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An Auristatin-based nanoconjugate reduces leukemia burden in a disseminated AML model

Researchers of the Nanotoxicology Unit of the the CIBER-BBN ICTS NANBIOSIS (u18-nanotoxicology-unit), leaded by Ramon Mangues and Isolda Casanova at the Research Institute of the Hospital de Sant Pau and of the NANBIOSIS (nanbiosis.es) Protein Platform (u1-protein-production-platform-ppp) leaded by Antonio Villaverde and Neus Ferrer Miralles of the Institute of Biotechnology and Biomedicine at the Autonomous University of Barcelona, have developed a novel protein-Auristatin nanoconjugate that specifically targets CXCR4-overexpressing acute myeloid leukemia (AML) cells. It selectively accumulates in target cancer cells expressing this receptor and deliver the toxin Auristatin within their cytosol. There, Auristatin potently blocks microtubule polymerization, provoking mitotic catastrophe, followed by apoptotic induction. Since Auristatin can kill both cycling and quiescent cells, the administration of the nanoconjugate at repeated dosage is able to dramatically reduce the leukemia burden in circulating blood, bone marrow, liver and spleen; thus, producing a potent antineoplastic effect, in the absence of systemic toxicity.

It is known that CXCR4 overexpression is involved in bopne marrow colonization by leukemic cells, displacing normal hematopoietic stem cells, an effect that associates with quiescence, resistance to classical chemotherapy, development of minimal residual disease and relapse, which leads to shorter patient survival.  Therefore, this Auristatin-based nanoconjugate could be a novel approach for the treatment of CXCR4-overexpressing AML that relapses after classical chemotherapy, offering hope to an effective clinical translation and industrial transfer, aqn activity that which could increase the effectiveness of AML treatment while reducing the adverse effect associated with current therapy.

Reference:

Pallarès V, Unzueta U, Falgàs A, Sánchez-García L, Serna N, Gallardo A, Morris GA, Alba-Castellón L, Álamo P, Sierra J, Villaverde A, Vázquez E, Casanova I, Mangues R. An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination. doi: 10.1186/s13045-020-00863-9.

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A nanotoxin targeting the receptor CXCR4 blocks lymphoma dissemination

Researchers at the Nanotoxicology Unit of CIBER-BBN ICTS NANBIOSIS (u18-nanotoxicology-unit), led by Ramon Mangues and Isolda Casanova of the Research Institute at the Hospital de Sant Pau and the Researchers of the NANBIOSIS (nanbiosis.es) 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, have participated in the development of a novel protein nanoparticle that incorporates the Exotoxin of the bacteria Pseudomonas aeruginosa, capable of targeting lymphoma cells that overexpress the CXCR4 receptor.

They internalize selectively in target cancer cells through CXCR4 receptor-mediated endocytosis due to the incorporation in its nanostructure of the T22 peptide ligand, with multivalent display (10 peptides per nanoparticle). In addition, it contains an endosomal escape domain to avoid lysosomal degradation to achieve the delivery of undegraded exotoxin in the target cancer cell cytosol. There, the exotoxin blocks protein translation by inhibiting the elongation factor 2, leading to the induction of apoptosis in a diffuse large B-cell lymphoma model blocking their dissemination throughout the body, in the bone narrow, lymph nodes and the liver. Since lymphoma cells overexpressing the CXCR4 receptor are associated with increased dissemination and resistance to Rituximab plus CHOP chemotherapy, this novel nanomedicine could be useful for its clinical translation, especially for the treatment of lymphoma patients that relapse after classical chemotherapy.

The bioluminescent follow-up of cancer cells and toxicity studies has been performed in the ICTS NANBIOSIS using its CIBER-BBN Nanotoxicology Unit Protein production has been also performed at the ICTS NANBIOSIS  Init 1 PPP

Reference:

Falgàs A, Pallarès V, Serna N, Sánchez-García L, Sierra J, Gallardo A, Alba-Castellón L, Álamo P, Unzueta U, Villaverde A, Vázquez E, Mangues R, Casanova I. Selective delivery of T22-PE24-H6 to CXCR4+ diffuse large B-cell lymphoma cells leads to wide therapeutic index in a disseminated mouse model. doi: 10.7150/thno.43231. eCollection 2020.

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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.

Reference:

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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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 NANBIOSIS, whatever is the nature of their contribution: technical, scientific development, management, coordination, direction, etc; just to mention some examples:
Neus Ferrer and Mercedes Márquez in the Scientific Direction and Coordination 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
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 and Margarita Hierro 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
Isolda Casanova 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 Platformt
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, Anna Aviñó in the Scientific Coordination of U29 Oligonucleotide Synthesis Platform (OSP) – and

Nerea Argarate in the coordination of NANBIOSIS

Thanks to all of you and your teams!

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Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles

In the frame of the collaboration of three units of NANBIOSIS, researchers of CIBER-BBN Groups proposed a strategy to simultaneously deliver anticancer drug pairs, composed by a tumor-targeted protein nanoparticle and an antiproliferative drug, with specific activ-ity for the same type of cancer.

These three units are:

The results on the investigation have been published in an article entitled “Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles”· by Acta Biomaterialia

The researchers have explored the possibility to conjugate tumor-targeted cytotoxic nanoparticles and conventional antitumoral drugs in single pharmacological entities using CXCR4-targeted self-assembling protein nanoparticles based on two potent microbial toxins, the exotoxin A from Pseudomonas aeruginosa and the diphtheria toxin from Corynebacterium diphtheriae, to which oligo-floxuridine and monomethyl auristatin E respec- tively have been chemically coupled.

The resulting multifunctional hybrid nanoconjugates, with a hydro- dynamic size of around 50 nm, are stable and internalize target cells with a biological impact. Although the chemical conjugation minimizes the cytotoxic activity of the protein partner in the complexes, the concept of drug combination proposed is fully feasible and highly promising when considering multiple drug treatments aimed to higher effectiveness or when facing the therapy of cancers with acquired resistance to classical drugs.

Thus, these results open a wide spectrum of opportunities in nanomedical oncology.

Article of reference:

Eric Voltà-Durán, Naroa Serna, Laura Sánchez-García, Anna Aviñó, Julieta M. Sánchez, Hèctor López-Laguna, Olivia Cano Garrido, Isolda Casanova, Ramón Mangues, Ramon Eritja, Esther Vázquez, Antonio Villaverde, Ugutz Unzueta Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles. Acta Biomaterialia, Volume 119, 1 January 2021, Pages 312-322), 57746-57756 https://doi.org/10.1016/j.actbio.2020.11.018 

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Smart-4-Fabry final workshop

Next Wedneday, February 3, 2021 will take place the on-line event Smart-4-Fabry Final Workshop.  

Smart-4-Fabry is a european project, coordinated by CIBER-BBN wich has been developed during four years. This project is a sign of cooperation at European level to boost nanomedicine development and translation to clinical stages.

This project is also a clear example of the relevance of access to advanced research infrastructures as NANBIOSIS -ICTS. Four NANBIOSIS units have collaborated and contributed to Smart-4-Fabry development:

“The Fabry disease (FD) is a lysosomal storage disorder (LSD) that currently lacks an effective treatment” as Prof. Nora Ventosa, IP of the project, explained for NANBIOSIS blog – The aim of Smart-4-Fabry is to obtain a new nanoformulation of GLA, that will improve the efficacy and toleration compared to the actual treatment with non-formulated GLA.

In the final workshop experts will talk about how, why and for what the solution proposed by Smart4Fabry was conceived.

Registrations and program at https://smart4fabry.cientifis.com/

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The Autonomous University of Barcelona, in the elite of the 300 best universities in the world

The Academic Ranking of World Universities (ARWU), known as Shanghai Ranking, which was made public on August 15, places the Autonomous University of Barcelona among the elite of the 300 best universities in the world and the first of the Spanish universities.

This indicator organizes up to 20,000 university centers worldwide,
based on transparent methodology and objective third-party data. ARWU is regarded as one of the three most influential and widely observed university rankings

The Autonomous University of Barcelona houses two of NANBIOSIS Units:

U1 Protein Production Platform (PPP), led by Toni Villaverde, Neus Ferrer and Paolo Saccardo, offer an “tailored” service for the design, production and purification of recombinant proteins using both prokaryotic and eukaryotic expression systems

U25 NMR: Biomedical Applications I, led by Carles Arús and Ana Paula Candiota, with a recognized research track record in the use of NMR as a tool for biomedical applications, and more especifically to identify biomarkers of different pathologies, the main objective of this unit is the acquisition, processing and/or interpretation of Nuclear Magnetic Resonance data



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A new nanoconjugate blocks acute myeloid leukemia tumor cells without harming healthy ones

Researchers from NANBIOSIS U18 Nanotoxicology Unit at the Institut d’Investigació Biomèdica de Sant Pau (IIB Sant Pau) and NANBIOSIS U1 Protein Production Platform (PPP) at the Universitat Autònoma de Barcelona (UAB) toghether with researchers of Institut de Recerca contra la Leucèmia Josep Carreras (IJC) have demonstrated the efficacy of a new nanoconjugate, designed in house, that blocks dissemination of leukemic cells in animal models of acute myeloid leukemia. These results have been published in a high impact scientific journal in the field of oncology and hematology, Journal of Hematology and Oncology. Most of the experimental work has been performed in the nanotoxicology and protein production ICTS “NANBIOSIS” platforms from CIBER-BBN.

NANBIOSIS U1 PPP has advised and helped the researchers in the production of recombinant proteins, which has allowed to successfully explore the capacity of proteins from the human microbiome, that is, from bacteria and their bacteriogages, to generate, through genetic engineering, biocompatible nanomaterials and Non-immunogenic for potential use in human clinics, such as vehicles for drug delivery or regenerative medicine.

Acute myeloid leukemia (AML) is a heterogeneous disease which usual treatment is very aggressive and produces severe side effects to the patients. In order to reduce these adverse effects, the researchers have developed a nanomedicine that is specifically targeted to the tumor cells without damaging normal cells. This new protein nanoparticle is bound to a toxin, named Auristatin, which is between 10 and 100 times more potent than the drugs typically used in the clinic. In particular, this nanoconjugate is targeted only to the cells that express in their membrane a receptor called CXCR4, which is overexpressed in leukemic cells. Thus, this nanoparticle can only enter and deliver the toxin into the cells that express this receptor. It should be noted that CXCR4 is overexpressed in a large proportion of leukemic cells in patients with poor prognostic or refractory disease, so it could have a major clinical impact on these AML patients.

The researcher team led by Ramon Mangues, from IIB Sant Pau, Antonio Villaverde and Esther Vázquez, from UAB, all members of CIBER-BBN, has demonstrated that the nanoconjugate is able to internalize in the leukemic cells through the CXCR4 receptor and kill them. In addition, they have demonstrated the capacity of this nanoparticle to block dissemination of leukemic cells in a mouse model producing without any kind of associated toxicity or adverse effects. Thanks to its targeting to leukemic cells it could help AML patients that cannot be treated with current drugs because of their high toxicity, such as this experienced by elderly patients or patients with other non-favorable characteristics that exclude conventional treatment. Furthermore, the novel nanoparticle could be used to treat patients that have developed resistance to drugs or those that have experienced relapse, since their leukemic cells would likely have high expression of the CXCR4 receptor. Hence, there is a wide range of patients that could benefit of this new treatment, which could have  a major clinical impact if its effectiveness was confirmed in further clinical trials.

It is worth pointing out that the CXCR4 receptor is overexpressed in more than 20 different cancer types, which expression associates with poor prognosis. Therefore, this nanodrug could be evaluated in the near future as a possible treatment in other tumor types of high prevalence.

The intellectual property of this nanomedicine has been licensed to the SME biotech Nanoligent, which aim is continuing the so far successful access to public and private funds to complete the preclinical development to enter clinical trials in acute myeloid leukemia, before being tested in other cancer types.

Article of reference:

An Auristatin Nanoconjugate Targeting CXCR4+ Leukemic Cells Blocks Acute Myeloid Leukemia Dissemination. Victor Pallarès, Ugutz Unzueta, Aïda Falgàs, Laura Sánchez-García, Naroa Serna, Alberto Gallardo, Gordon A Morris, Lorena Alba-Castellón, Patricia Álamo, Jorge Sierra, Antonio Villaverde, Esther Vázquez, Isolda Casanova, Ramon Mangues. DOI: 10.1186/s13045-020-00863-9

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NANBIOSIS researchers featured in the 15th Edition of Spanish Researchers Ranking

The 15th edition of the Webometrics Ranking of World Universities has been published, ranking researchers in Spain as well as Spaniards doing research abroad. A total of 11 Directors of NANBIOSIS units appear on the most recent list, featured on the top 2000. The list is ordered by the h-index, a metric that calculates research impact based on a correlation of papers published and number of citations, and then by number of citations. The result is a list of whose’s publications have had more impact online.

NANBIOSIS researchers featured are Fernando Albericio (#207), scientific director of U3 Synthesis of Peptides Unit, Ramón Martínez Máñez (#342) U26 NMR: Biomedical Applications II, Jaume Veciana (#459) U6 Biomaterial Processing and Nanostructuring Unit, José Luis Pedraz (#906) U10 Drug Formulation unit, Jesús Santamaría (#912) U9 Synthesis of Nanoparticles Unit, Ramón Eritja (#1022) U29 Oligonucleotide Synthesis Platform (OSP), Pablo Laguna (#1153) U27 High Performance Computing, Antoni Villaverde (#1249) U1 Protein Production Platform (PPP), Laura Lechuga (#1511) U4 Biodeposition and Biodetection Unit M.Pilar Marco (#1517), U2 Custom Antibody Service (CAbS), and Josep Samitier (#1836) U7 Nanotechnology Unit.

This list reflects on the impact online publication can have as a tool to share knowledge. 

For further information: here

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A recombinant SARS-CoV-2 vaccine

NANBIOSIS Protein Production Platform (PPP) Unit 1 (of CIBER-BBN and Autonomous University of Barcelona) is involved in a micro-patronage project for the development of a vaccine for COVID 19.

NANBIOSIS Unit 1 is directly involved in the initial part of the Virus Like Particles and Proteins expression and purification project of SARS-COV-2

Most vaccines used today are based on either attenuated forms of the original pathogen, or are inactivated vaccines, in which the pathogen has undergone physical or chemical treatments to eliminate its infectivity. The project proposes to use a new vaccine strategy based on recombinant proteins in imitation of viruses (virus-like particles or VLPs). The same strategy with which, for example, papillomavirus and hepatitis B virus vaccines have been created.

VLPs contain recombinant structural proteins, obtained by the introduction and expression of a gene in cultured cells, that form nanostructures similar to viral particles but do not contain their genetic information and, therefore, are not infectious. These particles are capable of arousing a strong immune response as they form a three-dimensional structure where the virus epitopes are exposed, but they are very safe.

VACCINE PROTOTYPE:

Design
First, we will design the genes that encode the structural proteins of the virus. At this point, the different sequences of the virus genome deposited in public databases must be analyzed and compared in detail. In this way, we can select the most representative sequence. On the other hand, we will carry out some control tests to detect the different fragments of the proteins where the response of the immune system is concentrated, the so-called antigens.
These studies will be carried out using bioinformatics tools by the Computational Biology Group of dr. Xavier Daura from the UAB Institute of Biotechnology and Biomedicine (IBB).

Production and purification
To carry out these productions, we need to use cultured cell lines in which we introduce the genes that encode the virus’s proteins and establish optimal obtaining conditions, without the need to use highly biological containment laboratories. Once produced, we will carry out a purification process and they can be validated.

This block will be carried out in parallel by the research group led by Dr. Francesc Godia from the Department of Chemical, Biological and Environmental Engineering, and Dr. Neus Ferrer from the Department of Genetics and Microbiology and member of the Nanobiotechnology Group led by Dr Antoni Villaverde, attached to the IBB and the CIBER-BBN. In addition, we will have the help of UAB research-scientific-technical services, such as the Microscopy Service (SM), and the Proteomics and Structural Biology Service (sePBioEs) and a unique scientific-technical infrastructure called NANBIOSIS.

Validation with patient serum and cell models
Once the proteins are purified, it is necessary to validate the vaccine formulations with patient serum. In other words, it must be demonstrated that the patient sera of the COVID-19 are linked to the vaccine proposals developed. This task will be coordinated by dr. Eduard José Cunilleras from the UAB Department of Animal Medicine and Surgery in collaboration with doctors from the Parc Taulí, Germans Trias, Vall d’Hebron and Santa Creu i Sant Pau hospitals, and the help of the scientific-technical service to support the research of the Crop, Antibody and Cytometry Service (SCAC) of the UAB.

TESTS ON ANIMALS

Any product to be administered to humans must first go through a preclinical phase in animal models. All trials, when they reach this stage, must be approved by the Ethics Committee on Animal and Human Experimentation. The safety and efficacy of the vaccine are tested in these models.

During vaccination trials we will monitor the weight of the animals and their general condition. The presence of antibodies in the blood of vaccinated animals will be evaluated in cell cultures. The serum of the vaccinated animals will be incubated with the SAR-CoV-2 and we will proceed to the infection of cell cultures. If the antibodies are capable of reducing the infectivity of the virus, then we will move on to the final part of this stage, which will consist of infecting the vaccinated animals with the virus to see if they are protected from infection. A group of unvaccinated animals will also be infected and we will compare the results with another group of unvaccinated and uninfected animals. The vaccine should give similar results to the last group of animals.

Further information about the project and FAQs about donations: https://micromecenatge.uab.cat/vacunacoronavirus

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