Generation of a selective senolytic platform using a micelle-encapsulated Sudan Black B conjugated analog
The emerging field of senolytics is centered on eliminating senescent cells to block their contribution to the progression of age-related diseases, including cancer, and to facilitate healthy aging. Enhancing the selectivity of senolytic treatments toward senescent cells stands to reduce the adverse effects associated with existing senolytic interventions. Taking advantage of lipofuscin accumulation in senescent cells, we describe here the development of a highly efficient senolytic platform consisting of a lipofuscin-binding domain scaffold, which can be conjugated with a senolytic drug via an ester bond. As a proof of concept, we present the generation of GL392, a senolytic compound that carries a dasatinib senolytic moiety. Encapsulation of the GL392 compound in a micelle nanocarrier (termed mGL392) allows for both in vitro and in vivo (in mice) selective elimination of senescent cells via targeted release of the senolytic agent with minimal systemic toxicity. Our findings suggest that this platform could be used to enhance targeting of senotherapeutics toward senescent cells.
Authors
- Fotios Sampaziotis (ORCID: https://orcid.org/0000-0003-0812-7586)
- Dimitris-Foivos Thanos
- Vassilis G. Gorgoulis (ORCID: https://orcid.org/0000-0001-9001-4112)
- Dimitris Thanos (ORCID: https://orcid.org/0000-0003-4288-3027)
- Nefeli Lаgopati (ORCID: https://orcid.org/0000-0001-9317-9510)
- Konstantinos Evangelou (ORCID: https://orcid.org/0000-0002-2462-5748)
- Μαρία Γεωργίου (ORCID: https://orcid.org/0000-0001-7879-7003)
- Panagiotis Marakos
- Russell Petty (ORCID: https://orcid.org/0000-0003-2055-4572)
- Constantin Tamvakopoulos (ORCID: https://orcid.org/0000-0001-9627-4812)
- Athanassios Kotsinas (ORCID: https://orcid.org/0000-0003-2397-4118)
- Nikos Boukos (ORCID: https://orcid.org/0000-0001-7542-0649)
- Stergios Pispas (ORCID: https://orcid.org/0000-0002-5347-7430)
- Dimitris Veroutis
- Konstantinos Kambas (ORCID: https://orcid.org/0000-0002-9264-8458)
- Nicole Pouli (ORCID: https://orcid.org/0000-0003-3272-759X)
- Nikolaos Lougiakis (ORCID: https://orcid.org/0000-0003-0582-4415)
- Sophia Havaki (ORCID: https://orcid.org/0000-0003-0660-2179)
- Sophia Magkouta
- Νatassa Pippa (ORCID: https://orcid.org/0000-0002-1197-9010)
- Nicholas Kotopoulos
- Angelos Papaspyropoulos (ORCID: https://orcid.org/0000-0003-0475-3985)
- Anastasia Palaiologou
Institutions
- Intel (United States) (US)
- University of Dundee (GB)
- National and Kapodistrian University of Athens (GR)
- National Centre of Scientific Research "Demokritos" (GR)
- Academy of Athens (GR)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Manchester Academic Health Science Centre (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Ninewells Hospital (GB)
- University of Manchester (GB)
- Biomedical Research Foundation of the Academy of Athens (GR)
- Pasteur Hellenic Institute (GR)
- National Hellenic Research Foundation (GR)
- Cancer Research UK Manchester Institute (GB)
- RGenix (United States) (US)
- Evangelismos Hospital (GR)
Publication Details
- Journal
- Nature Aging
- Published
- 2024-12-27
- DOI
- https://doi.org/10.1038/s43587-024-00747-4
- Citations
- 32
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 10.45
Funders
- General Secretariat for Research and Technology
- Foundation for Education and European Culture
- Hellenic Foundation for Research and Innovation