Biorthogonal Catalytic Scaffold for in situ Personalized Cancer Chemo-Immunotherapy

Informazioni relative al progetto

BiorthoCat-Immuno

ID dell’accordo di sovvenzione: 101106805

DOI

10.3030/101106805

Progetto chiuso

Data della firma CE 23 Marzo 2023

Data di avvio 1 Luglio 2024

Data di completamento 30 Giugno 2026

Finanziato da

• Marie Skłodowska-Curie Actions (MSCA)

Costo totale

Nessun dato

Contributo UE

€ 206 887,68

Coordinato da

KAROLINSKA INSTITUTET
Sweden

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

Periodo di rendicontazione: 2024-07-01 al 2026-06-30

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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.