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Workshop on Hyperthermic Oncology

Next Friday, June 9, 2023, a Workshop on Oncological Hyperthermia entitled “Clinical Implementation of Oncological Hyperthermia in Spain and Europe: current situation and prospects” will be held in Barcelona. The location of the event is at the Hotel Front Marítim in Barcelona and the scheduled time is from 9:00 a.m. to 5:30 p.m.

Relevant speakers will present an updated vision on the different modalities of hyperthermia that are being used for cancer treatment. Jorge Contreras (Coordinator of the Spanish Society of Radiation Oncology ) will give a session on the current situation of clinical hyperthermia in Spain. Daniel Ortega (Coordinator of the National Network of Nanotechnology in Translational Hyperthermia) and Teresa Macarulla (Coordinating Investigator of the NoCanTher study on the use of magnetic nanoparticles associated with hyperthermia treatment in pancreatic cancer) will present their experience with a nanotechnological health product in said trial. After a break, Giammaria Fiorentini (Director of the Oncology Unit of the Muraglia di Pesaro Hospital) will give a vision of the use of electro-modulated hyperthermia in pancreatic cancer and in a round table, different professionals will give therir global vision of the application of these techniques from preclinical to clinical implementation.

In addition, regulatory aspects will also be covered. Luc van Hove (Medical, Regulatory and Clinical Affairs expert) will speak from a European perspective on the regulation of medical devices and in vitro diagnostics; while Julia Caro (Head of the area of the National Center for Certification of Sanitary Products) will do so from the perspective of a notified body.

Further information and registration at this link: https://forms.office.com/e/0251iMc2LT

There is additional information at:
-Linkedin https://www.linkedin.com/posts/safenmt_hyperthermia-magnetic-barcelona-activity-7062697943509737472-85wP?utm_source=share&utm_medium=member_desktop.
-Twitter https://twitter.com/abasolo_vhir/status/1659074218850484224

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Researchers of two NANBIOSIS units success in the Third Millennium Awards

Researchers of two NANBIOSIS units success in the Third Millennium Awards: the Young Research Talent award to Julia Ramirez (NANBIOSIS U27) and the Research and Future Award to the NFP group (NANBIOSIS U9)

Last November 8, four initiatives received the highest award in the eighth edition of the HERALDO contest Third Millennium Awards which represent the recognition of the Aragonese community from the youngest to the most consolidated trajectories in knowledge transfer, innovation, and scientific dissemination.

The Paraninfo of the University of Zaragoza hosted this event in which researchers CIBER-BBN – NANBIOSIS were recognised this year:

The Films and Nanostructured Particles (NFP) group of INMA and CIBER-BBN, directed by Jesús Santamaría and coordinating NANBIOSIS U9 “Synthesis of Nanoparticles Unit“, was recognised with the Research and Future Award: Manufacturing drugs inside tumors.

Julia Ramírez, from the BSiCoS group of the I3A and CIBER-BBN, coordinator of unit 27 “High Performance Computing Unit” of NANBIOSIS, received the “Young Research Talent” award for her work in the biomedical signal processing.

The Third Millennium Awards’ objective is to recognize the work of people, research centers and groups, institutions and companies in Aragon in three main axes:

Innovation:  Technological Innovation Award

Divulgation:  Best Science and Technology Dissemination Initiative

Research:

– Young Research Talent Awards

– Transfer of Science and University to Business Award

– Research and future award

Julia Ramirez

During her doctorate at Unizar (2017), she developed a methodology to quantify morphological variations in the electrocardiogram (ECG). This quantification led to the T-wave morphology restoration (TMR) index, which was shown to be a stronger predictor of sudden cardiac death than standard clinical indices.

After her doctorate, she moved to work at Queen Mary University of London (QMUL) in London. This was a key point in her research career because she broadened her knowledge in engineering, gaining experience in genetics and bioinformatics. During those years, she obtained two highly competitive European Postdoctoral Fellowships: a WHRI-Academy Cofund (2017) and a Marie Skłodowska-Curie (2018). In recognition of her work, in April 2020, QMUL promoted her to Lecturer in Genetics and Cardiovascular Data Science.

Since January of this year, Julia Ramírez has been back in Zaragoza thanks to a María Zambrano International Talent Attraction Scholarship, giving up the highly competitive Category 2 Talent Attraction of the Community of Madrid, which she had also been awarded. In total, the researcher from Zaragoza has contributed to her field of research with 32 peer-reviewed publications in different disciplines, including bioengineering, cardiology and genetics (13 of her as first author).

In her speech recognized “being in a happy moment”, for being back in Zaragoza, “being away is not always easy” and also for collecting an award for her work that always motivates her to continue forward in a career as the researcher, long and complicated.

The Films and Nanostructured Particles (NFP) group:

«This initiative is the work of many people. It has been a fantastic trip”, said Jesús Santamaría, Principal researcher of the NFP Group

The NFP of the Group was created in 2007 by researchers from different backgrounds, with the aim of concentrating efforts in the development and application of nanostructured materials with an emphasis on nanoparticles, nanoporous interfaces and hybrid systems. Its members have made pioneering developments in the synthesis of nanomaterials and their application in fields ranging from medicine to energy and the environment.

The award recognised the group’s work in the cancer research throughout the project CADENCE (Catalytic Dual-Function Devices Against Cancer), that aims to find a new way to fight this disease, avoiding the problems associated with conventional chemotherapy and its devastating side effects. Three fundamental problems had to be solved. First, developing suitable catalysts (catalytic nanoparticles) capable of operating inside a tumour and manufacturing toxic molecules there. Alternatively, nanoparticles can operate in other ways (by heating remotely) and also produce tumour death. It is also necessary to selectively deliver these catalysts to the tumour, avoiding their accumulation in other organs. Finally, these catalysts must be selectively activated inside the tumour. The answers obtained to each of these problems have opened new paths in the fight against cancer: Catalysts capable of manufacturing toxic substances from within the tumour are used, minimising their diffusion through the body.

This research was funded for five years through an ERC Advanced Grant project endowed with 2.5 million euros. The ERC Advanced Grants are the most prestigious European projects, awarded by the European Research Council in a highly competitive international competition.

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How engineered protein helps Nanomedicine againts Cancer

The use of protein nanoparticles as biomaterials have been rising in recent years due to their characteristics: high biocompatibility, structural versatility, biodegradability and plasticity of design. We can later incorporate peptide ligands for specific targeting as fusion proteins and use these nanoparticles for targeted nanomedicine.

However, not all proteins can be used as scaffolds for targeted drug delivery, as they need to meet certain criteria. First, it is crucial that the proteins used as a scaffold allow site-specific drug conjugation. The stability and proteolysis resistance of these proteins is also important to remain assembled during the bloodstream circulation. In addition, the scaffolds must be biologically neutral, meaning that they should not interact with other human proteins that interfere with their capacity to reach and specifically deliver their cargo. The lack of immunogenicity of these proteins is also desired to avoid immune system recognition. And, ideally, the proteins used as a scaffold should not have post-translational modifications to ensure that they fold equally in both prokaryotic and eukaryotic cell factories for production.

The scaffolds that have all these properties have a better chance to both achieve a proper biodistribution and to successfully deliver their cargo molecules into the target cells. The Green Fluorescent Protein (GFP) satisfy most of the desired characteristics for a scaffold. Moreover, its intrinsic fluorescence allows the tracking of the protein distribution and intracellular localization both in vitro and in vivo.

The use of GFP as a protein scaffold for targeted drug delivery has been extensively studied in our group. We have been able to deliver cytotoxic drugs through our patented platform for targeted delivery. This platform consists of a cationic peptide ligand (T22) and a hexa-histidine peptide that act as self-assembling tags. T22 is a CXCR4 ligand that enables a targeted delivery to CXCR4+ cells, a receptor that is overexpressed in metastatic cancer cells. We have demonstrated previously in an in vivo model that more than the 85% of the administered product was accumulated in the tumor and that we could efficiently conjugate Floxuridine (a genotoxic antimetabolite) to our T22-GFP-H6 nanoparticles, resulting in a strong anti-metastatic activity.

Despite these very promising results, GFP is an exogenous protein from Aequorea victoria and, consequently, triggers an immune response, which limits its clinical use. Thus, we needed to find a human protein that matches the exceptional properties of GFP as a protein scaffold. Fortunately, a non-fluorescent GFP-like protein has been described in humans and it corresponds to one of the three globular domains of Nidogen, a structural protein that binds to collagen IV, laminin and perlecan with high affinity. The globular domain G2 has a beta-barrel structure with a central alpha-helix that folds very similarly to the GFP, despite that these proteins share very low sequence identity. Notably, this domain does not have post-translational modifications that could interfere with its production and folding in prokaryotic cells.

However, perlecan and collagen IV binding sites have been reported within this G2 domain. Therefore, we needed to selectively mutate these binding sites in order to assure the biological neutrality of the nanoparticles. After a thorough structural analysis, we incorporated four different mutations to engineer a biologically neutral product that was named HSNBT. There were no differences detected between the wild-type G2 domain and the engineered HSNBT protein regarding the predicted structural epitopes, which suggested that the introduced mutations would not generate immunogenicity.

In order to validate the new scaffold, we used the above-mentioned patented platform with T22 and the hexa-histidine tag, replacing GFP for the new HSNBT scaffold. First, we characterized the resulting nanoparticles and we determined, both by Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM), that they had a size of around 10 nanometers. Then, we observed that the T22-HSNBT-H6 nanoparticles were internalized effectively by CXCR4+ cells. This specificity was corroborated when we used a CXCR4 antagonist (AMD) and we saw a notable decrease of their internalization. Then, we successfully conjugated floxuridine to the nanoparticles (T22-HSNBT-H6-FdU) through the free lysine-amino groups of the protein and we demonstrated that the nanoconjugates had a potent cytotoxic effect in CXCR4+ cells.

Once we have validated these nanoconjugates in vitro, we tested them in a colorectal cancer mouse model. Notably, we saw an important tumor growth inhibition after several doses of these nanoconjugates. The inhibitory effect was slightly higher when using the new scaffold than with GFP. We also saw a significant increase in cell death bodies and caspase-3 activation in the tumor after the treatment with the nanoconjugates. Again, the effect was more potent with HSNBT as a scaffold than with GFP. Remarkably, the treatment did not result in any histological toxicity and there were no differences between the weight of the treated mice when compared to the untreated mice.

This technology is protected by 3 patents: The ligand to enter CXCR4+ cells (WO2012/095527), the nanoconjugates (EP17382461.6) and the human scaffold protein HSNBT, (EP19383201), all three licensed to Nanoligent SL.

All in all, these results confirm that the G2 domain of nidogen can be used as a protein scaffold for targeted drug delivery. Its performance both in vitro and in vivo not only matches the observed with GFP, but it is even more efficient than GFP when conjugated with floxuridine. Therefore, the engineered HSNBT protein shows a very exciting potential to be used in the development of protein-based nanomedicines.  

By Carlos Martínez Torró (NANBIOSIS U1 PPP)

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Is it possible to communicate microorganisms from different kingdoms? Yes, it is, using “Nanotranslators”

CIBER, March 28 2022

Researchers from the Polytechnic University of Valencia (UPV) and the CIBER-BBN has demonstrated, for the first time, the potential of using “translator” nanoparticles to facilitate communication between different types of cells or microorganisms. His study could have application in multiple fields, especially in the medical field for the prevention and treatment of cancer.

“We have shown that it is possible to communicate microorganisms from different kingdoms using nanoparticles as translators. The nanoparticles process a message produced by the first type of cells (bacteria) and transform it into an understandable message for the second type of cells (yeast) that respond to it. In this way, the information flows from the emitting cells (bacteria) to the nanodevice and from the latter to the receiving cells (yeast), which allows communication between two microorganisms that would not otherwise interact. This is an advance in the design of nanoscale communication systems and opens the door for the development of future applications”, says Ramón Martínez Máñez, researcher at the Institute for Molecular Recognition and Technological Development (IDM) at the UPV and scientific director of the CIBER-BBN and Scientific Director of NANBIOSIS U26,”Biomedical Applications II”.

Among these future applications, the UPV-CIBER-BBN team highlights the possible regulation of the interactions between bacteria and human cells, for example, to prevent infections, kill bacteria or modulate our intestinal microbiome, and for the treatment of diseases such as cancer. “In this case, it would help cells of our immune system to recognize cancer cells more efficiently, regulating the interactions between them,” says Antoni Llopis, a CIBER-BBN researcher at the IDM Institute.

It could also be useful for designing particles that make it possible for plants and fungi to communicate with each other, which could help develop new plant protection strategies. “We could establish communication between plant cells and other microorganisms in their environment in order to prevent pests or use them as a treatment to improve plant performance,” says Ángela Morellá, a researcher at the Institute for Molecular Recognition and Technological Development (IDM) and study co-author.

In any case, the UPV and CIBER-BBN team insist that the results obtained are incipient –“it is a proof of concept”, they emphasize-, although they open a path with great potential for the field of micro/ nanotechnology and synthetic biology.

“Perhaps the biggest challenge will be reading whether the communication between those two kingdoms has been successful or not. In our study, we have used the expression of fluorescent protein by receptor cells, which facilitated the monitoring of the process. The development of future applications will require more advanced methodologies to allow the monitoring of chemical communication processes in complex biological environments”, concludes Ramón Martínez Máñez.

Article of reference

Beatriz de Luis, Ángela Morellá-Aucejo, Antoni Llopis-Lorente, Javier Martínez-Latorre, Félix Sancenón, Carmelo López, José Ramón Murguía, and Ramón Martínez-Máñez. Nanoprogrammed Cross-Kingdom Communication Between Living Microorganisms. Nano Letters 2022 22 (5), 1836-1844. DOI: 10.1021/acs.nanolett.1c02435

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Multivalent self-assembled platforms for the delivery of chemotherapeutic drugs

Twenty years ago, the 4 February was declared World Cancer Day with the global challenge of cancer would not be forgotten. Since then, huge progress has been made to understand, prevent, diagnose, and treat cancer.

NANBIOSIS as an ICTS (Singular Scientific and Technical infrastructures) for biomedical research plays a very important role in the fight against cancer.

Dr. Miriam Royo, who leads NANBIOSIS unit 3 of Synthesis of Peptide, explains one of the projects in which the ICTS is involved in relation with cancer therapy.

The improvement of solubility and stability of clinically approved chemotherapeutic drugs still represent a big challenge in cancer therapy. In fact, many of these drugs have low water solubility, which forces to administer larger volume doses to achieve the desired biological effect, and increases the side effects suffered from patients. The active principle can be chemically modified to increase the solubility, and administered as prodrug which, however, has to be enzymatically metabolized to have therapeutic effect and only a low percentage of the free drug is achieved. Moreover, some of the chemotherapeutic drugs are unstable at physiological conditions due to their chemical structure, and rapidly degrades before reaching the tumor tissue, further reducing the effectiveness of the treatment. Drugs commonly used in clinical chemotherapy treatments for advanced colorectal cancer and triple negative breast cancer, such as SN38, 5-fluorouracil (5-FU) and paclitaxel (PTX), have presented these problems, which affect their efficacy and tolerance to treatment by patients.

Drug delivery nanosystems based on biocompatible polyethylene glycol (PEG)-based multivalent platforms conjugated to hydrophobic drugs (SN38, PTX among others) are developed by the Multivalent Systems for Nanomedicine (MS4N) goup of Centro de Investigación Biom´dcia en Red (CIBER-BBN) at the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC). The resulting water-soluble conjugates have also the ability to self-assemble in aqueous media in nanoscale micellar structures improving the pharmacokinetic profile of drugs. In these systems, the intact active principle can be released in a controlled manner thanks to the presence of degradable bonds, between the drug and the polymer, which are sensitive to chemical or biological stimuli, favoring its accumulation in tumor.

Systems containing only one drug (SN38 or PTX) for monotherapy and two different drugs (as SN38 and 5-FU) for combined therapy treatments are developed to improve the therapeutic efficacy of the free drugs and decrease their secondary effects.  The multivalence nature of these systems also allows the possibility to add targeting agents, such as tumor specific peptide ligands thus increasing the specificity of the platforms towards the cancer cells. These peptide ligands have been produced at the Synthesis of Peptides Unit (U3) of NANBIOSIS.

This project (RTI2018-093831-B-I00) is funded by MICIN/AEI/10.13039/501100011033 and by “ERDF A way to of making Europe and performed in collaboration with Dr. Ibane Abasolo group of CIBER-BBN at Vall d’Hebron Research Institute (VHIR) and the In Vivo Experimental Platform (U20) of NANBIOSIS under the frame of CIBER BBN intramural collaborative projects (PolyPlaTher, Colocomb and Nanomets).

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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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Nanoparticles to eradicate Cancer Stem Cells

Colorectal cancer (CRC) has a high prevalence worldwide and resistance to conventional chemotherapies and tumor relapse are usually related with a population of cells with malignant properties – Cancer Stem Cells (CSC).

Scientists of CIBER-BBN and VHIR have led a research with the goal not only to treat the primary CRC, but also eradicate CSC. For both purposes, the use of nanoparticles (NP) is a useful strategy. These “bullets” carrying a drug in its core, are able to reach tumor tissue due to its small size. Cancer cells, and in particular CSC, present at their surface receptors that could be specifically recognized by molecules used to decorate NP, driven the drug of interest to these cells. In this work we developed a type of NP decorated with an antibody fragment that specifically recognize the receptor CD44v6, which is overexpressed in CSC and was previously demonstrated to be present in patients with metastasis and poor-prognosis. Moreover, researchers have encapsulated Niclosamide (NCS), a drug that demonstrated efficacy against breast CSC, inside their NP.  NP increased the efficacy of NCS and​ accumulated in the tumors reducing its systemic exposure and increasing safety. Most importantly, the developed system significantly reduce circulating tumor cells, precursors of metastasis, reducing CSC malignancy.

This system has the potential to create a new therapeutic approach that could bring a new hope for CRC treatment and prevention of cancer relapse.​

The work has been developed at the group of CIBBIM-Nanomedine_Drug Deliver & Targeting of Vall d’Hebron Institute of Research (VHIR) and CIBER-BBN, in collaboration with Bruno Sarmento (University of Porto, Portugal) and Marika Nestor (Uppsala University, Sweden) that helped to developed the NP and the targeting antibody, respectively. In vivo assays on the safety and efficacy of the NPs were conducted thanks to the contribution of the FVPR/U20 of ICTS-Nanbiosis. ​

Article of reference

Fernanda Andrade, Diana Rafael, Mireia Vilar-Hernández, Sara Montero, Francesc Martínez-Trucharte, Joaquin Seras-Franzoso, Zamira V.Díaz-Riascos, Ana Boullosa, Natalia García-Aranda, Patricia Cámara-Sánchez, Diego Arango, Marika Nestor, bane Abasolo, Bruno Sarmento, Simó SchwartzPolymeric micelles targeted against CD44v6 receptor increase niclosamide efficacy against colorectal cancer stem cells and reduce circulating tumor cells in vivo Journal of Controlled Release Volume 331, 10 March 2021, Pages 198-212 https://doi.org/10.1016/j.jconrel.2021.01.022

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NANBIOSIS research to fight cancer

Twenty years ago, the 4 February was declared World Cancer Day with the global challenge of cancer would not be forgotten. Since then, huge progress has been made to understand, prevent, diagnose, and treat cancer.

NANBIOSIS as an ICTS (Singular Scientific and Technical infrastructures) for biomedical research plays a very important role in the fight against cancer. Some examples of the work carried out during the last year, are bellow:

Unit 20 of NANBIOSIS  at VHIR, works in several proyects reletaed to cancer as  H2020-NoCanTher: magnetic nanoparticles against pancreatic cancer through the use of hyperthermia combined with conventional treatment. H2020-Target-4-Cancer: nanotherapy based on polymeric micelles directed against specific receptors of tumor stem cells in colorectal cancer. H2020-DiamStar: nanodiamonds directed against leukemia for the potentiation of chemotherapy. FET-OPEN EvoNano: in silico and tumor-tumor models for the prediction of PK / PD and tumor efficacy of antitumor nanomedicines against tumor stem cells.

The activities of U1 of Protein Production Platform (PPP) are also strongly committed with several projects devoted to develop new, more selective and more efficient antitumoral drugs, with antimetastatic effects.
oordinated action between units U1 of Protein Production Platform (PPP),
U18 of Nanotoxicology and U29 of Nucleic Acid Synthesis, shows promising results in development of nanopharmaceuticals with a high degree of efficacy for the treatment of metastases in colon cancer

Unit 6 of NANBIOSIS Biomaterial Processing and Nanostructuring Unit  is also working on a joined initiative between CIBER-BBN and CIBER-ONC to improve the current ex vivo immune cell expansion systems to help introduce immunotherapies such as the adoptive cell therapies, which have shown complete remissions of terminal cancer patients, to the clinics overcoming the limitation of having enough therapeutic cells with novel Nanobiomaterials. Researchers of Unit 6 and researchers of Laboratory of Translational Research in Child and Adolescent Cancer from the Vall d’Hebron Research Institute (VHIR), are working on a project financed by the Spanish Government and CIBER-BBN, for the development of a new nanomedicine for the treatment of high-risk neuroblastoma, one of the most frequent childhood cancers.

In our unit U26. NMR: Biomedical Applications II,  several studies for cancer biomarker discovery are being carried out. NMR studies on biofluids for the design of novel strategies for diagnosis support, easily transferable into the clinical practice, are being developed in biofluids in the context of cancer. Urine is one of the most easily obtainable biofluid and is a non-invasive source of biomarkers. Among these studies, we can mention the good discrimination achieved between urine from bladder cancer patients before surgery (cancer) and urine after surgery (free of cancer) and in the follow up of the disease, to monitor relapses

Some of the results of these researchs have been published in scientific magazines of high impact as for exemple;

Integrative Metabolomic and Transcriptomic Analysis for the Study of Bladder Cancer Alba Loras, Cristian Suárez-Cabrera, M. Carmen Martínez-Bisbal, Guillermo Quintás , Jesús M. Paramio, Ramón Martínez-Máñez,
Salvador Gil and José Luis Ruiz-Cerdá. Cancers 2019, 11, 686; doi:10.3390/cancers11050686

Nanostructured toxins for the selective destruction of drug-resistant human CXCR4+ colorectal cancer stem cells Naroa Serna, Patricia Álamo, Prashanthi Rameshef, Daria Vinokurovaef, LauraSánchez-García, Ugutz Unzueta, Alberto Gallardo, María  Virtudes Céspedes, Esther Vázquez, Antonio Villaverde, Ramón Mangues, Jan Paul Medema. . Journal of Controlled Release.  Volume 320, 96-104, 2020 https://doi.org/10.1016/j.jconrel.2020.01.019

Controlling self-assembling and tumor cell-targeting of protein-only nanoparticles through modular protein engineering Voltà-Durán, E., Cano-Garrido, O., Serna, N. et al. C. Sci. China Mater.63, 147–156 (2020). https://doi.org/10.1007/s40843-019-9582-9

Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci, María Virtudes Céspedes  Olivia Cano‐Garrido  Patricia Álamo  Rita Sala  Alberto Gallardo  Naroa Serna  Aïda Falgàs  Eric Voltà‐Durán  Isolda Casanova  Alejandro Sánchez‐Chardi  Hèctor López‐Laguna  Laura Sánchez‐García  Julieta M. Sánchez  Ugutz Unzueta  Esther Vázquez  Ramón Mangues  Antonio Villaverde . Advanced Materiasls Número de artículo: 1907348 , Dec. 2019 https://doi.org/10.1002/adma.201907348

Artificial Inclusion Bodies for Clinical Development 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, Advanced Science. 2019 https://doi.org/10.1002/advs.201902420

Nanostructured Nucleolin-Binding Peptide for Intracellular Drug Delivery in Triple-Negative Breast Cancer Stem Cells Mireia Pesarrodona, Laura Sánchez-García, Joaquin Seras-Franzoso, Alejandro Sánchez-Chardi, Ricardo Baltá-Foix, Patricia Cámara-Sánchez, Petra Gener,  José Juan Jara, Daniel Pulido, Naroa Serna, Simó Schwartz Jr. Miriam Royo, Antonio Villaverde, Ibane Abasolo, Esther Vazquez ACS Applied Materials & Interfaces DOI: 10.1021/acsami.9b15803  

Nanostructure Empowers Active Tumor Targeting in Ligand‐Based Molecular Delivery López‐Laguna, H., Sala, R., Sánchez, J. M., Álamo, P., Unzueta, U., Sánchez‐Chardi, A., Serna, N., Sánchez‐García, L., Voltà‐Durán, E., Mangues, R., Villaverde, A., Vázquez, E., . Part. Part. Syst. Charact. 2019, 36, 1900304. https://doi.org/10.1002/ppsc.201900304

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NANBIOSIS U1 PPP will take a critical role in one of the projects selected by La Marató TV3 to fight against cancer

“Selectively humanized nanomedicines aimed at killing CXCR4 + tumor cells for the treatment of acute myeloid leukemia”  is one of the Project awarded by La Marató TV3 Foundation and is participated by Dr. Antonio Villaverde, Estrategic of NANBIOSIS U1 Protein Production Platform (PPP)

The main objective of the project is the design and validation of humanized protein nanoparticles for the targeted delivery of antitumoral drugs for the treatment of acute myeloid leukemia. This will be done by the generation of protein-based nanoconjugates that will be targeted to the cytokine receptor CXCR4, overexpressed in this human neoplasia. The drugs will consist in a protein part, that will ofer nanoscale size, stability and CXCR4-targeting, and a small molecular weight chemical that will perform the cytotoxic effect over tumoral cells. The Protein Production Platform (U1 of NANBIOSIS), will have a critical role in the design and production of the protein amounts required for the in vivo experiments, that will be performed at the Institut de Recerca of Sant Pau Hospital.

In the 2018 La Marató TV3 edition, dedicated to cancer, 192 projects were presented, which were evaluated by 149 international scientists specialized in this field based on their quality, methodology and relevance. The management of the evaluation was carried out by the Health and Quality Assessment Agency of Catalonia, from the Department of Health. In accordance with the proposal of the Scientific Advisory Commission of the La Marató de TV3 Foundation, the Board agreed to distribute 13,149,870.76€ among the 43 scientific research projects.

The Project “Selectively humanized nanomedicines aimed at killing CXCR4 + tumor cells for the treatment of acute myeloid leukemia“. Will be developed by the research groups led by:

  • Dr. Jordi Sierra GilHospital de la Santa Creu i Sant Pau – IRHSCSP Institut de Recerca Hospital de la Santa Creu i Sant Pau
  • Dr. Antonio Villaverde CorralesFacultat de Medicina – UAB Universitat Autònoma de Barcelona
  • Dra. Lourdes Farré Vallvé Institut Català d’Oncologia – IDIBELL Institut d’Investigació Biomèdica de Bellvitge

Financing: 399.178,75 €

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Nano-carrier to release drugs into damaged cells

Senescent cells are damaged cells that do not perform their normal roles anymore but that are not dead –hence they are commonly known as zombi cells. These cells interfere with the functioning of the tissue in which they accumulate. Senescence is a cell program that is triggered by many types of damage and senescent cells are present in many diseases. They accumulate in diverse types of tissues during aging, thus contributing to the progressive deterioration associated to aging. Eliminating these zombi cells is one of the challenges facing science today.

In the Cellular Plasticity and Disease lab headed by the ICREA researcher Manuel Serrano at the Institute for Research in Biomedicine (IRB Barcelona) and supported by “la Caixa” Banking Foundation, the researchers devise strategies to eliminate senescent cells. In a study published in EMBO Molecular Medicine, they present a proof of principle of a drug delivery system with selectivity for tissues that harbour senescent cells.

In collaboration with a team headed by Ramón Martínez-Máñez, Scientific Diirector of NANBIOSIS Unit 26 NMR: Biomedical Applications II ,  the IRB Barcelona scientists have exploited a particular hallmark of senescent cells in order to design a delivery system that specifically targets them. They have demonstrated its efficacy in cells in vitro and in two experimental mouse models, namely pulmonary fibrosis and cancer. These diseases are characterized by the presence of damaged cells, and in the case of cancer this is particularly true after treatment with chemotherapy.

In these models, the senescent cells take up the carrier more efficiently than other cells and once inside the cell the casing of the carrier degrades to release the drug cargo. When the nano-vehicles contained cytotoxic compounds, the senescent cells were killed and this resulted in therapeutic improvements in mice with pulmonary fibrosis or with cancer.

“This nano-carrier may pave the way for new therapeutic approaches for serious conditions, such as pulmonary fibrosis or to eliminate chemotherapy-induced senescent cells,” explains Manuel Serrano. Another outcome of this study is that these nano-carriers could be used for diagnostic tests of senescence as they can transport a fluorescent compound or marker.

This study, performed by IRB Barcelona in collaboration with the Universidad Politécnica de Valencia, CNIO, the University of Cambridge, CIBER-BBN, and the company Pfizer in the US, is a step towards achieving the capacity to eliminate senescent cells. Developing tools to specifically eliminate senescent cells is currently a central goal for many pharmaceutical companies, among them the one set up by Manuel Serrano himself together with Ramón Martínez-Máñez and José Ramón Murguia, Senolytic Therapeutics, which is located at the Barcelona Science Park and in Boston.

The study has been funded by “la Caixa” Banking Foundation, the Botín Foundation, the European Research Council, CRUK Cambridge Centre Early Detection Programme, the Ministry of Economy and Competitiveness/ERDFs and the Catalan Governmen

Daniel Muñoz‐Espín, Miguel Rovira, Irene Galiana, Cristina Giménez, Beatriz Lozano‐Torres, Marta Paez‐Ribes, Susana Llanos, Selim Chaib, Maribel Muñoz‐Martín, Alvaro C Ucero, Guillermo Garaulet, Francisca Mulero, Stephen G Dann, Todd VanArsdale, David J Shields, Andrea Bernardos, José Ramón Murguía, Ramón Martínez‐Máñez, Manuel Serrano A versatile drug delivery system targeting senescent cells EMBO Molecular Medicine (2018) DOI 10.15252/emmm.201809355

Image: The figure shows two views, frontal and lateral, of the image obtained by CT of the lungs of a mouse with fibrosis (grey areas) before and after receiving nano-therapy directed at senescent cells. (Guillem Garaulet and Francisca Mulero, CNIO)

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