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Infrared sensitive hydrogels to control the regeneration of bone tissue.

NANBIOSIS U9 Synthesis of Nanoparticles Unit has participated in a research carried out bu researchers of CIBER-BBN group FIOBI-HULP at Hospital de la Paz, led by Nuria Vilaboa. reclently published in the scientific journal Biomaterials The researchers have used transgenic cells, which are incorporated into the scaffolding, to regulate the physiological production of bone growth factors and induce the osteoinduction process.

Achievement of spatiotemporal control of growth factors production remains a main goal in tissue engineering. In the present work, we combined inducible transgene expression and near infrared (NIR)-responsive hydrogels technologies to develop a therapeutic platform for bone regeneration. A heat-activated and dimerizer-dependent transgene expression system was incorporated into mesenchymal stem cells to conditionally control the production of bone morphogenetic protein 2 (BMP-2). Genetically engineered cells were entrapped in hydrogels based on fibrin and plasmonic gold nanoparticles that transduced incident energy of an NIR laser into heat. In the presence of dimerizer, photoinduced mild hyperthermia induced the release of bioactive BMP-2 from NIR-responsive cell constructs. A critical size bone defect, created in calvaria of immunocompetent mice, was filled with NIR-responsive hydrogels entrapping cells that expressed BMP-2 under the control of the heat-activated and dimerizer-dependent gene circuit. In animals that were treated with dimerizer, NIR irradiation of implants induced BMP-2 production in the bone lesion. Induction of NIR-responsive cell constructs conditionally expressing BMP-2 in bone defects resulted in the formation of new mineralized tissue, thus indicating the therapeutic potential of the technological platform.

Thanks to the participation of NANBIOSIS U9 Synthesis of Nanoparticles Unit it has been possible to explore the use of gold plasmonic nanoparticles, capable of absorbing light in the near-infrared (NIR) area and converting it into heat

Article of reference:

Sánchez-Casanova, S., Martin-Saavedra, F.M., Escudero-Duch, C., Falguera Uceda, M.I., Prieto, M., Arruebo, M., Acebo, P., Fabiilli, M.L., Franceschi, R.T., Vilaboa, N. Local delivery of bone morphogenetic protein-2 from near infrared-responsive hydrogels for bone tissue regeneration. Biomaterials 241:119909. https://doi.org/10.1016/j.biomaterials.2020.119909

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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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NANOMOL group, coordinator of NANBIOSIS Unit 6 collaborates with the VHIR in the developement of a new nanomedicine for the treatment of a childhood cancer

Within the MOTHER project (Molecule-based materials and supramolecular organizations for therapy, diagnosis and tissue engineering), the NANOMOL group from ICMAB collaborates with the Vall d’Hebron Institute of Research (VHIR), on the developement of a new nanomedicine for the treatment of high risk neuroblastoma, one of the most typical childhood cancers. Now, researchers from VHIR have identified new microRNAs that reduce the progression of this type of cancer.

The participation of NANOMOL group and NANBIOSIS unit 6 Biomaterial Processing and Nanostructuring Unit, as experts in nanoparticles and nanovesciles for nanomedicine, is on the synthesis of the adequate nanocapsules to protect, stabilize and direct this microRNAs molecules to the cancer tumours. The near future goal is to be able to administer the identified microRNAs for the treatment of high-risk neuroblastoma.

For further information

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Nanoparticle uptake and in vivo estimates of therapeutic efect and toxicity

Ramón Mangues, Scientific Dierctor of unit 18 of NANBIOSIS, Unit of nanotoxicology, explains in this video some of the animal models used in the unit for preclinical validation of nanoparticles, especially of application in cancer

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Intracellular trafficking of a dynein-based nanoparticle designed for gene delivery

Unit 1 of NANBIOSIS, Protein Production Platform (PPP) and the  Nanobiotechnology research group of CIBER-BBN in collaboration with the Universidade Estadual de Campinas and the Universidade de São Paulo have recently published, in the European Journal of Pharmaceutical Sciences, the results of the research devoted to the improvement of protein-only based nanoconjugates for gene therapy. The evaluated gene-therapy vehicle prototype  displayed a similar transfection efficiency to that of the commercial vector LipofectamineTM 2000.

Article of reference:

https://doi.org/10.1016/j.ejps.2017.11.002

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Nanoparticles capable of bi-directional communication

The results of a research co-led by Ramón Martínez-Máñez, Scientific Director of Unit 26 of NANBIOSIS and CIBER-BBN have been published by Nature Communication last May 30th, showing how to prepare a nanoparticles chemical communication system using lactose. So far, his group had managed to establish communication between three nanoparticles but only in a unidirectional way. “We have managed to get a nanoparticle to send a chemical messenger to the second nanoparticle, who understands the message and sends another chemical messenger back to the first one. Upon receiving it, it performs an action, in this case releasing a dye,” explains Martínez-Máñezto Efefuturo.

This is a very important “basic” research due to the lack of proven results at the nanoscopic level. This research is the first step in getting the nanoparticles to work in a collaborative and coordinated way, anticipating a future of intelligent nanoparticle networks and advanced controlled release systems, drugs or complex systems based on nanotechnology.

The characterization of the system has been done with NMR unit of NANBIOSIS

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