Targeting primary cilia with polymeric nanoparticles

Abstract

The field of nanomedicine is a promising future in providing huge clinical impacts on advanced disease management and personalized medicine. Nanoparticles (NPs) have been used for targeted delivery at a desired site and a sustained release of a drug, which decreases the overall toxicity by delivering a smaller drug dosage. An extensively investigated NPs is poly lactic‐co‐glycolic acid (PLGA) which is an FDA approved biodegradable polymer and they are currently used in clinical setting. Hence in our current study, we used PLGA nanoparticles labeled with dopamine receptor 5 antibody to target primary cilia. Further these NPs were loaded with fenoldopam to improve cilia structure and function. The conjugation and loading was confirmed by UV‐visible spectroscopy, transmission electron microscopy (TEM), X‐ray photoelectron spectroscopy (XPS), dynamic light scattering (DLS), zeta potential measurements and Fourier transform infrared spectroscopy (FTIR). TEM confirmed the synthesized nanoparticles were around 120 nm and spherical in shape. FTIR confirms the drug loading and antibody interactions with the PLGA. When we injected these NPs to ciliopathic hypertensive mice, significantly improved cardiac function in the ciliopathic hypertensive models, in which the hearts also exhibited arrhythmia, which was corrected with the PLGA‐NPs. Intraciliary and cytosolic Ca2+ were increased when cilia were induced with fluid flow, and this served as a cilia‐dependent mechanism of the PLGA‐NPs. Fenoldopam‐alone caused an immediate decrease in blood pressure, followed by hypertrophy with compromised functions in left ventricle pressure, stroke volume, ejection fraction. Our drug delivery profiles confirmed that the PLGA‐NPs were a potential delivery system for targeting cilia more specifically, efficiently, and effectively than fenoldopam‐alone. In conclusion, our results indicate that nanomedicine provides a possibility for targeted ciliotherapy.Support or Funding InformationThis work was supported by the National Institute of Health (HL131577), Congressionally Directed Medical Research Program (PR130153) and American Heart association (19IPLOI34730020).