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Dr Ramón Mangues, new member of the Royal Academy of Pharmacy of Catalonia

Dr. Ramon Mangues, head of the Oncogenesis and Antitumor Group and Scientific Director of NANBIOSIS U18 Nanotoxicology Unit of CIBER-BBN at the Sant Pau Research Institute, has been recently elected as a new member of the Royal Academy of Pharmacy of Catalonia.

The celebration will take place on November 8 at 7 pm, at the headquarters of the RAFC, (Royal Academy of Pharmacy of Catalonia) which was the headquarters of the old Hospital de la Santa Cruz since the 15th century, located at Calle del Hospital, 56, in Barcelona.

During the event, Dr. Mangues will read his admission speech “Selective delivery of drugs to metastatic stem cells“, which can be followed by zoom and live on Youtube using the following links:

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Development of a protein-only drug delivery system for sustained release

The Nanotoxicology Unit of CIBER-BBN ICTS NANBIOSIS (u18-nanotoxicology-unit), led by Ramon Mangues at the Research Institute of the Hospital de Sant Pau and the NABIOSIS (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 drug delivery system able to achieve sustained release of proteins with intrinsic antitumor activity. This delivery system consists on inclusion bacterial bodies formed by recombinant fusion proteins that precipitate while being expressed in bacteria, acquiring an amyloid structure, but remaining functional. Thus, these amyloids are able to release protein monomers that generate soluble nanoparticles that selectively internalize within target cancer cells because of the incorporation ion the protein nanoparticles of a specific ligand that interacts with a surface receptor expressed in target cancer cells.

On this basis, we have subcutaneously administered inclusion bodies containing cytotoxic nanoparticles that incorporate the Pseudomonas aeruginosa Exotoxin (PE24), to demonstrate their capacity of sustained release since they reach cancer tissues through the blood to selectively killing target colorectal (CRC) cancer cells. This cancer specific targeting occurs because the released protein is functionalized with the peptidic ligand T22 for the CXCR4 receptor (overexpress in CRC cells). In addition, we have evaluated their anticancer effect in the different localization where metastatic foci growth in a colorectal cancer (CRC) model. The administration, in these models of 500 micrograms of T22-PE24 amyloids, induces a potent inhibition of primary tumor growth and a dramatic reduction, both in number and size, of the metastases in lymph nodes, liver, lung and peritoneum, an effect that is achieved, in the absence of systemic toxicity.

One of the main applications of these functional amyloid structures could be their use by subcutaneously injectable drug depots that could release the active protein drug at sustained levels, during a long time (weeks or months). This may change the way that current protein-based drugs (e.g. antibodies targeting specific receptors) are administered, since this approach will allow to dosage the drug only once every 2-3 weeks or a month, avoiding the current intravenous injection schedule, which is 2-3 times a week. When applied to targeted drugs, as the one here described, which demonstrate high efficacy with low adverse effects, could establish a novel approach to treat cancer patients by visits of sanitary personnel at their home, avoiding the need of their hospitalization, which is required when receiving intravenous injections; and therefore, dramatically reducing the cost of patient treatment for the health system. 

Reference:

Céspedes MV, Cano-Garrido O, Álamo P, Sala R, Gallardo A, Serna N, Falgàs A, Voltà-Durán E, Casanova I, Sánchez-Chardi A, López-Laguna H, Sánchez-García L, Sánchez JM, Unzueta U, Vázquez E, Mangues R, Villaverde A. Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci. Advanced materials. 2020.  https://doi.org/10.1002/adma.201907348

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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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The Need to Determine the Therapeutic Window of Novel Targeted Anticancer Nanomedicines

The Nanotoxicology Unit of CIBER-BBN ICTS NANBIOSIS, leaded by Ramon Mangues at the Research Institute of the Hospital de Sant Pau is devoted to evaluate effectiveness and toxicity of novel nanoparticles.  This Unit advises clients on the need to study simultaneously anticancer activity and associated toxicity. Thus, preclinical evaluation of novel Nanomedicines is usually carried out performing studies that assess their therapeutic effect, separated from additional experiments devoted to evaluate the toxicity associated with treatment. The dosage used to assess the therapeutic effect, often, significantly differs from the one used to study toxicity, since one is aiming to know the biodistribution of the nanoparticle and whether it is able to control cancer growth, whereas the other tries to identify the maximal tolerated dosage that can be achieved without conferring severe toxicity or lethality.

However, to maximize the effectiveness of novel nanoparticles in the preclinical assessment and their subsequent clinical translation it is important to consider a crucial point of divergence between nanomedicines and classical low molecular weight drugs.

On the one hand, lipophilic small drug bidodistribute by passive diffusion, reaching similar concentration in tumor and non-tumor tissues. Besides, they display a steep dose/effect curve, so that higher doses reach higher anticancer effect (e.g. genotoxic drugs, such as 5-fluorouracil or cisplatin). Nevertheless, this increased effect, obtained intensifying the drug dosage, is achieved at the expense of higher toxicity, that is also dose dependent. In contrast, this situation differs in the case of nanomedicines that use targeted drug delivery, which are capable of selectively concentrating the payload drug delivered by the nanocarrier in target cancer cells, leading to an enhanced uptake in tumor tissue. This effect makes it unnecessary and inefficient to increase the nanomedicine dosage over the one that effectively kill target cells, while maintaining low the associated toxicity. This is because nanomedicines that exploit targeted drug delivery do not have a dose dependent increase in antitumor activity; whereas if administered at high dosage they lose selectivity in their delivery, triggering off-target toxicity, that is likely to be dose-dependent. Thus, increasing the dosage of targeted nanoparticles may increase off-target effects without increasing anticancer effectiveness. In this regard, administering a dosage higher than the one that reaches optimal therapeutic effect can only lead to unspecific internalization in non-target cells and subsequent toxicity.

Therefore, it is our opinion that the evaluation of the tumor and non-tumor tissues biodistribution and the assessment of the therapeutic effect is more informative if at the same time and in the same model is tested the associated toxicity. The testing of various dosage levels will determine which of the evaluated dosage achieves the highest therapeutic window, that is, the one that achieves effective cancer cell killing and optimal antitumor activity without associated toxicity, and the one for which an additional increase in dosage will not improve further the antitumor effect, while increasing instead its toxicity

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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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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 Scientists discover a promising effective alternative to reduse relapse rates in Diffuse Large B-cell Lymphoma Cells

Researchers of NANBIOSIS-ICTS Units from CIBER-BBN: U1 Protein Production Platform (PPP) at IBB-UAB, led by Antoni Villaverde and Unit 18 Nanotoxicology Unit at IBB-Hospital Sant Pau, led by Ramón Mangues, have demonstrated a potent T22-PE24-H6 antineoplastic effect, especially in blocking dissemination in a CXCR4+ DLBCL model without associated toxicity. Thereby, T22-PE24-H6 promises to become an effective alternative to treat CXCR4+ disseminated refractory or relapsed DLBCL patients.

Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK.

One of the major problems in the therapeutic strategies is the relapse rates. CXCR4-overexpressing cancer cells are good targets for therapy because of their association with dissemination and relapse in R-CHOP treated DLBCL patients but show a narrow therapeutic index due to their systemic toxicity wich generate the induction of severe side effects. NANBIOSIS researchers have developed a therapeutic nanostructured protein T22-PE24-H6 that incorporates exotoxin A from Pseudomonas aeruginosa, which selectively targets lymphoma cells because of its specific interaction with a highly overexpressed CXCR4 receptor (CXCR4+) in DLBCL, demonstrating a potent T22-PE24-H6 antineoplastic effect, without associated toxicity. Thereby, T22-PE24-H6 promises to become an effective alternative to treat CXCR4+ disseminated refractory or relapsed DLBCL patients

The bioluminescent follow-up of cancer cells and toxicity studies has been performed in the ICTS Nanbiosis Platform, using its CIBER-BBN Nanotoxicology Unit and Protein production has been performed by the ICTS “NANBIOSIS”, more specifically by the Protein Production Platform of CIBER-BBN/ IBB

Article of 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. Theranostics 2020; 10(12):5169-5180. doi:10.7150/thno.43231. Available from http://www.thno.org/v10p5169.htm

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