(150p) Injectable Senolytic Hydrogel Depot for the Clearance of Senescent Cells | AIChE

(150p) Injectable Senolytic Hydrogel Depot for the Clearance of Senescent Cells

Authors 

Tibbitt, M., ETH Zürich
Mazza, E., ETH Zurich
Cuni, F., Politecnico di Milano
Garau Paganella, L., ETH Zürich
Labouesse, C., ETH Zürich
Giampietro, C., ETH Zürich
Mantero, S., Politecnico di Milano
Aging is the greatest risk factor for many chronic diseases. The immune system develops a low-level and systemic inflammation leading healthy cells into a state of permanent cell cycle arrest, called cellular senescence.[1] Senescent cells impair regeneration and promote age-related diseases including atherosclerosis, myocardial infarction, and cardiac fibrosis.[2] Senolytics such as Navitoclax, a BCL-2 inhibitor, are emerging therapies which systemically clear senescent cells and promote regeneration, however, these drugs often cause adverse effects due to the high doses administered.[3]

In this work, we nano-formulated Navitoclax into an injectable hydrogel formulation for the clearance of senescent human umbilical vein endothelial cells (HUVECs). We induced inflammatory senescence in HUVECs by treating them periodically with tumor necrosis factor-alpha (TNF-α). Senescent cells showed distinctive morphological alterations, a lower expression of the proliferation marker Ki67, and an increased expression of the cyclin-dependent kinase inhibitor p21. Navitoclax is highly insoluble in water and was nanoprecipitated into stable nanoparticles, dH ~115 nm. We established the half-maximal inhibitory concentration of non-formulated and nano-formulated navitoclax, and it resulted that the nanoparticles shifted the therapeutic window to lower drug concentrations. We included Navitoclax nanoparticles in polymer–nanoparticle (PNP) hydrogels, a class of injectable hydrogels that is suitable to form minimally-invasive subcutaneous drug depots.[4] Their effect on senescent and healthy HUVECs was evaluated in vitro.

In total, we used an injectable hydrogel to deliver nano-formulated Navitoclax nanoparticles and mitigated the inflammatory-induced senescence in HUVECs. These results underline the potential of injectable senolytic depots for the mitigation of senescent-associated diseases.

References:
[1] B. Uyar. et al., Ageing Research Reviews, 2020, 64, 101156.

[2] F. Fyhrquist. et al., Nature Reviews Cardiology. 2013, 10,274.

[3] Y. Zhu et al., Aging Cell, 2015, 15, 428.

[4] E. A. Appel and M. W. Tibbitt et al, Nature Communications, 2015, 6, 6295