Enhancing Safety and Efficacy of Senolytic Therapies with Advanced Controlled Release Strategies

Abstract The elimination of senescent cells by senotherapeutic interventions is being evaluated in several clinical trials for the treatment of age-related diseases; however, these approaches present several limitations, including a low senotherapeutic index (i.e., the safety margin between the dose of the drug that produces a desired effect and the dose that produces unwanted side effects is relatively low) and, in some cases, concerns regarding their elimination. Here, we report a nanoparticle (NP) formulation selected from a library of 42 polymeric NP formulations that is biocompatible, fully degradable, and presents a senotherapeutic index at least 44 times greater than that observed for the soluble drug. The NP is endocytosed by both proliferative and senescent cells, but only in the latter is it degraded at a sufficient level in the endolysosome to release the encapsulated senotherapeutic drug, which can then cross a damaged endolysosomal membrane, reach the cell cytoplasm and induce apoptosis. Importantly, our results show that the release kinetics of the senotherapeutic drug from the NP affect its efficacy. We demonstrate the full potential of this formulation in the aged liver, particularly in the vascular compartment. The NP formulation, which is injected intravenously into naturally aged Wistar rats, accumulates significantly in the aged liver, reducing the senescence burden in the endothelial cell compartment. This contributes to decreases in portal pressure and liver fibrosis. Taken together, the strategy reported here increases the safety and efficacy of pharmacological interventions to treat age-related diseases.