Researchers here propose a way to make existing senolytic small molecules more efficient by attaching them to a compound that binds to lipofusin, a form of molecular waste originating in lysosomes that is hard to break down. The resulting compound senolytic molecule is encapsulated in some form of delivery system for cell uptake, here a micelle, but other forms of nanoparticle would probably also do the job. Lipofuscin accumulation is a feature of senescent cells. It is also found in very long-lived non-dividing cells in old tissues, such as neurons, so some thought should probably be given to limiting their exposure to such a drug.
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.
Link: https://doi.org/10.1038/s43587-024-00747-4
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