| Autor: |
Sestito LF; Wallace H. Coulter School of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.; Department of Mechanical Engineering and Bioengineering, Valparaiso University, 1900 Chapel Dr, Valparaiso, IN 46383, USA., To KHT; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA., Cribb MT; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.; Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA., Archer PA; Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA., Thomas SN; Wallace H. Coulter School of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.; Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA., Dixon JB; Wallace H. Coulter School of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.; Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA. |
| Abstrakt: |
Dysfunction of collecting lymphatic vessel pumping is associated with an array of pathologies. S-(-)-Bay K8644 (BayK), a small-molecule agonist of L-type calcium channels, improves vessel contractility ex vivo but has been left unexplored in vivo because of poor lymphatic access and risk of deleterious off-target effects. When formulated within lymph-draining nanoparticles (NPs), BayK acutely improved lymphatic vessel function, effects not seen from treatment with BayK in its free form. By preventing rapid drug access to the circulation, NP formulation also reduced BayK's dose-limiting side effects. When applied to a mouse model of lymphedema, treatment with BayK formulated in lymph-draining NPs, but not free BayK, improved pumping pressure generated by intact lymphatic vessels and tissue remodeling associated with the pathology. This work reveals the utility of a lymph-targeting NP platform to pharmacologically enhance lymphatic pumping in vivo and highlights a promising approach to treating lymphatic dysfunction. |
