News U18

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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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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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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NANBIOSIS Unit 18 expands its equipments and capabilities

NANBIOSIS U18 Nanotoxicology Unit, led by Dr. Dr. Ramón Mangues, has recently added new equipment as a result of its participation in the project FICTS1420-20, selected by the MINECO for co-financing by the FEDER Program in ICTS 2014-2020.

The new equipment consists in a Autostainer System for the automation of manual staining methods used in Immunohistochemistry, pharmacodiagnostic, immunofluorescence and chromogenic development for in situ hybridization (AUTOSTAINER-TOX). Includes small equipment for deparaffinization, hydration and antigenic unmasking of paraffin-embedded tissue, complete kit for deparaffinization, hydration and antigenic unmasking of paraffin-embedded tissue. The equipment management software allows monitoring of staining status, request requests, and reporting and obtaining statistics.

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Non-Hodgkin lymphoma treatment with protein nanoparticles

A study result of collaboration between researchers of two NANBIOSIS units managed to produce a potent antitumor effect in an animal model with non-Hodgkin lymphoma

A non-Hodgkin’s lymphoma, NHL is a cancer that starts in white blood cells called lymphocytes, which are part of the body’s immune system.
Lymphoma. NHL is a term that’s used for many different types of lymphoma that share some characteristics. The most prevalent type of non-Hodgkin lymphoma is called diffuse large B-cell lymphoma (LDCGB). Although there are treatments for this pathology, there are non-responders.

This nanoparticle can be developed as a nanopharmaceutical, in order to introduce a new treatment, which could be used in 40 percent of patients with non-Hodgkin lymphoma who do not respond to current therapy, and avoiding the adverse effects associated with conventional treatment.

The research conducted by the CIBER-BBN at the Hospital de Sant Pau, led by Ramón Mangues (Nanbiosis U18 Nanotoxicology Unit) and the Autonomous University of Barcelona, led by Antoni Villaverde Nanbiosis U1 Protein Production Platform (PPP) has demonstrated the high selectivity of a protein-based nanomedicine and created by the researchers themselves, for the targeted delivery of a toxin in the tumor cells to induce their selective death. The objective is that these nanoparticles can be developed as a nanopharmaceutical, which could be used in 40 percent of patients with non-Hodgkin lymphoma who do not respond to current therapy, avoiding the adverse effects associated with conventional treatment

This selective effect of the nanopharmaceutical is due to the specific interaction between a targeting peptide that contains the protein nanoparticle that carries the toxin and the CXCR4 cell receptor that is highly overexpressed in lymphoma cells. This is the first time that the uptake of protein nanoparticles in different organs of a hematological neoplasm is quantified.

This observation has shown that 86 percent of the administered dose accumulates in cancer cells, a substantial improvement compared to other non-protein nanoparticles or other drug targeting systems such as drug-antibody conjugates, which only reach 1 percent of the dose in the tumor.

As Ramón Mangues, Scientific Director of Nanbiosis U18 Nanotoxicology Unit, explains, “the new protein nanoparticle contains a ligand that identifies a CXCR4 receptor on the surface of cancer cells in which it enters selectively, reaching a very high uptake of the tumor and very low in the rest of the body, which greatly exceeds the tumor uptake of drugs used for this type of lymphoma.”

The bioluminescent follow-up of cancer cells and nanoparticle biodistribution and toxicity studies has been performed in the ICTS NANBIOSIS Nanotoxicology Unit Protein production has been partially performed by the ICTS “NANBIOSIS”, more specifically by the Unit of Protein Production Platform.

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The first Nanocomposite that slows the spread of colon cancer

The creation of a nanodrug capable of blocking the spread of the disease, which is known as metastasis, has been highlighted by Guia Medica, as a heavy blow struck against to colon cancer, the malignant tumor with the highest incidence in our country, a process that affects 40% of the million cases of this type of cancer that are diagnosed every year in the world, and that represents the main cause of death.

The research, jointly carried out by scientists from the IIB Sant Pau, Sant Pau Hospital, the UAB, CSIC and CIBER-BBN, led by Esther Vázquez and Antonio Villaverde, Strategy Director of NANBIOSIS U1. Protein Production Platform (PPP) in the IBB-UAB and Ramon Mangues, Scientific Director of NANBIOSIS U18. Nanotoxicology Unit in the Sant Pau Hospital, were published in the scientific journal EMBO Molecular Medicine ando pen a new way to prevent metastasis in colorectal cancer in humans, using a nanomedicine that selectively eliminates metastatic stem cells.

NANBIOSIS Unit 18 of Nanotoxicology has been involved in the study of the biodistribution and the antimetastatic effect and on normal organs of the nanoconjugate administered and the unit and Unit 1 PPP, has contributed to the production of the protein part of the nanoconjugate.

The new drug works like a drone that identifies a receptor (CXCR4) in metastatic stem cells. Once localized, it administers the drug and destroys it, blocking the metastasis, according to research sources. By acting only on metastatic tumor cells, the new nanodrug avoids the general toxicity associated with the usual treatments against cancer and preserves healthy cells. Although up to now it has been successfully tested in animals suffering from colorectal cancer, the researchers who have carried out the trial believe that it could be used in 20 types of additional tumors, which also express CXCR4, as in prostate, breast, ovarian and other tumors.

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

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

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

NANBIOSIS wants to acknowledge the efforts made by scientific women who struggle every day to contribute their bit to Science and highlight their essential role in nowadays research. Especially we want to recognize the work of scientists women involved in our units, whatever is the nature of their contribution: technical, scientific development, management, coordination, direction, etc; just to mention some examples:
Neus Ferrer in the Scientific Direction of Unit 1 Protein Production Platform (PPP)
Pilar Marco and Nuria Pascual in the Management and Scientific Coordination of U2 Custom Antibody Service (CAbS)
Miriam Royo in the Scientific Direction of U3 Synthesis of Peptides Unit
Laura Lechuga and M.Carmen Estevez in the Direction and Scientific Coordination of U4 Biodeposition and Biodetection Unit
Nora Ventosa and Nathaly Segovia in the Scientific Direction and Technical Coordination of U6 Biomaterial Processing and Nanostructuring Unit
Isabel Oliveira and Teresa Galán in the Coordination of U7 Nanotecnology Unit
Rosa Villa and Gemma Gabriel in the Management and Scientific Coordination of U8 Micro – Nano Technology Unit
Gema Martínez in the Scientific Coordination of U9 Synthesis of Nanoparticles Unit
Fany Peña in the Scientific Coordination of U13 Tissue & Scaffold Characterization Unit
Mª Luisa González Martín in the of Direction and Scientific Coordination of U16 Tissue & Scaffold Characterization Unit
Gemma Pascual and Isabel Trabado in the Coordination of the U17 Confocal Microscopy Service
Mª Virtudes Céspedes in the Scientific Coordination of U18 Nanotoxicology Unit
Beatriz Moreno in the Scientific Direction of Unit 19 Clinical tests lab
Ibane Abásolo in the Scientific Coordination of Unit 20 In Vivo Experimental Platform t
Verónica Crisóstomo in the Scientific Direction of Unit 24 Medical Imaging
Ana Paula Candiota in the Scientific Coordination of Unit 25 Biomedical Applications I
Maria Luisa García in the Scientific Direction of U28 NanoImaging Unit from Bionand, recently incorporated to NANBIOSIS

Thanks to all of you and your teams!

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