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Posts Taged cancer-cells

A discovery in one of the most aggressive cancers will allow more efficient diagnosis

The extracellular vesicles secreted by triple-negative breast cancer stem cells are markers of lung metastasis, according to a study carried out by researchers at CIBER.

The work has been carried out by researchers from various CIBER-BBN groups (Bioengineering, Biomaterials and Nanomedicia), and CIBERONC (CIBER area focused on cancer) has participated in it. The research has been led by Joaquín Seras, from the Vall d’Hebron Research Institute (VHIR), a specialist in targeted drug therapies.

Physicochemical EVs characterization and all the in vivo studies were performed by NANBIOSISunits of CIBER, specifically NTA analysis was carried out at Unit 6 of Biomaterial Processing and Nanostructuring, led by Nora Ventosa at ICMB-CSIC and animal experimentation at Unit 20 “In vivo experimental platform”, led by Ibane Abasolo at VHIR.

The vesicle, in cell biology, is an organelle that forms a small, closed compartment, separated from the cytoplasm by a lipid bilayer just like the cell membrane. The vesicles store, transport or digest cellular products and waste. According to Joaquin Seras, leader of the research: “the identification of this subpopulation of cancerous extracellular vesicles, and their important role in the progression of the disease, will allow in the future to develop systems more effective and less invasive diagnostic methods based on their detection directly from blood samples”.

In different types of tumors, including triple negative breast cancer, it has been observed that the extracellular vesicles generated by tumor cells play an important role in the generation of pre-metastatic niches. Triple negative breast cancer, one of the most aggressive, highly plastic and heterogeneous, is characterized by a significant presence of malignant stem cells.

The study carried out by the Spanish researchers from CIBER with promising results, published in the “International Journal of Cancer”, shows, both in in vitro and in vivo models of the disease, that the vesicles actively contribute to the formation of areas with favorable conditions for the formation of metastases, thus favoring way, the spread of the disease.

Research contributions
In the opinion of Joaquin Seras, the great contribution of this work is that it “describes how the extracellular vesicles secreted by certain subpopulations of cancer cells, specifically those derived from cancer stem cells, have the potential to modify the microenvironment of the future metastatic niche to promote tumor growth.

In other words, continues the leader of the study: “the research sheds new information on the pathogenic mechanism of the disease, and suggests these extracellular vesicles as markers with diagnostic potential. It should be noted that these nanoparticles are secreted into the bloodstream by tumor cells, and effective capture and identification would allow them to be exploited as a diagnostic tool”.

On the characterization of extracellular vesicles of cancer cells
The complex composition and functional differentiation of cancer cells in a tumor also increases the heterogeneity of the subsets of vesicles secreted by cancer.

This phenomenon is particularly relevant in triple negative breast cancer, one of the most aggressive, highly plastic and heterogeneous cancers, characterized by a significant presence of malignant stem cells. However, until now the diversity of the vesicles secreted by cancer cells had not been studied, a diversity that is closely related, in turn and as the study shows, to cellular heterogeneity in triple-negative tumors.

The importance of the CIBER study lies at this point: the vesicles secreted by different tumor subpopulations and grouped by their degree of differentiation show fundamentally different activities in terms of their impact on cancer progression.

In the investigation, the extracellular vesicles secreted by up to three different types of neoplastic cells have been isolated and characterized, observing different bioburdens for each type, with the consequent differential effect on stromal cells. In addition, and as the study shows, cancer stem cell-derived vesicles contribute to converting healthy lung cells into receptive niches for the metastatic growth of cancerous breast cells.

Article reference:

González-Callejo P, Gener P, Díaz-Riascos ZV, Conti S, Cámara-Sánchez P, Riera R, Mancilla S, García-Gabilondo M, Peg V, Arango D, Rosell A, Labernadie A, Trepat X, Albertazzi L, Schwartz S Jr, Seras-Franzoso J, Abasolo I. Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs. Int J Cancer. 2023 Jan 27. doi: 10.1002/ijc.34447. Epub ahead of print. PMID: 36705298.

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Ramón Martínez Máñez, Scientific Director of NANBIOSIS U26 obtains an ERC Advanced Grant

Ramón Martínez Máñez, researcher at the Polytechnic University of Valencia (UPV) and scientific director of the Bioengineering, Biomaterials and Nanomedicine area of ​​the CIBER (CIBER-BBN) and NANBIOSIS U26, has obtained an ERC Advanced Grant –the most prestigious grant from the European Research Council– endowed with 2.5 million euros for the development of the EDISON project (Engineered Particles for Chemical Communication).

This project focuses on the field of chemical or molecular communication. Its objective is the study, development and application of nanoparticles that are capable of communicating with each other and whose application would represent a revolution in the field of chemical research.

“Our goal is to advance the understanding of how abiotic micro/nanoparticles can communicate with the others and with living systems. In this context, one way to establish communication at the nanometric level is to mimic how nature communicates, that is, through the use of chemical messengers. If we are able to lay the foundations for communication between micro/nanoparticles and between them and cells, the future potential applications in the biomedical field, and in other fields such as the environment and industrial technology, are almost limitless”, highlights Ramón Martínez Máñez, who is currently deputy director of the Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM) of the Universitat Politècnica València and the Universitat de València.

Unveiling the keys to the prevention and treatment of cancer
In the medical field, for example, these nanoparticles could help reveal the keys to the prevention and treatment of cancer, since they could act as nanotranslators that help connect cancer cells with cells of the immune system, regulating the interactions between them and , in general, to connect cells to each other that would not otherwise communicate. They could also be key in the development of new strategies to eliminate biofilms and resistant microorganisms, being able to detect the presence of chemical species used by bacteria to create the biofilm and inhibiting these signals.

The research proposed by EDISON will be carried out in the IDM, the CIBER-BBN and in the Mixed Units in which Ramón Martínez Máñez participates with the Príncipe Felipe Research Center and with the La Fe Hospital in Valencia.

5 years of work
The project, which began on October 1, will run for 5 years until September 30, 2027. In a first phase, the team from the IDM Institute of the Universitat Politècnica de València will create the basic components to study chemical communication; in the second, EDISON will focus on the development of systems capable of establishing communication between nanoparticles and living systems. Finally, the UPV researchers will work on the development of nanosystems that integrate stimulus-sensitive nanoparticles and electronics to create new hybrid communication structures.

“Every year hundreds of nano/microparticles are described but in practically all cases they are used as independent entities with no connection between them. The connection/communication between particles is the basis for developing more complex cooperative systems with new functionalities”, says Professor Martínez-Máñez, who will dedicate most of his time to the development of the EDISON project with the aim of laying the foundations for this new idea.

Obtaining this prestigious aid will allow the research group to focus on promoting a new form of communication at the nanoscale based on the use of chemical messengers that will facilitate the development of new applications at the nanometric scale beyond what is possible using information and communication technologies on the macroscale that we know today.

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A potential solution to decrease toxicity in colorectal cancer treatment

Cancer is one of the world’s leading causes of death, with over 18.1 million cases and 9.6 million deaths in 2018. One of the most successful drugs used in chemotherapy for the treatment of diverse severe cancers is 5-Fluorouracil (5-FU), however, one of the major problems described in clinical practice is 5-FU cell resistance.

Resarchers of the Nucleic Acids group and the Colloidal and interfacial Chemistry Group of CIBER-BBN at IQAC-CSIC have collaborated in a research to  inspect and test the ability of parallel G-quadruplexes to deliver floxuridine oligonucleotides into different types of cancer cells; finally, the internalization ability and the antiproliferative action of these oligoFdU-G-quadruplexes have been evaluated in FU-resistant cell lines.

Recently an article has been published with the research results by the Jorunal of Molecules entitled Parallel G-quadruplex structures increase cellular uptake and cytotoxicity of 5-Fluoro-2′-deoxyuridine Oligomers in 5-Fluorouracil resistant cells”

The article describes a potential solution to decrease the toxicity of floxuridine, a known nucleoside antimetabolite used in the treatment of colorectal cancer, explains Ramón Eritja, Scientific Director of NANBIOSIS U29 from CIBER-BBN and IQAC-CSIC.

The authors used the NANBIOSIS Unit 29 Oligonucleotide Synthesis Platform (OSP) to prepare short oligonucleotides that form a tetrameric structure that is recognized by cancer cells facilitating the specific delivery to the tumor cells. Once inside of the cells, the oligonucleotides generate the active drug by nuclease degradation as a Trojan horse.

Article of reference:

Clua A, Fàbrega C, García-Chica J, Grijalvo S, Eritja R. Parallel G-quadruplex Structures Increase Cellular Uptake and Cytotoxicity of 5-Fluoro-2′-deoxyuridine Oligomers in 5-Fluorouracil Resistant CellsMolecules. 2021; 26(6):1741. [DOI] 

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Selective CXCR4+ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin

Researchers of NANBIOSIS Unit 1 and NANBIOSIS Unit 18, led by Prof Antoni Villaverde have published the article “Selective CXCR4+ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin” at SMALL journal.

Under the unmet need of efficient tumor‐targeting drugs for oncology, a recombinant version of the plant toxin ricin (the modular protein T22‐mRTA‐H6) is engineered to self‐assemble as protein‐only, CXCR4‐targeted nanoparticles. The soluble version of the construct self‐organizes as regular 11 nm planar entities that are highly cytotoxic in cultured CXCR4+ cancer cells upon short time exposure, with a determined IC50 in the nanomolar order of magnitude. The chemical inhibition of CXCR4 binding sites in exposed cells results in a dramatic reduction of the cytotoxic potency, proving the receptor‐dependent mechanism of cytotoxicity. The insoluble version of T22‐mRTA‐H6 is, contrarily, moderately active, indicating that free, nanostructured protein is the optimal drug form. In animal models of acute myeloid leukemia, T22‐mRTA‐H6 nanoparticles show an impressive and highly selective therapeutic effect, dramatically reducing the leukemia cells affectation of clinically relevant organs. Functionalized T22‐mRTA‐H6 nanoparticles are then promising prototypes of chemically homogeneous, highly potent antitumor nanostructured toxins for precise oncotherapies based on self‐mediated intracellular drug delivery.

See article: https://doi.org/10.1002/smll.201800665

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NANOLIGENT, the first drug designed to eliminate metastases stem cells

NANBIOSIS researchers have developed a nanomedicine for the treatment of metastases by the selective elimination of tumor stem cells. It is a system based on nanoparticles that transport a chemotherapeutic drug and release it into cancer cells.

The research team, led by Esther Vázquez and Antonio Villaverde, Strategy Director of NANBIOSIS U1. Protein Production Platform (PPP), in the IBB-UAB, and Ramon Mangues, Scientific Director of NANBIOSIS U18. Nanotoxicology Unit, in the Sant Pau Hospital, have already created a prototype of the drug and have conducted in vivo trials in animal models of colorectal cancer. They have demonstrated their effectiveness, selective biodistribution and low toxicity.

To promote the development of the drug towards the clinic, the reserachers have created Nanoligent a start-up company, based in Barcelona, led by Manuel Rodríguez, a professional with experience in the field of investment and the creation and growth of biotech companies. The technology is patented in Europe and USA and has been licenced to Nanoligent

The therapy created by the researchers is aimed at blocking the development of metastasis, mainly of colorectal cancer, through new strategies aimed at certain cell types. It consists of a new drug administration system based on protein nanoparticles that selectively conduct the therapeutic agent in tumor cells. The drug acts only on cancer cells, because it is based on the specific interaction between a protein present in the nanoparticle and a cellular receptor (CXCR4), which is overexpressed in tumor cells. “This interaction is crucial, because it allows attacking only tumor cells and not healthy cells, thus avoiding secondary effects derived from classical chemotherapy,” emphasizes Antonio Villaverde.

The CXCR4 receptor is overexpressed in many types of tumors, so that “this technology can be directed to the treatment of different types of neoplasms in addition to colorectal cancer and derived metastases, such as lymphoma, leukemia or endometrial cancer, in animal models already available to the group of Sant Pau “, comments Ramon Mangues. In addition, nanoparticles are compatible with a huge variety of possible drugs and therefore they become highly versatile vehicles that can carry a wide range of therapeutic molecules.

“There is an urgent need for more effective and personalized treatments for cancer. The toxicity and the lack of efficacy of conventional drugs are pushing alternative experimental strategies directed and designed to achieve only defined cell types. Nanoparticles, thanks to their capacity for penetration, dissemination and functionality, offer a promising nanomedical landscape to create new drugs,” explains Esther Vázquez.

In this direction, the technology of Nanoligent opens a new door in anti-pelagic therapy, as it allows to design a treatment with greater cellular specificity than that of existing treatments, while offering greater biosecurity and biodegradability and lower toxicity,” he said. Antonio Villaverde points out.

Currently, there are no drugs in the market that selectively eliminate metastatic stem cells. Although Nanoligent technology is still under development, researchers say they have a lot of potential and consider that it could have a high clinical impact as regulatory trials are overcome.

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