Activatable senoprobes and senolytics: Novel strategies to detect and target senescent cells. (March 2022) - Morsli, Samir
Highlights: Cellular senescence is associated with ageing and multiple age-related disorders where it contributes to the pathological manifestations. Senotherapies have recently shown great promise in multiple pre-clinical disease models, and are being tested in clinical trials. Despite promising proof-of-principle evidence, there are toxicities associated with these compounds, thereby limiting their translatability and clinical applications. Galacto-conjugation of a variety of modular systems and compounds is a versatile therapeutic and detection strategy to facilitate preferential targeting of senescent cells . Senotherapies and detection tools are expected to impact precision medicine in human settings over the next few years. Abstract: Pharmacologically active compounds that manipulate cellular senescence ( senotherapies ) have recently shown great promise in multiple pre-clinical disease models, and some of them are now being tested in clinical trials. Despite promising proof-of-principle evidence, there are known on- and off-target toxicities associated with these compounds, and therefore more refined and novel strategies to improve their efficacy and specificity for senescent cells are being developed. Preferential release of drugs and macromolecular formulations within senescent cells has been predominantly achieved by exploiting one of the most widely used biomarkers of senescence, the increase in lysosomal senescence-associated β-galactosidase (SA-β-gal) activity, a common feature of most reported senescent cell types. Galacto-conjugation is a versatile therapeutic and detection strategy to facilitate preferential targeting of senescent cells by using a variety of existing formulations, including modular systems, nanocarriers, activatable prodrugs, probes, and small molecules. We discuss the benefits and drawbacks of these specific senescence targeting tools and how the strategy of galacto-conjugation might be utilised to design more specific and sophisticated next-generation senotherapeutics, as well as theranostic agents. Finally, we discuss some innovative strategies and possible future directions for the field.