Lymphatic-draining nanoparticles deliver Bay K8644 payload to lymphatic vessels and enhance their pumping function

by Selleckchem | Jul 06 2023

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.

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The passage you provided describes a study that explores the use of S-(-)-Bay K8644 (BayK), a small-molecule agonist of L-type calcium channels, in improving lymphatic vessel function and treating lymphatic dysfunction. Lymphatic dysfunction is associated with various pathological conditions.

Initially, the use of BayK in vivo has been limited due to difficulties in accessing the lymphatic system and the potential for harmful off-target effects. However, the researchers in this study developed a formulation of BayK within lymph-draining nanoparticles (NPs) to overcome these limitations. This NP formulation allowed for targeted delivery of BayK to the lymphatic vessels, improving their function.

The researchers observed that when BayK was administered in its free form, it did not produce the same effects on lymphatic vessel function as when it was formulated in the lymph-draining NPs. The NP formulation enhanced lymphatic pumping by increasing the contractility of the vessels. Additionally, the NP formulation prevented rapid access of the drug to the circulation, reducing the dose-limiting side effects associated with BayK.

To evaluate the therapeutic potential of BayK in treating lymphedema, a mouse model of the condition was used. Lymphedema is a condition characterized by impaired lymphatic drainage and tissue remodeling. Treatment with BayK formulated in lymph-draining NPs improved the pumping pressure generated by intact lymphatic vessels and also led to positive changes in tissue remodeling associated with lymphedema.

Overall, this study demonstrates the effectiveness of a lymph-targeting nanoparticle platform in enhancing lymphatic pumping and highlights a promising approach for treating lymphatic dysfunction. By specifically delivering BayK to the lymphatic system, the researchers were able to improve lymphatic vessel function while minimizing the risk of off-target effects.