Descrizione del progetto
Esaminare l’uso di nanoparticelle lipidiche per il trattamento del cancro al seno
Il progetto MaxFUSE LNPS, finanziato dal CER, studierà come le nanomedicine possano essere ingegnerizzate per migliorare il trattamento del cancro al seno avanzato. Il progetto esaminerà i meccanismi di fondo al modo in cui le nanoparticelle lipidiche trasportano i carichi di mRNA nelle cellule. L’uso delle nanoparticelle lipidiche nel trattamento del cancro presenta delle sfide, e le attuali formulazioni di nanoparticelle lipidiche devono affrontare problemi di tossicità, prestazioni e specificità. Uno dei passaggi chiave del processo di trasporto delle nanoparticelle lipidiche, la fuga endosomiale, è particolarmente inefficiente. I ricercatori studieranno ulteriormente la fuga endosomiale e mireranno a potenziarla tramite l’ingegneria su nanoscala. Gli obiettivi del progetto includono lo sviluppo di modelli di endosomi del cancro al seno, la progettazione di nanoparticelle lipidiche per una fusione endosomica potenziata e la convalida di nanoparticelle lipidiche ingegnerizzate per una maggiore fusione e una minore tossicità nei trattamenti del cancro al seno.
Obiettivo
There is a strong need for personalised genetic medicines for the treatment of advanced breast cancer. LNP-mRNA nanomedicines have already been proven as safe and cost effective in the SARS-CoV-2 vaccines. However, cancer treatments often require (i) repeat dosing (ii) controlled immune response (iii) adaptability to combat drug resistance. There are several LNP-RNA clinical cancer trials ongoing, many of which have reported challenges with toxicity, performance and specificity (off target effects). For an LNP-RNA cancer therapeutic to function, they need to localise in the correct organ, enter the cancer cells and escape the cellular (endosomal) processing pathway to release their RNA cargo. In current LNP-RNA formulations only a small fraction (<10 %) of LNPs successfully escape the endosome. However, these ‘null’ LNPs can still contribute to toxicity which places huge restrictions on their clinical application and performance. The aim of this proposal is to provide mechanistic insight into the endosomal escape of LNPs and use nanoscale engineering to target the endosome and improve LNP endosomal escape. This is particularly relevant in breast cancer as the majority of LNP systems are optimised for liver applications and designed to undergo fusion under ‘healthy’ endosomal conditions. In breast cancer, the composition (lipid, protein) and environment (pH) of the endosome differ significantly between healthy and cancer cells.
Objectives:
- Use omics approaches to quantify key differences in the endosome in healthy and breast cancer sub type cells and develop breast cancer sub type endosome models
- Design LNPs with enhanced fusion to endosomes using (i) lipid composition (ii) protein – protein / lipid interactions (iii) pH mediated fusion
- Validate novel LNPs with increased endosomal fusion and lower toxicity for breast cancer treatment
Campo scientifico
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistance
- medical and health sciencesmedical biotechnologynanomedicine
- medical and health sciencesclinical medicineoncologybreast cancer
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
100 44 Stockholm
Svezia