(150p) Injectable Senolytic Hydrogel Depot for the Clearance of Senescent Cells
AIChE Annual Meeting
2023
2023 AIChE Annual Meeting
Materials Engineering and Sciences Division
Poster Session: Materials Engineering & Sciences (08B - Biomaterials)
Tuesday, November 7, 2023 - 3:30pm to 5:00pm
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 polymerânanoparticle (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