Biorthogonal Catalytic Scaffold for in situ Personalized Cancer Chemo-Immunotherapy

Informations projet

BiorthoCat-Immuno

N° de convention de subvention: 101106805

DOI

10.3030/101106805

Projet clôturé

Date de signature de la CE 23 Mars 2023

Date de début 1 Juillet 2024

Date de fin 30 Juin 2026

Financé au titre de

• Marie Skłodowska-Curie Actions (MSCA)

Coût total

Aucune donnée

Contribution de l’UE

€ 206 887,68

Coordonné par

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 1 - BiorthoCat-Immuno (Biorthogonal Catalytic Scaffold for in situ Personalized Cancer Chemo-Immunotherapy)

Période du rapport: 2024-07-01 au 2026-06-30

Résumé du contexte et des objectifs généraux du projet

Bioorthogonal metal-catalyzed reactions enable selective activation of prodrugs with unprecedented spatiotemporal control. These new reactions provided particular benefit to the use of cancer drugs that suffer from a narrow therapeutic index. Nevertheless, efficiently performing bioorthogonal metal catalysis in living organisms remains challenging since the complex biological environment rapidly deactivates catalysts. This project focused on the development of a biomaterials platform to efficiently convert through heterogeneous bioorthogonal catalysis to deliver a combination of chemoimmunotherapeutic drugs, with the goal of safely delivering a personalized cancer vaccine.
The scientific work performed in this project focused on (i) identification of a Pd catalyst (i.e. nanozyme) able to efficiently perform depropargylation reactions in biologically relevant conditions; (ii) integrating the nanozyme into a support structure that provided tissue integration near tumor sites; (iii) demonstrating the functionality of this system in vitro.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

After an initial screen of a series of different nanocatalysts based on Pd and Au using a depropargylation reaction of a caged Rhodamine compound, the best performing Pd nanozyme was selected. While this catalyst performed efficiently in simplified buffer (PBS), its activity quickly dropped to zero when exposed to biologically relevant conditions. This therefore justified the encapsulation of these nanozymes in protective nanoreactors. Pd nanozymes were loaded in a small library of polymeric and lipidic nanoreactors. All vesicular nanoreactors protected the Pd nanozymes in biological environment to different extent.
The surface of the nanoreactors was modified first introducing free amines, used to then conjugate a collagen binding peptide. This strategy retained particles features, including size and catalytic activity, and demonstrated good adhesion to collagen, key component of the extracellular matrix.
These nanoreactors activateted in vitro a prodrug of a chemotherapeutic, leading to tumor cell killing both intracellularly and extracellularly. Finally, the same nanoreactors activateted a prodrug of an immunotherapeutic, leading to activation of multiple immune cells.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The project main scientific achievement was the development of a bioorthogonal nanoreactor with unprecedented stability in biological conditions. While a series of nanoreactors have been reported in the literature, this output stands compared to the state of the art as it targets the overseen challenge of catalysts stability under physiological environments. While demonstrated for a cancer application, this system could be adapted to a series of different therapeutic scenarios that could benefit from a localized treatment and rely on drugs with narrow therapeutic indices. On a societal and economical level, the localized therapy here developed hold great potential to address the unmet clinical need for safer delivery of compounds with serious off-target side effects.