A Drug Delivery System that Preferentially Targets Senescent Cells
Senescent cells are thought to be one of the root causes of aging, and there is a sizable amount of evidence to back this view. The approach of removing senescent cells in order to turn back aspects of aging and extend life has been quite comprehensively demonstrated in mice, and a growing number of companies are now developing therapies for human medicine. In that context, this paper outlines what seems a promising line of work, a delivery system that is claimed to preferentially target senescent cells based on their distinctive biochemistry. The question, as is always the case, is the degree to which the delivery system prefers senescent cells in practice.
Present senolytics, therapies capable of destroying senescent cells, kill senescence cells versus normal cells at a ratio somewhere in the range of 3:1 to 12:1. The compounds that destroy more non-senescent cells tend to be those with worse side effects, for all the obvious reasons. These compounds and their side effects set a low bar, and they can certainly be improved upon. A reliable, selective delivery method should make it that much easier for the development community to engineer significant improvement.
Upon persistent damage or during aging, senescent cells accumulate, probably due to an inefficient clearance by immune cells, and this accumulation may lead to chronic inflammation and fibrosis. Indeed, evidence in mice indicates that the accumulation of senescent cells actively contributes to multiple diseases and aging. In this regard, genetic ablation of senescent cells delays and ameliorates some aging-associated diseases, reverts long-term degenerative processes associated with chemotherapy, and extends longevity. Importantly, senescent cells present vulnerabilities to particular small molecule inhibitors, known as "senolytics", that trigger apoptosis preferentially in senescent cells. These pharmacological treatments reduce the number of senescent cells in vivo and show therapeutic activity against senescence-associated diseases and aging.
Senescent cells in vitro are characterized by high levels of lysosomal β-galactosidase activity, known as senescence-associated β-galactosidase. In addition to β-galactosidase, senescent cells present high levels of most tested lysosomal hydrolases. Indeed, senescent cells show a remarkable accumulation of lysosomes, together with abnormal endosomal traffic and autophagy. Interestingly, damaged or diseased tissues generally contain cells that are positive for SAβGal, while normal healthy tissues are negative for this marker.
Here, we have explored the possibility of using lysosomal β-galactosidase as a vulnerable trait of senescent cells that can be exploited to deliver tracers or drugs preferentially to diseased tissues with high content of senescent cells. Our approach is based on the encapsulation of diagnostic or therapeutic agents with β(1,4)-galacto-oligosaccharides and their delivery to lysosomes via endocytosis. In a model of chemotherapy-induced senescence, encapsulated cytotoxic drugs target senescent tumor cells. Moreover, in a model of pulmonary fibrosis in mice, encapsulated cytotoxics target senescent cells, reducing collagen deposition and restoring pulmonary function. Finally, 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.
What is the ratio of senescent cells killed to normal cells killed for Oisin's approach?