News

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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BASIC COURSE FOR UROLOGIS: INTRACORPOREAL SUTURING

CCMIJU has organised the II Urological Laparoscopy Course: Suture Management and Intracorporeal Knotting which wil take place at JUMISC from 3 to 5 February under the Direction of Álvaro Serrano Pascual (Urology Service Specialist at the San Carlos Clinical Hospital, Madrid) and Francisco Miguel Sánchez Margallo (Deputy Scientific Director of NANBIOSIS)

It is a basic course of Laparoscopic Urology where the techniques of Laparoscopic Radical and Partial Nephrectomy will be carried out. The objective of this course is for specialists in Urology to improve their skills in suture management and intracorporeal knotting.

Programm and inscriptions here

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A step forward in the field of organic free radicals acting as chiral emitters

Researchers of NANBIOSIS U6. Biomaterial Processing and Nanostructuring Unit have just published the article titled “An enantiopure propeller ‐ like trityl ‐ brominated radical: Bringing together a high racemization barrier and an efficient circularly polarized luminescent magnetic emitter” in the scientific magazine Chemistry A European Journal.
The urgent need to cope with the more and more specific requirements in electronic devices is nowadays behind the search for new multifunctional materials. In this work, a step forward has been done in the field of organic free radicals acting as chiral emitters. The recently developed brominated trityl derivative, namely TTBrM radical, shows a satisfactory luminescent dissymmetry factor (|glum(592 nm)| ≈ 0.7 x 10-3) despite its pure organic nature. However, in contrast to its chlorinated homologues, no hints of racemization were observed up to 60 ° C for more than two hours, due to the higher steric hindrance imposed by the bulky Br atoms. Moreover, improved derivatives can be envisaged from this compound thanks to the wide possibilities that Br atoms at para-positions offer for further functionalization.

To see the article:

Jaume Veciana, Paula Mayorga-Burrezo, Vicente G. Jiménez, Davide Blasi, Teodor Parella, Imma Ratera, Araceli G. Campaña. An enantiopure propeller‐like trityl‐brominated radical: Bringing together a high racemization barrier and an efficient circularly polarized luminescent magnetic emitter. Chem. Eur. J. 10.1002/chem.202000098. 9 January 2020

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A step forward for the design of multifunctional protein nanomaterials for cancer therapies

Researchers of NANBIOSIS Unit 1 and NANBIOSIS Unit 18, led by Prof Antoni Villaverde have published the article at the prestigious scintific magazine titled Collaborative membrane activity and receptor-dependent tumor cell targeting for precise nanoparticle delivery in CXCR4+ colorectal cancer

The researchers have shown that the combination of cell-penetrating and tumor cell-targeting peptides dramatically enhances precise tumor accumulation of protein-only nanoparticles intended for selective drug delivery, in mouse models of human colorectal cancer. This fact is a step forward for the rational design of multifunctional protein nanomaterials for improved cancer therapies.

Protein production has been partially performed by the ICTS NANBIOSIS U1, Protein Production Platform and the nanoparticle size analysis by the U6 of NANBIOSIS Biomaterial Processing and Nanostructuring Unit. Biodistribution studies were performed by the U18 of the ICTS NANBIOSIS, Nanotoxicology Unit.

Article of reference:

Rita Sala, LauraSánchez-García, Naroa Serna, María Virtudes Céspedes, Isolda Casanova, Mònica Roldán, Alejandro Sánchez Chardig, Ugutz Unzueta, Esther Vázquez, Ramón Mangues, Antonio Villaverde. Collaborative membrane activity and receptor-dependent tumor cell targeting for precise nanoparticle delivery in CXCR4+ colorectal cancer. Acta Biomaterialia, 99, Pages 426-432. 2019,

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Pilar Marco honored by the Spanish National Research Council (CSIC)

Maria Pilar Marco Colás has been honored by the Spanish National Research Council (CSIC) in appreciation for having complited 25 years of work at the CSIC, an intense period of 25 years at the service of Science, 11 of them as Scientific Director of Custom Antibody Service (CAbS), unit 2 of NANBIOSIS since its inclusion in the national ICTS map.

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Why the poor biodistribution so far reached by tumor-targeted medicines?

Cell-selective targeting is expected to enhance effectiveness and minimize side effects of cytotoxic agents. Functionalization of drugs or drug nanoconjugates with specific cell ligands allows receptor-mediated selective cell delivery. However, it is unclear whether the incorporation of an efficient ligand into a drug vehicle is sufficient to ensure proper biodistribution upon systemic administration, and also at which extent biophysical properties of the vehicle may contribute to the accumulation in target tissues during active targeting. To approach this issue, structural robustness of self-assembling, protein-only nanoparticles targeted to the tumoral marker CXCR4 is compromised by reducing the number of histidine residues (from six to five) in a histidine-based architectonic tag. Thus, the structure of the resulting nanoparticles, but not of building blocks, is weakened. Upon intravenous injection in animal models of human CXCR4+ colorectal cancer, the administered material loses the ability to accumulate in tumor tissue, where it is only transiently found. It instead deposits in kidney and liver. Therefore, precise cell-targeted delivery requires not only the incorporation of a proper ligand that promotes receptor-mediated internalization, but also, unexpectedly, its maintenance of a stable multimeric nanostructure that ensures high ligand exposure and long residence time in tumor tissue.

The concept presented by the authors of the present research might represent a convincing explanation of the poor biodistribution so far reached by tumor-targeted medicines, including antibody-drug conjugates. In addition to this, they offer a potential developmental roadmap for the improvement of these drugs, of high intrinsic therapeutic potential, to reach satisfactory efficiencies in the clinical context.

Hèctor López-Laguna, Rita Sala, Julieta M. Sánchez, Patricia Álamo, Ugutz Unzueta, Alejandro Sánchez-Chardi, Naroa Serna, Laura Sánchez-García, Eric Voltà-Durán, Ramón Mangues, Antonio Villaverde and Esther Vázquez. Nanostructure Empowers Active Tumor Targeting in Ligand-Based Molecular Delivery. Part. Part. Syst. Charact. 2019.

DOI: 10.1002/ppsc.201900304

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Artificial inclusion bodies for controlled drug release

Researchers from NANBIOSIS-CIBER-BBN have developed a new type of protein biomaterial that allows a continuous release over time of therapeutic proteins when administered subcutaneously in laboratory animals.

These results are the result of the stable scientific collaboration between the researchers of NANBIOSIS Units 1 Protein Production Platform (PPP)and 18 Nanotoxicology Unit, led by Toni Villaverde and Ramón Mangues at the Institute of Biotechnology and Biomedicine of the Autonomous University of Barcelona (IBB-UAB) and the Institut About the Hospital de Sant Pau and has had the participation of the Institute of Biological and Technological Research of the National University of Córdoba-CONICET, in Argentina

“These structures, of a few micrometers in diameter, contain functional proteins that are released in a manner similar to the release of human hormones in the endocrine system,” says Antonio Villaverde. Ramón Mangues explains that “the new biomaterial mimics a common bacterial product in biotechnological processes called ‘inclusion bodies’, of pharmacological interest, which in this artificial version offers a wide range of therapeutic possibilities in the field of oncology and in any other field clinic that requires sustained release over time.” Researchers have used common enzymes in biotechnology as a model and a nanostructured bacterial toxin that targets metastatic cells of human colorectal cancer, which has been tested in animal models. “In this way we have managed to generate both immobilized catalysts and a new long-acting anti-tumor drug,” said the researchers responsible for the research.

The developed artificial protein granules, which had previously been proposed as ‘nanopills’ (tablets of therapeutic material on a nanoscopic scale), mimic bacterial inclusion bodies and offer enormous clinical potential in the field of vaccinology and as release systems Drug controlled.

“We have seen that natural inclusion bodies, administered as medicines, can generate unwanted immune responses due to the inevitable contamination with bacterial materials,” the researchers comment. However, in the new work, the development of artificial inclusion bodies with secretion capacity “avoids many of the regulatory problems associated with the potential development of bacterial nanopills, and offers a cross platform for obtaining functional components in cosmetics and in clinic” they add.

This work points to artificial inclusion bodies as a new exploitable category of biomaterials for biotechnological applications with a more simple manufacturing and clinical applications.

Reference article:
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 Artificial Inclusion Bodies for Clinical Development

https: //doi.org/10.1002/advs.201902420

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A new method simple and efficient for the preparation of Oligonucleotide-protein conjugates

Oligonucleotide-protein conjugates have important applications in biomedicine. Four units of NANBIOSIS have collaborated to come across with more simple and efficient methods for the preparation of these conjugates.

In the publication of the research results, a new method is described in which a bifunctional linker is attached to thiol-oligonucleotide to generate a reactive intermediate that is used to link to the protein. Having similar conjugation efficacy compared with the classical method in which the bifunctional linker is attached first to the protein, this new approach produces significantly more active conjugates with higher batch to batch reproducibility. In a second approach, direct conjugation is proposed using oligonucleotides carrying carboxyl groups. These methodologies have been applied to prepare nanoconjugates of an engineered nanoparticle protein carrying a T22 peptide with affinity for the CXCR4 chemokine receptor and oligomers of the antiproliferative nucleotide 2′-deoxy-5-fluorouridine in a very efficient way. The protocols have potential uses for the functionalization of proteins, amino-containing polymers or amino-lipids in order to produce complex therapeutic nucleic acid delivery systems.

Protein production and DLS have been partially performed by the NANBIOSIS Units of CIBER-BBN U1 Protein Production Platform (PPP) at IBB-UAB and U6 Biomaterial Processing and Nanostructuring Unit of CIBER-BBN and ICMAB-CSIC. Also, NANBIOSIS U18 of Nanotoxicology at the Hospital de la Santa Creu i Sant Pau has been used and the team of researcher counted with the NANBIOSIS expertise of U29 Oligonucleotide Synthesis Platform (OSP) at IQAC-CSIC

Article of reference:

Avino, Anna; Unzueta, Ugutz; Cespedes, Maria Virtudes; Casanova, Isolda; Vazquez, Esther; Villaverde, Antonio; Mangues, Ramon; Eritja, Ramon. Efficient bioactive oligonucleotide-protein conjugation for cell-targeted cancer therapy. CHEMISTRYOPEN 8, 3 (382-387), 2019

https://doi.org/10.1002/open.201900038

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A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models

Researchers of NANBIOSIS Unit 1 and NANBIOSIS Unit 18, led by Ramón Mangues, have published the article titled CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models .

One-third of diffuse large B-cell lymphoma patients are refractory to initial treatment or relapse after rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy. In these patients, CXCR4 overexpression (CXCR4+) associates with lower overall and disease-free survival. Nanomedicine pursues active targeting to selectively deliver antitumor agents to cancer cells, a novel approach that promises to revolutionize therapy by dramatically increasing drug concentration in target tumor cells. In the study carried out at NANBIOSIS ICTS the resarchers intravenously administered a liganded protein nanocarrier (T22-GFP-H6) targeting CXCR4+ lymphoma cells in mouse models to assess its selectivity as a nanocarrier, by measuring its tissue biodistribution in cancer and normal cells. No previous protein-based nanocarrier has been described to specifically target lymphoma cells. T22-GFP-H6 achieved a highly selective tumor uptake in a CXCR4+ lymphoma subcutaneous model, as detected by fluorescent emission. We demonstrated that tumor uptake was CXCR4- dependent because pretreatment with AMD3100, a CXCR4 antagonist, significantly reduced tumor uptake. Moreover, in contrast to CXCR4+ subcutaneous models, CXCR4- tumors did not accumulate the nanocarrier. Most importantly, after intravenous injection in a disseminated model, the nanocarrier accumulated and internalized in all clinically relevant organs affected by lymphoma cells, with negligible distribution to unaffected tissues. Finally, the researchers obtained antitumor effect without toxicity in a CXCR4+ lymphoma model by T22-DITOX-H6 administration, a nanoparticle incorporating a toxin with the same structure as the nanocarrier. Hence, the use of T22-GFP-H6 nanocarrier could be a good strategy to load and deliver drugs or toxins to treat specifically CXCR4-mediated refractory or relapsed diffuse large B-cell lymphoma without systemic toxicity.

The bioluminescent follow-up of cancer cells and nanoparticle biodistribution and toxicity studies has been performed in the ICTS NANBIOSIS, using its unit 18 of Nanotechnology of CIBER-BBN and Hospital Sant Pau The Protein production has been partially performed by the Protein Production Platform (PPP) Unit 1 of ICTS NANBIOSIS of CIBER-BBN and IBB-UAB.

Article of reference:

Aïda Falgàs, Victor Pallarès, Ugutz Unzueta, María Virtudes Céspedes, Irene Arroyo-Solera, María José Moreno, Alberto Gallardo, María Antonia Mangues, Jorge Sierra, Antonio Villaverde, Esther Vázquez, Ramon Mangues, and Isolda Casanova. A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models. Haematologica 2019

doi:10.3324/haematol.2018.211490

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Inkjet printing and paper sensors to control different analytes with low cost technologies

‘I investigate, I am CSIC’ is a competition hold by The Spanish National Research Council (CSIC) for its doctoral students to disseminate their doctoral thesis. Through short videos of maximum duration of 3 minutes, predoctoral scientists explain their research and results in an informative language.

Miguel Zea, a member of the NANBIOSIS U8 Micro– Nano Technology Unit presents his video explaining how paper sensors can be manufactured to control different analytes with low cost technologies such as Inkjet Printing.

A jury composed of five experts in communication or scientific dissemination will choose eight videos taking into account the originality, impact, convenience and consistency of the video content. In addition, clarity will be valued when exposing the research work and the communicative capacity of the participant. The votes of the public through the YouTube channel of the Postgraduate Department will decide the selection of two other participants.

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