Generation of a selective senolytic platform using a micelle-encapsulated Sudan Black B conjugated analog

Nat Aging. 2025 Jan;5(1):162-175. doi: 10.1038/s43587-024-00747-4.

Sophia Magkouta ^# ¹ ² ³, Dimitris Veroutis ^# ¹ ³, Angelos Papaspyropoulos ^# ¹, Maria Georgiou ^# ⁴, Nikolaos Lougiakis ⁴, Natassa Pippa ⁵, Sophia Havaki ¹, Anastasia Palaiologou ⁶, Dimitris-Foivos Thanos ¹, Konstantinos Kambas ⁷, Nefeli Lagopati ¹ ⁸ ⁹, Nikos Boukos ¹⁰, Nicole Pouli ⁴, Panagiotis Marakos ⁴, Athanassios Kotsinas ¹, Dimitris Thanos ⁹, Konstantinos Evangelou ¹, Fotios Sampaziotis ¹¹ ¹² ¹³, Constantin Tamvakopoulos ⁶, Stergios Pispas ¹⁴, Russell Petty ³, Nicholas Kotopoulos ¹, Vassilis G Gorgoulis ¹⁵ ¹⁶ ¹⁷ ¹⁸ ¹⁹

Affiliations

1 Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
2 Marianthi Simou and G.P. Livanos Labs, 1st Department of Critical Care and Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens,'Evangelismos' Hospital, Athens, Greece.
3 Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
4 Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece.
5 Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupolis Zografou, Athens, Greece.
6 Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
7 Hellenic Pasteur Institute, Athens, Greece.
8 Laboratory of Biology, Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
9 Biomedical Research Foundation, Academy of Athens, Athens, Greece.
10 Institute of Nanoscience and Nanotechnology, National Center for Scientific Research 'Demokritos', Agia Paraskevi, Greece.
11 Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK.
12 Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
13 Department of Medicine, University of Cambridge, Cambridge, UK.
14 Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, Athens, Greece.
15 Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece. vgorg@med.uoa.gr.
16 Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. vgorg@med.uoa.gr.
17 Biomedical Research Foundation, Academy of Athens, Athens, Greece. vgorg@med.uoa.gr.
18 Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK. vgorg@med.uoa.gr.
19 Intelligencia, Inc., New York, NY, USA. vgorg@med.uoa.gr.
# Contributed equally.

PMID: 39730824 DOI: 10.1038/s43587-024-00747-4

Abstract

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-170851

GL392

Senolytic Agent

Apoptosis

Cancer

Name
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