Abstract:
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[EN] 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 beta-galactosidase ...[+]
[EN] 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 beta-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.
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Thanks:
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We are grateful to D. Megias, L. Martinez, O. Dominguez, F. Al-Shahrour, C. Fustero, O. Graria, G. Garnez-Lapez, A. De Martino, P. Gonzalez, M. Udriste for technical support. Work in the laboratory of R.M.-M was funded by ...[+]
We are grateful to D. Megias, L. Martinez, O. Dominguez, F. Al-Shahrour, C. Fustero, O. Graria, G. Garnez-Lapez, A. De Martino, P. Gonzalez, M. Udriste for technical support. Work in the laboratory of R.M.-M was funded by Projects MAT2015-64139-C4-1-R, PROMETE011/2014/047, and by Institute de Salud Carlos III through the project "DTS16/00205" (Co-funded by European Regional Development Fund/European Social Fund "Investing in your future"). Work in the laboratory of M.S. was funded by the CNIO and the IRB, and by grants from the Spanish Ministry of Economy (MINECO, SAF), the European Research Council (ERC Advanced Grant), the Botin Foundation and Banco Santander (Santander Universities Global Division), and by "la Caixa" Foundation. CNIO and IRB Barcelona are recipients of a Severo Ochoa Award of Excellence from the MINECO. D.M.-E was holder of a "Ramon y Cajal" Programme Senior Grant (MINECO, RYC-2013-14471) and was funded by a National Programme for Research Aimed at the Challenges of Society (MINECO, BFU2014-60020-R). Work in the laboratory of D.M.-E. was funded by Cancer Research UK (CRUK, C9685/A25177), and by the CRUK Cambridge Centre Early Detection Programme (RG86786). M.R. was holder of a "la Caixa"-Severo Ochoa PhD scholarship. I.G., B.L.-T., and A.B. were funded by the Generalitat Valenciana and the MINECO. Part of this work has been funded by a research collaboration agreement between Pfizer Inc. and the laboratories of RM.-M. and M.S. The fenders had no role in data collection and analysis, decision to publish, or preparation of the manuscript.
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