IP: Simó Schwartz Navarro

We focus into new targeting strategies to ensure a specific delivery of therapeutic compounds into the most appropriate target cell to improve treatment response and achieve lower toxicity and higher therapeutic activities in several human diseases, with particular interest in delivery of chemotherapeutic drugs to cancer cells and enzyme replacement therapies for rare diseases. In addition, alternative targeting strategies are being designed to improve imaging-based diagnostics by using new cell-targeted nanoconjugates.

Some of the projects explained bellow are developed in collaboration with other groups at CIBER-BBN (Centro de Investigaciones en Red en Biomateriales, Bioingenería y Nanomedicina, Instituto de Salud Carlos III) or within specific European consortiums.  

i) Enzyme replacement therapy for storage diseases: new therapeutic strategies

Fabry disease is an X-linked recessive disorder caused by a deficiency of lysosomal hydrolase ?-galactosidase A (GLA). This enzymatic defect causes the progressive cellular accumulation of neutral glycosphingolipids, giving rise to a multisystemic clinical symptomatology. Current enzyme replacement therapy (ERT) has a limited treatment efficacy in patients with advanced stages of the disease. The objective of this research line is to improve the ERT by using new therapeutic compounds (nanoparticles or specifically designed proteins) of GLA targeted to the endothelial cells, one of the main cell type affected by GLA substrate accumulation. In addition, we also collaborate in a project focused on the validation of new integrated, multi-host approaches for the improved microbial production of high quality GLA enzymes for industrial purposes (IMAPPROT).

ii) NANOSTEM: Targeting Combined Therapy to Cancer Stem Cells

In many solid tumors, resistance to therapy and metastatic disease seem to be sustained by the presence within the tumors of the cancer stem cells (CSC) capable of regenerating a tumor after chemotherapy and/or radiation treatment. In breast cancer, these cells correspond to a small fraction of cells within the tumor that express stem cell markers (CD44+/CD24-/low/lin-) which provides a useful target to the delivery of therapeutic agents to CSC. In this network project some of the partners will focus into the design of specific vehicles for the simultaneous deliver of chemotherapeutic drugs and/or shRNAs with known antitumor activity to breast CSC. To this end, different types of nanoparticles will be directed to the CSC compartment by using the CD44 receptor as a target. Such systems will allow specific CSC-targeting, and together with the enhanced retention an permeability effect (EPR) will improve accumulation of drugs into the tumor area and should yield better therapeutic response. At CIBBIM-Nanomedicine, therapeutic activity, nanoparticle internalization and toxicology of these nanoparticulated systems will be addressed by using adequate in vitro and in vivo CSC models.

iii) ONCONANOTARGET: Advancing the field of drug delivery - combined targeted treatments against human breast cancer and human leukemia

The idea in the ONCONANOTARGET Network is to selectively abrogate tumour-protective functions aiming at either improving sensitivity of tumour cells to chemotherapy or finding synergistic combinations that may improve the clinical outcome for the treatment of breast cancer or leukaemia patients.

Therefore, the main objectives of this project are: (i) To design and characterise ligand-targeted nanosystems for nucleic acid (siRNA) and drug delivery; (ii) To compare, in vitro, the gene-silencing efficiency of the developed targeted lipid-based or polymeric-based nanosized systems containing nucleic acids against Bcl-2 oncogene in breast cancer leukaemia and cells; (iii) To evaluate the cytotoxic activity of individual treatments with either gene silencing with targeted system previously selected or targeted polymer-anticancer drug conjugate as compared to combined treatments (targeted gene silencing combined with targeted polymer-anticancer drug conjugates) against leukaemia and breast tumour cells; and (iv) Therapeutic evaluation of the treatment modality previously selected in an animal model of human breast cancer. In this project, in vivo proof of concept will be limited to breast cancer.

iv) Treatment of advanced colorectal cancer by novel drug delivery systems, sensitive to metalloproteinases

Current chemotherapeutic treatment for colorectal cancer implies the use of high doses of cytotoxic medicaments, specifically adjuvant combinations of 5-fluorouracil and Irinotecan, which bring many adverse effects to the affected patient. This project proposes a program centred on the development of new nanomedicines, based on polymers of multifunctional character that brought together different chemotherapeutic agents, allowing a combined double or triple therapy using much lower systemic doses and significantly reducing undesirable side-effects. In this case, we will focus on increasing these advantages with the utilization of synthetic peptides sensitive to degradation by matrix metalloproteases (MMP), which will bind the polymeric nanocarrier to the chemotherapeutic drug. The activity of MMPs will favour the liberation of the drug and its activity in MMP rich environments, so to say primary tumors and metastatic sites. The project includes the processes of synthesis, chemical characterization and optimization of the nanomedicines, as well as their in vitro and in vivo validation.

IP: Simó Schwartz Navarro

We focus into new targeting strategies to ensure a specific delivery of therapeutic compounds into the most appropriate target cell to improve treatment response and achieve lower toxicity and higher therapeutic activities in several human diseases, with particular interest in delivery of chemotherapeutic drugs to cancer cells and enzyme replacement therapies for rare diseases. In addition, alternative targeting strategies are being designed to improve imaging-based diagnostics by using new cell-targeted nanoconjugates.

Some of the projects explained bellow are developed in collaboration with other groups at CIBER-BBN (Centro de Investigaciones en Red en Biomateriales, Bioingenería y Nanomedicina, Instituto de Salud Carlos III) or within specific European consortiums.  

i) Enzyme replacement therapy for storage diseases: new therapeutic strategies

Fabry disease is an X-linked recessive disorder caused by a deficiency of lysosomal hydrolase ?-galactosidase A (GLA). This enzymatic defect causes the progressive cellular accumulation of neutral glycosphingolipids, giving rise to a multisystemic clinical symptomatology. Current enzyme replacement therapy (ERT) has a limited treatment efficacy in patients with advanced stages of the disease. The objective of this research line is to improve the ERT by using new therapeutic compounds (nanoparticles or specifically designed proteins) of GLA targeted to the endothelial cells, one of the main cell type affected by GLA substrate accumulation. In addition, we also collaborate in a project focused on the validation of new integrated, multi-host approaches for the improved microbial production of high quality GLA enzymes for industrial purposes (IMAPPROT).

ii) NANOSTEM: Targeting Combined Therapy to Cancer Stem Cells

In many solid tumors, resistance to therapy and metastatic disease seem to be sustained by the presence within the tumors of the cancer stem cells (CSC) capable of regenerating a tumor after chemotherapy and/or radiation treatment. In breast cancer, these cells correspond to a small fraction of cells within the tumor that express stem cell markers (CD44+/CD24-/low/lin-) which provides a useful target to the delivery of therapeutic agents to CSC. In this network project some of the partners will focus into the design of specific vehicles for the simultaneous deliver of chemotherapeutic drugs and/or shRNAs with known antitumor activity to breast CSC. To this end, different types of nanoparticles will be directed to the CSC compartment by using the CD44 receptor as a target. Such systems will allow specific CSC-targeting, and together with the enhanced retention an permeability effect (EPR) will improve accumulation of drugs into the tumor area and should yield better therapeutic response. At CIBBIM-Nanomedicine, therapeutic activity, nanoparticle internalization and toxicology of these nanoparticulated systems will be addressed by using adequate in vitro and in vivo CSC models.

iii) ONCONANOTARGET: Advancing the field of drug delivery - combined targeted treatments against human breast cancer and human leukemia

The idea in the ONCONANOTARGET Network is to selectively abrogate tumour-protective functions aiming at either improving sensitivity of tumour cells to chemotherapy or finding synergistic combinations that may improve the clinical outcome for the treatment of breast cancer or leukaemia patients.

Therefore, the main objectives of this project are: (i) To design and characterise ligand-targeted nanosystems for nucleic acid (siRNA) and drug delivery; (ii) To compare, in vitro, the gene-silencing efficiency of the developed targeted lipid-based or polymeric-based nanosized systems containing nucleic acids against Bcl-2 oncogene in breast cancer leukaemia and cells; (iii) To evaluate the cytotoxic activity of individual treatments with either gene silencing with targeted system previously selected or targeted polymer-anticancer drug conjugate as compared to combined treatments (targeted gene silencing combined with targeted polymer-anticancer drug conjugates) against leukaemia and breast tumour cells; and (iv) Therapeutic evaluation of the treatment modality previously selected in an animal model of human breast cancer. In this project, in vivo proof of concept will be limited to breast cancer.

iv) Treatment of advanced colorectal cancer by novel drug delivery systems, sensitive to metalloproteinases

Current chemotherapeutic treatment for colorectal cancer implies the use of high doses of cytotoxic medicaments, specifically adjuvant combinations of 5-fluorouracil and Irinotecan, which bring many adverse effects to the affected patient. This project proposes a program centred on the development of new nanomedicines, based on polymers of multifunctional character that brought together different chemotherapeutic agents, allowing a combined double or triple therapy using much lower systemic doses and significantly reducing undesirable side-effects. In this case, we will focus on increasing these advantages with the utilization of synthetic peptides sensitive to degradation by matrix metalloproteases (MMP), which will bind the polymeric nanocarrier to the chemotherapeutic drug. The activity of MMPs will favour the liberation of the drug and its activity in MMP rich environments, so to say primary tumors and metastatic sites. The project includes the processes of synthesis, chemical characterization and optimization of the nanomedicines, as well as their in vitro and in vivo validation.

La identificación de biomarcadores en las células madres tumorales nos permite desarrollar sistemas nanotecnológicos dirigidos (targeted nanosystems), ya sea porque se utilizan agentes direccionalizadores (anticuerpos o secuencias peptídicas sobre la superficie de las nanopartículas) o porque se actúa directamente sobre moléculas esenciales en el mantenimiento de la población CSC (Pesarrodona et al. Biofabrication 2016). Los  sistemas terapéuticos consisten en polímeros biodegradables que anclan de forma covalente el fármaco o bien lo incorporan en estructuras micelares (Gener et al. Nanomedicine, 2015; Andrade et al. Nanomedicine, 2015, Rocas et al. J Mater Chem, 2015). La utilización de estos sistemas permite aumentar la eficacia y reducir la toxicidad de los tratamientos convencionales (Schwartz. Nanomedicine 2017). En paralelo, trabajamos también en la utilización combinada de tratamientos quimioterápicos con tratamientos alternativos como la hipertermia mediante nanopartículas magnéticas (proyecto Nocanther).

En el grupo de DDT los sistemas nanotecnológicos no solamente se utilizan para terapia sino también para diagnóstico por imagen, inicialmente con nanosistemas no direccionalizados que se acumulan en las zonas tumorales por el defecto propio de la vasculatura tumoral (Candiota et al. J Nanobiotechnology, 2014; Bomatí-Miguel et al. J Nanoparticle Res), pero también mediante sistemas direccionalizados.

Proyectos: Targets4Cancer, DiamESTar, NoCanTher and FIS

PI: Eva Baldrich Rubio

One of the greatest challenges in global healthcare is the lack of adequate diagnostic tools for early disease detection and adequate treatment monitoring. Accordingly, the development of low-cost, rapid, sensitive and robust bioassays and biosensors has become a priority for the healthcare sector and the research community. It is for this reason that the recent advances in rapidly evolving fields, such as Nanotechnology and Biosensor development, have raised great expectations and bitter controversies. DINA is brought to live in 2014 with a main goal: the exploitation of nanostructures, nanomaterials and nanocomponents as transducers, biofunctionalization platforms and signal amplifiers for fast assay and biosensor development. But always bearing in mind a final and clear objective: the production and/or improvement of realistic diagnostic tools that could be effectively used at a diagnostics laboratory.

i) Electrochemical Biosensors as diagnostic tools.

By definition, a biosensor is a bioanalytical device that incorporates a molecular recognition element (bioreceptor) associated to, or integrated with, a physicochemical transducer. According to this, a biosensor is formed by three components: a bioreceptor able to capture specifically the target of interest, a signal transducer able to convert target binding into a measurable electrical signal, and a signal processor that quantifies, analyzes and displays the results. In this way, analyte biocapture can be directly translated into a measurable signal. To date, numerous biosensors have been developed using a wide variety of biorecognition elements (ranging from “classical” bioreceptors such as antibodies, nucleic acid probes, antigens or enzymes, to novel alternatives like aptamers, biomimetic polymers or phage displayed peptides) and types of transducers (principally clustered into optical, electrochemical and micromechanical).

ii) Nanocomponents and Nanostructured Materials in Fast Assay and Biosensor Development.

Nanotechnology is a rapidly emerging field that is having an enormous impact on assay and biosensor development and, by extension, in their application to diagnostics. Nanomaterials can display almost unlimited combinations of composition, size, dimensions and shape, which can be tailored and coupled to bioreceptors in order to produce nanoprobes with desired properties. Since nanostructures are characterized by high surface to volume ratios, they have been extensively used as multi-label carriers for signal amplification. In opposition to detection using bioreceptors conjugated to a single label unit, multi-label nanoparticles have been claimed to provide higher and faster responses, contributing to improved bioassay/biosensor detection limits by up to three orders of magnitude. Alternatively, a variety of nanomaterials, such as fullerene derivatives, gold nanoparticles, rare earth nanoparticles and ferromagnetic nanoparticles, have been explored as artificial enzymes or enzyme mimics (nanozymes) thanks to their intrinsic non-enzymatic catalytic activity for a variety of molecular substrates. Used as labels in bioassay/biosensor development, nanozymes appear to be more stable and cheaper alternatives than natural enzymes. A particular example is nanoparticle-induced metal deposition. For instance gold nanoparticles can selectively reduce silver and gold salts to silver or gold, respectively, in the presence of a reducing agent. This results in significantly increased size which affects directly electrode transduction.