Technological Development) to explain the financing opportunities for the companies as well as a presentation by the NANBIOSIS Coordinator, Jesús Izco, to show the new Cutting Edge Biomedical Solutions offered by the ICTS-NANBIOSIS

After lunch, the groups and companies had the opportunity to discuss in more detail, during bilateral interviews coordinated by NANBIOSIS a, those aspects that had attracted their attention, as well as, in some cases, to draw potential collaborations. The event was successfully developed with 45 attendees and more than 50 individual B2B mettings.


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NANBIOSIS organizes a forum for researchers and companies. Dates (probably February 2018) and location (probably Madrid) will be announced soon.

NANBIOSIS organizes a forum for researchers and companies. Dates (probably February 2018) and location (probably Madrid) will be announced soon.


The forum is presented through 2 sessions:

• First session: Short interventions of the latest advances and developments in the lines of research developed by the groups and platforms of Nanbiosis and description of the needs and demands of industry in that area. The companies and groups that request it will be able to have about 10 ‘to present their lines of research and / or needs and demands in relation to the thematic of the forum.
• Second session: Bilateral company-group / platform meetings to identify possible collaborations. These meetings will be pre-scheduled on request.

If you are interested in participating, contact Eduard Farré (628.943.198, efarre@arvor-ing.com) or with Jesús Izco (679.490.537, jmizco@ciber-bbn.es).


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Government of Aragón, Spain, paid tribute to the seven scientists who have a grant of European excellence and develop their projects at the University of Zaragoza: Jesús Santamaría, Diego Gutierrez, Igor Irastorza, Esther Pueyo, Manuel Arruebo, José Manuel García Aznar and Jesús Martínez de la Fuente.

President of the Government of Aragon, Javier Lambán, has personally expressed his gratitude and appreciation for the work of seven researchers from the University of Zaragoza who have been granted with projects of excellence funded by the European Research Council.

Jesús Santamaría, Scientific Director of Unit 9 of NANBIOSIS, with an Advanced Grant funded with 1.85 million euro, is working on a project to develop a microreactor that enables the industry to save energy and raw materials.

Esther Pueyo, member of the research group BSICoS of CIBER-BBN, which coordinates Unit 27 of NANBIOSIS, has a Starting Grant of 1.5 million and is studying the aging of the heart to propose new markers of risk for arrhythmias in the aging population.

Manuel Arruebo member of the research group Nanostructured films and particles of CIBER-BBN, which coordinates Unit 9 of NANBIOSIS, with a Grant Consolidator 1.5 million for the project Nanohedonism, develops injectable nanoparticles created with microfluidic reactors for the controlled and remote delivery of drugs in the treatment of chronic pain.


Nanbiosis_U27_U9_Three researchers of NANBIOSIS among the seven Aragonese scientists granted with an ERC.
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Ramon Martinez Mañez, Scientific Director of Unit 26 of NANBIOSIS, has participated in the development of  new nanodevices that allow the controlled release of drugs, namely doxorubicin, for therapies against breast cancer.

So far, the work has focused on cellular assays, with positive results, that could open new ways to improve the effectiveness of some drugs used in the treatment of breast cancer.

The main novelty of these nanodevices is that the molecule covering the nanodevice not only controls when the transported drugs are released, but also controls where they are released to direct them to cells expressing TLR3, a protein of the innate immune system overexpressed in some cell lines of breast cancer. Through this protein it is also launched a death signal that ends with the tumor cell.

Their study was published last January in Chemistry-A European Journal:

Ultimo A, Giménez C, Bartovsky P, Aznar E, Sancenón F, Marcos MD, Amorós P, Bernardo AR, Martínez-Máñez R, Jiménez-Lara AM, Murguía JR.Targeting Innate Immunity with dsRNA-Conjugated Mesoporous Silica Nanoparticles Promotes Antitumor Effects on Breast Cancer Cells. Chemistry. Chemistry – A European Journal. DOI: 10.1002/chem.201504629

Nanbiosis_U26_New nanodevices to improve therapy for breast cancer
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The Scientific Director and the Coordinator of NANBIOSIS, Jaume  Veciana and Jesús Izco, were invited by Professor Stefano Geuna (Professor of Human Anatomy at the Department of Clinical and Biological Sciences of the University of Torino) last 9th of March 2016 to present the CIBER-BBN, its scientific program and  its technologies to researchers of l’Università di Torino, in order to explore the possibilities of collaboration between the two institutions and promoting joint projects.

The meeting took place at the Molecular Biotechnology Center of the Molecular Biotechnology and Health Science department (www.mbc.unito.it/en ). The audience was made up of members representing six departments such as Department of Molecular Biotechnology and Health Sciences, Department of Neurosciences or the Department of Medical Sciences among others. After the presentations, up to ten face to face meetings were organized with research groups and staff of the Internalization Office from different departments to look for synergies and find out ways of collaboration. Topics such as nanoencapsulation for drug delivery, functionalization of biomaterials for regenerative medicine, especially for nerve regeneration or cell therapy for cancer were discussed and many common interests were detected. Following up the meeting, several actions were agreed and some of them have been already initiated to start new collaborations between both institutions.

L’Università di Torino is actively developing biotechnologies in the field of biomedical sciences, with specific focus on the study of the molecular mechanisms at the basis of physiopathological processes that have a great impact on human health, such as cardiovascular diseases, inflammation, stem cell biology and cancer. These researches are based on experimental work carried out by the biomedical departments of l’ Università di Torino.

Nanbiosis U6_Partnering opportunities with l’Università degli studi di Torino 9March2016
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