National Projects:

Agencia Estatal de Investigación: 

Instituto de Salud Carlos III:

AMATOX: Selective depletion of CXCR4+ colorectal cancer stem cells by targeted inhibition of RNA polymerase II (PI23/00318). 2024-2026 

In this project, we propose the targeted delivery of a very potent and innovative antitumoral payload (α-amanitin) by a highly efficient and multivalent protein nanocarrier (T22-GFP-H6) that selectively targets CXCR4+ Colorectal cancer stem cells, responsible of tumor aggressiveness and metastasis. This potent antitumoral drug, that cannot be administered as a standalone therapy, shows very promising properties because of its singular and cell-cycle independent mechanism of action (RNA polymerase II inhibition) and its capacity to overcome the main multi-drug resistance (MDR) limitations. Moreover, hemizygous co-deletion of TP53/POLR2A genes, usually found in human cancers, makes colorectal cancer cells specially vulnerable to this particular antitumoral agent. Thus, T22-GFP-H6-amanitin nanoconjugates are expected to: 1) selectively eliminate CXCR4+ CRC Stem cells, 2) show high effectivity over non-dividing dormant tumor cells, responsible of tumor recurrences, 3) overcome the main MDR mechanisms and 4) show an enhanced therapeutic window because of the excellent targeting capacity of our multivalent protein nanocarriers that benefits from receptor superselectivity (>85% uptake in target cells). Althogether, this proposal will generate a new therapeutic weapon against CRC that not only will impact on the future clinical practice by increasing the effectivity of the treatment, but will also improve their quality of life by reducing its systemic toxicity. Principal Investigator: Ugutz Unzueta. Budget: 230.000 €

NANOLINK: Site-directed conjugation of smart protein nanomedicines for improved therapy of metastatic colorectal cancer (PI20/00400). 2021-2025

In this project, we propose to evaluate the improved antitumor and antimetastatic effect of fully optimized new generation of multivalent nanoconjugates targeting metastatic colorectal cancer stem cells (CXCR4+) that have been rationally engineered using site directed conjugation strategies. These innovative conjugation methods will significantly improve the therapeutic efficiency of our new nanoconjugates compared to previous ones developed using unspecific conjugation methods by 1) enhancing their antitumor and antimestastatic activity in-vivo and 2) significantly improving the control, characterization and homogeneity of the final nanoconjugate reaching the rigorous requirements imposed by the regulatory agencies to reach the clinic. Principal Investigator: Ugutz Unzueta. Budget: 171.820 €. Principal Investigator: Ugutz Unzueta. Budget: 171.820 €

NANOSCAPE: Improved colorectal cancer therapy by targeting the CXCR4 receptor using functional protein nanoparticles with enhanced cytosolic release (CP19/00028). 2020-2023

Although the intracellular delivery of therapeutic proteins has raised a huge interest in the treatment of many diseases, including cancer, the entrapment of protein therapeutics in endo-lysosomal compartments leading to proteolysis has been reported to be a major reason for impairment or even loss of their efficacy. Although fusogenic peptide domains have been described to efficiently induce cytosolic release of their protein cargo, many of them have also cell penetrating activities, which impairs receptor specific cell penetrability in targeted protein therapeutics. To avoid this problem, this project proposes to explore the incorporation of an effective endosomal escape domain within our intrinsically active CXCR4-targeted protein nanoparticles that by using different membrane disruption mechanisms will induce their efficient cytosolic release from endosomes, significantly enhancing their bioavailability and therefore their therapeutic effect, but without interfering with their receptor specificity. Principal Investigator: Ugutz Unzueta. Budget: 40.000 €