# Chemical Strategies for the Detection and Elimination of Senescent Cells

## TL;DR

This paper explores new chemical methods to detect and eliminate senescent cells, which are linked to aging and diseases like cancer.

## Contribution

The paper introduces novel chemical strategies using probes, nanoparticles, and prodrugs to detect and target senescent cells with higher specificity.

## Key findings

- New one- and two-photon probes were developed for deeper tissue penetration to detect senescent cells.
- Renal clearable fluorogenic probes were created for in vivo detection of β-galactosidase activity.
- Gated nanoparticles loaded with cytotoxic agents were tested to selectively eliminate senescent cells.

## Abstract

Cellular senescence can be defined
as an irreversible stopping
of cell proliferation that arises in response to various stress signals.
Cellular senescence is involved in diverse physiological and pathological
processes in different tissues, exerting effects on processes as differentiated
as embryogenesis, tissue repair and remodeling, cancer, aging, and
tissue fibrosis. In addition, the development of some pathologies,
aging, cancer, and other age-related diseases has been related to
senescent cell accumulation. Due to the complexity of the senescence
phenotype, targeting senescent cells is not trivial, is challenging,
and is especially relevant for in vivo detection
in age-related diseases and tissue samples. Despite the elimination
of senescent cells (senolysis) using specific drugs (senolytics) that
have been shown to be effective in numerous preclinical disease models,
the clinical translation is still limited due to the off-target effects
of current senolytics and associated toxicities. Therefore, the development
of new chemical strategies aimed at detecting and eliminating senescent
cells for the prevention and selective treatment of senescence-associated
diseases is of great interest. Such strategies not only will contribute
to a deeper understanding of this rapidly evolving field but also
will delineate and inspire new possibilities for future research.

In this Account, we report our recent research in the development
of new chemical approaches for the detection and elimination of senescent
cells based on new probes, nanoparticles, and prodrugs. The designed
systems take advantage of the over-representation in senescent cells
of certain biomarkers such as β-galactosidase and lipofuscin.
One- and two-photon probes, for higher tissue penetration, have been
developed. Moreover, we also present a renal clearable fluorogenic
probe for the in vivo detection of the β-galactosidase
activity, allowing for correlation with the senescent burden in living
animals. Moreover, as an alternative to molecular-based probes, we
also developed nanoparticles for senescence detection. Besides, we
describe advances in new therapeutic agents to selectively eradicate
senescent cells using β-galactosidase activity-sensitive gated
nanoparticles loaded with cytotoxic or senolytic agents or new prodrugs
aiming to increase the selectivity and reduction of off-target toxicities
of current drugs. Moreover, new advances therapies have been applied in vitro and in vivo. Studies with the
probes, nanoparticles, and prodrugs have been applied in several in vitro and in vivo models of cancer,
fibrosis, aging, and drug-induced cardiotoxicity in which senescence
plays an important role. We discuss the benefits of these chemical
strategies toward the development of more specific and sophisticated
probes, nanoparticles, and prodrugs targeting senescent cells.