A versatile drug delivery system targeting senescent cells

Abstract

Senescent cells accumulate in multiple aging‐associated diseases, and eliminating these cells has recently emerged as a promising therapeutic approach. Here, we take advantage of the high lysosomal β‐galactosidase activity of senescent cells to design a drug delivery system based on the encapsulation of drugs with galacto‐oligosaccharides. We show that gal‐encapsulated fluorophores are preferentially released within senescent cells in mice. In a model of chemotherapy‐induced senescence, gal‐encapsulated cytotoxic drugs target senescent tumor cells and improve tumor xenograft regression in combination with palbociclib. Moreover, in a model of pulmonary fibrosis in mice, gal‐encapsulated cytotoxics target senescent cells, reducing collagen deposition and restoring pulmonary function. Finally, gal‐encapsulation reduces the toxic side effects of the cytotoxic drugs. Drug delivery into senescent cells opens new diagnostic and therapeutic applications for senescence‐associated disorders.

Targeting senescent cells in translational medicine

“…In addition to cell labels, nanoparticles can encapsulate small molecules capable of killing senescent cells, potentially widening the therapeutic window of these agents ( and Fig ). Gal‐encapsulated doxorubicin, GalNP(dox), induced apoptosis in palbociclib‐induced senescent cells, but not in control (proliferative) cells, thus validating its therapeutic senescence‐targeting potential (Muñoz‐Espín et al , ). Of note, GalNP(dox) treatment restored lung function in mice with bleomycin‐induced pulmonary fibrosis and reduced the lung fibrotic scar.…”

“…One of the first methodologies to image and monitor senescence noninvasively in vivo was based on a sequential reporterenzyme bioluminescence technology to track b-gal activity by using Lugal, a caged galactoside-luciferin conjugate (Wehrman et al, 2006). Recent studies validated the use of nanoparticles and fluorescent probes to target senescent cells in mouse models (Lozano-Torres et al, 2017;Muñoz-Espín et al, 2018;Wang et al, 2019). Nanoparticles open up the possibility of encapsulating tracers and contrast agents for the imaging of senescence location and burden, and to be used as imaging biomarkers to direct promising therapies to populations most likely to benefit from them.…”

“…In addition, senescent fibroblasts accumulate in granulation tissues of healing cutaneous wounds and express antifibrotic genes (Jun & Lau, ). Senescence, however, intriguingly mediates fibrotic pulmonary disease, and removal of senescent cells using senolytics, therapeutic nanoparticles and anti‐inflammatory compounds reverts fibrosis and improves lung function in mice (Hecker et al , ; Lehmann et al , ; Schafer et al , ; Muñoz‐Espín et al , ). The antagonistic roles of cell senescence in a number of mouse models of human fibrotic diseases highlight the importance of a more detailed understanding of the triggers, intrinsic mechanisms and pathways driving the stable cell cycle arrest and distinct factors secreted by senescent cells before widespread clinical trials, particularly in otherwise healthy populations.…”

Galactose-modified duocarmycin prodrugs as senolytics

“…Previously, the potential to harness the elevated b-galactosidase activity of senescent cells have been exploited with galacto-oligosaccharide encapsulated nanoparticles (GalNP) (Agostini et al 2012). Combination of GalNP with different cargoes offers flexibility to image or eliminate senescent cells (Munoz-Espin et al 2018). However, this flexibility comes to the expense of having to use a modular system, comprised of both the GalNP and the cargo.…”

“…Indeed, it has been shown that galacto-oligosacharide encapsulated nanoparticles (GalNP) preferentially release their content on senescent cells (Agostini et al 2012). Consequently, this GalNP can be used in combination with different cargos to either image or kill senescent cells (Munoz-Espin et al 2018).…”