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A nanotoxin targeting the receptor CXCR4 blocks lymphoma dissemination

Researchers at the Nanotoxicology Unit of CIBER-BBN ICTS NANBIOSIS (u18-nanotoxicology-unit), led by Ramon Mangues and Isolda Casanova of the Research Institute at the Hospital de Sant Pau and the Researchers of the NANBIOSIS (nanbiosis.es) Protein Production Platform (u1-protein-production-platform-ppp) led by Antonio Villaverde and Neus Ferrer Miralles of the Institute of Biotechnology and Biomedicine at the Autonomous University of Barcelona, have participated in the development of a novel protein nanoparticle that incorporates the Exotoxin of the bacteria Pseudomonas aeruginosa, capable of targeting lymphoma cells that overexpress the CXCR4 receptor.

They internalize selectively in target cancer cells through CXCR4 receptor-mediated endocytosis due to the incorporation in its nanostructure of the T22 peptide ligand, with multivalent display (10 peptides per nanoparticle). In addition, it contains an endosomal escape domain to avoid lysosomal degradation to achieve the delivery of undegraded exotoxin in the target cancer cell cytosol. There, the exotoxin blocks protein translation by inhibiting the elongation factor 2, leading to the induction of apoptosis in a diffuse large B-cell lymphoma model blocking their dissemination throughout the body, in the bone narrow, lymph nodes and the liver. Since lymphoma cells overexpressing the CXCR4 receptor are associated with increased dissemination and resistance to Rituximab plus CHOP chemotherapy, this novel nanomedicine could be useful for its clinical translation, especially for the treatment of lymphoma patients that relapse after classical chemotherapy.

The bioluminescent follow-up of cancer cells and toxicity studies has been performed in the ICTS NANBIOSIS using its CIBER-BBN Nanotoxicology Unit Protein production has been also performed at the ICTS NANBIOSIS  Init 1 PPP

Reference:

Falgàs A, Pallarès V, Serna N, Sánchez-García L, Sierra J, Gallardo A, Alba-Castellón L, Álamo P, Unzueta U, Villaverde A, Vázquez E, Mangues R, Casanova I. Selective delivery of T22-PE24-H6 to CXCR4+ diffuse large B-cell lymphoma cells leads to wide therapeutic index in a disseminated mouse model. doi: 10.7150/thno.43231. eCollection 2020.

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NANBIOSIS Scientists discover a promising effective alternative to reduse relapse rates in Diffuse Large B-cell Lymphoma Cells

Researchers of NANBIOSIS-ICTS Units from CIBER-BBN: U1 Protein Production Platform (PPP) at IBB-UAB, led by Antoni Villaverde and Unit 18 Nanotoxicology Unit at IBB-Hospital Sant Pau, led by Ramón Mangues, have demonstrated a potent T22-PE24-H6 antineoplastic effect, especially in blocking dissemination in a CXCR4+ DLBCL model without associated toxicity. Thereby, T22-PE24-H6 promises to become an effective alternative to treat CXCR4+ disseminated refractory or relapsed DLBCL patients.

Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK.

One of the major problems in the therapeutic strategies is the relapse rates. CXCR4-overexpressing cancer cells are good targets for therapy because of their association with dissemination and relapse in R-CHOP treated DLBCL patients but show a narrow therapeutic index due to their systemic toxicity wich generate the induction of severe side effects. NANBIOSIS researchers have developed a therapeutic nanostructured protein T22-PE24-H6 that incorporates exotoxin A from Pseudomonas aeruginosa, which selectively targets lymphoma cells because of its specific interaction with a highly overexpressed CXCR4 receptor (CXCR4+) in DLBCL, demonstrating a potent T22-PE24-H6 antineoplastic effect, without associated toxicity. Thereby, T22-PE24-H6 promises to become an effective alternative to treat CXCR4+ disseminated refractory or relapsed DLBCL patients

The bioluminescent follow-up of cancer cells and toxicity studies has been performed in the ICTS Nanbiosis Platform, using its CIBER-BBN Nanotoxicology Unit and Protein production has been performed by the ICTS “NANBIOSIS”, more specifically by the Protein Production Platform of CIBER-BBN/ IBB

Article of reference:

Falgàs A, Pallarès V, Serna N, Sánchez-García L, Sierra J, Gallardo A, Alba-Castellón L, Álamo P, Unzueta U, Villaverde A, Vázquez E, Mangues R, Casanova I. Selective delivery of T22-PE24-H6 to CXCR4+ diffuse large B-cell lymphoma cells leads to wide therapeutic index in a disseminated mouse modelTheranostics 2020; 10(12):5169-5180. doi:10.7150/thno.43231. Available from http://www.thno.org/v10p5169.htm

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