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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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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 in the field of organic free radicals acting as chiral emitters

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

To see the article:

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

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

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

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

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

Article of reference:

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

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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.

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.

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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NANBIOSIS expertise on Nanoparticles Characterization by Amable Bernabé.

Amable Bernabé, Technical Coordinator of NANBIOSIS U6 Biomaterial Processing and Nanostructuring Unit has given a course from Monday, 7 October, to Wednesday, 9 October on “Characterization techniques for particulate materials”. The course has counted with 12 participants from different CSIC centers (including ICMAB, IBM-CNM, ICM, IQAC…) and has introduced the participants to different techniques to characterize nanoparticles and other particulate matter, including the basic fundamentals, sample preparation, practical examples and results interpretation. 

It is the second time that Amable Bernabé, technician from the Sof tLab, has decided to offer this course to all the CSIC community, so they can learn new methods to characterize nanoparticles, the theory behind the techniques, and how to manage the equipment.

Specifically, the techniques shown are:

Theory:

  • Dynamic Light Scattering (DLS) with Zetasizer Nano ZS (Malvern Instruments)
    • Size distribution
    • Z Potential 
  • Nanoparticle Tracking Analysis (NTA) with Nanosight NS300 (Malvern Instruments)
    • Size distribution
    • Particle concentration
    • Fluorescence
  • Light Scattering (LS) with Mastersizer 2000 (Malvern Instruments)
    • Size distribution

Practice:

  • Sample analysis and practical cases of Dynamic Light Scattering with the Zetasizer Nano ZS (Malvern Instruments) equipment.
  • Samples analysis and practical cases of the Nanoparticle Tracking Analysis (NTA) technique with the Nanosight NS300 (Malvern Instruments) equipment.
  • Sample analysis and practical cases of the Light Scattering (LS) technique with the Mastersizer 2000 (Malvern Instruments) instrument. 
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NANBIOSIS Scientific Director, Jaume Veciana, coauthor of an article highlighted in Chemistry Views

Jaume Veciana, Scientific Director of NANBIOSIS is coauthor of an article chosen to be highlighted on the ChemistryViews newsletter: “Organic Free Radicals as Circularly Polarized Luminescence Emitters”, published in Angewandte Chemie International Edition, and is about the intrinsic chiral emission of enantiometric organic free radicals.

The short news about the paper is entitled “Circulary Polarized Light from Organic Radicals” is available here. 

Circularly polarized luminescence (CPL) can occur when a luminescent compound has a chiral structure. Organometallic structures are leading in CPL activity. However, purely organic CPL emitters are promising alternatives in several applications where low toxicity is important
(i.e., bioimaging).

Jaume Veciana (Institut de Ciéncia de Materials de Barcelona (ICMAB), Spain), Araceli G. Campaña (University of Granada, Spain) and colleagues have found a new approach for the optimization of organic emitters with intrinsic chirality. In particular, tris(2,4,6-trichlorophenyl)methyl (TTM) and perchlorotriphenylmethyl (PTM) radicals, which both have a chiral propeller-like shape, were used. In addition to their chirality, these materials are magnetically active. They are also easy to modify in order to optimize their properties.

The team separated the two racemic compounds into their enantiomers using chiral stationary phase high-performance liquid chromatography (HPLC). The CPL spectra of the four resulting fractions (examples pictured) were recorded and the researchers found highly efficient chiral emission for both pairs of enantiomers. According to the researchers, this is the first time results about the intrinsic chiral emission from enantiomeric organic free radicals have been reported. The work might be a starting point for the development of improved chiral organic radical emitters.

Reference article:Organic Free Radicals as Circularly Polarized Luminescence Emitters
Paula Mayorga Burrezo, Vicente G. Jiménez, Davide Blasi, Imma Ratera, Araceli G. Campaña, Jaume Veciana,
Angew. Chem. Int. Ed.2019.
https://doi.org/10.1002/anie.201909398

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Biomarkers in semen to diagnose prostate cancer

Sara Larriba of the Human Molecular Genetics Group of Bellvitge Biomedical Research Institute (IDIBELL) has informed NANBIOSIS about a recent publication mentioning NANBIOSIS in the Acknowledgements for its participation in the results of their research. (The nanoparticle tracking analysis was performed by the ICTS NANBIOSIS U6 Biomaterial Processing and Nanostructuring Unit) The article has been published by the journal Scientific Reports of Nature Research.

The prediction of PCa in the early stage of the disease is one of the most important objectives in male urology. A significant decrease in deaths due to PCa has been associated with the use of serum PSA test recent years. However, the PSA test still has serious limitations and often gives false positives that lead to many unnecessary biopsies of benign disease. Therefore, researchers from the Human Molecular Genetics Group of Bellvitge Biomedical Research Institute (IDIBELL) decided to evaluate semen as a source of prostate cancer biomarkers, and studying extracellular miRNAs, which are present within semen in extraordinary concentrations since some of the Some of these extracellular miRNAs are specific to the prostate gland and, in addition, there is already research showing that extracellular miRNAs can reflect altered patterns of miRNA expression in prostate tumor tissue. The study conducted allowed scientists to discover a distinctive miRNA expression pattern in exosomal semen samples obtained from men with prostate cancer compared with that found in exosomal semen samples taken from healthy men. The next step would be to conduct more prospective studies in larger patient cohorts before this miRNA-based biomarker can be adopted in daily clinical practice.

Article of reference:

Semen miRNAs Contained in Exosomes as Non-Invasive Biomarkers for Prostate Cancer Diagnosis, Maria Barceló, Manel Castells, Lluís Bassas, Francesc Vigués2 & Sara Larriba. Scientific Reports volume 9, 24 Sept 2019.

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Targeting antitumoral proteins to breast cancer by local administration of functional inclusion bodies

Three units of NANBIOSIS have collaborated in obtaining the research results published in the article “Targeting Antitumoral Proteins to Breast Cancer by Local Administration of Functional Inclusion Bodies” published by Advanced Science

Protein production and DLS have been partially performed by the Unit 1 of ICTS NANBIOSIS Protein Production Platform (PPP) and the Unit 6 NANBIOBIS Biomaterial Processing and Nanostructuring Unit. Biodistribution and immunohistochemistry assays were performed at NANBIOSIS U20 In Vivo Experimental Platform/FVPR

Two structurally and functionally unrelated proteins, namely Omomyc and p31, are engineered as CD44‐targeted inclusion bodies produced in recombinant bacteria. In this unusual particulate form, both types of protein materials selectively penetrate and kill CD44+ tumor cells in culture, and upon local administration, promote destruction of tumoral tissue in orthotropic mouse models of human breast cancer. These findings support the concept of bacterial inclusion bodies as versatile protein materials suitable for application in chronic diseases that, like cancer, can benefit from a local slow release of therapeutic proteins.

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New publication by scientists of NANBIOSIS Unit 6 aims to motivate scientific community to start a new research line for organic and bio-organic electronics focused on the device fabrication

Researchers of Nanomol Group, coordinator of NANBIOSIS U6 of CIBER-BBN and ICMAB-CSIC, led by Inma Ratera and Jaume Veciana have publish a new article titled “Reversible switching of the Au(111) work function by near infrared irradiation with a bistable SAM based on a radical donor–acceptor dyad“, at Journal of Materials Chemistry C.

Article:
https://pubs.rsc.org/en/content/articlelanding/2019/TC/C9TC00906J#!divAbstract

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