A versatile drug delivery system targeting senescent cells
Daniel Muñoz-Espín 1, 2,* , Miguel Rovira 2, 5 , Irene Galiana 3 , Cristina Giménez 3 , Beatriz Lozano-
Torres 3, , Marta Paez-Ribes 1 , Susana Llanos 2 , Selim Chaib 2, 5 , Maribel Muñoz 2, 5 , Alvaro C. Ucero 2 ,
Guillermo Garaulet 2 , Francisca Mulero 2 , Stephen Dann 4 , Todd VanArsdale 4 , David J. Shields 4 ,
Andrea Bernardos 3 , José Ramón Murguía 3 , Ramón Martínez-Máñez 3 , Manuel Serrano 2, 5*
1 CRUK Cambridge Centre Early Detection Programme, Department of Oncology, University of
Cambridge, Cambridge, UK
2 Spanish National Cancer Research Centre (CNIO), Madrid, Spain
3 Inter University Research Institute for Molecular Recognition and Technological Development (IDM),
Polytechnic University of Valencia (UPV), Valencia, Spain
4 Oncology R&D Group, Pfizer Worldwide Research & Development, Pfizer Inc.
5 Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona),
Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Senescent cells accumulate in multiple ageing-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 targeted 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 and aged tissues.
Conflict of interest
S.D., T.V., and D.J.S. are employees of Pfizer Inc. and hold shares in the company. J.R.M., R.M.-M.,
and M.S. are founders of Senolytic Therapeutics, S.L. (Spain) and Senolytic Therapeutics, Inc.
(USA) aimed at developing senolytic therapies.