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ACS Nano. 2019 Mar 15. doi: 10.1021/acsnano.9b00033. [Epub ahead of print]

Ciliotherapy: Remote Control of Primary Cilia Movement and Function by Magnetic Nanoparticles.

Author information

1
Department of Biomedical & Pharmaceutical Sciences, Chapman University School of Pharmacy (CUSP), Harry and Diane Rinker Health Science Campus , Chapman University , Irvine , California 92618 , United States.
2
Department of Medicine , University of California Irvine , Irvine , California 92868 , United States.
3
Department of Medicine , Harvard Medical School , Boston , Massachusetts 02115 , United States.
4
Department of Physics, Computer Science & Engineering , Chapman University , Orange , California 92866 , United States.

Abstract

Patients with polycystic kidney disease (PKD) are characterized with uncontrolled hypertension. Hypertension in PKD is a ciliopathy, an abnormal function and/or structure of primary cilia. Primary cilia are cellular organelles with chemo and mechanosensory roles. In the present studies, we designed a cilia-targeted (CT) delivery system to deliver fenoldopam specifically to the primary cilia. We devised the iron oxide nanoparticle (NP)-based technology for ciliotherapy. Live imaging confirmed that the CT-Fe2O3-NPs specifically targeted primary cilia in cultured cells in vitro and vascular endothelia in vivo. Importantly, the CT-Fe2O3-NPs enabled the remote control of the movement and function of a cilium with an external magnetic field, making the nonmotile cilium exhibit passive movement. The ciliopathic hearts displayed hypertrophy with compromised functions in left ventricle pressure, stroke volume, ejection fraction, and overall cardiac output because of prolonged hypertension. The CT-Fe2O3-NPs significantly improved cardiac function in the ciliopathic hypertensive models, in which the hearts also exhibited arrhythmia, which was corrected with the CT-Fe2O3-NPs. Intraciliary and cytosolic Ca2+ were increased when cilia were induced with fluid flow or magnetic field, and this served as a cilia-dependent mechanism of the CT-Fe2O3-NPs. Fenoldopam-alone caused an immediate decrease in blood pressure, followed by reflex tachycardia. Pharmacological delivery profiles confirmed that the CT-Fe2O3-NPs were a superior delivery system for targeting cilia more specifically, efficiently, and effectively than fenoldopam-alone. The CT-Fe2O3-NPs altered the mechanical properties of nonmotile cilia, and these nano-biomaterials had enormous clinical potential for ciliotherapy. Our studies further indicated that ciliotherapy provides a possibility toward personalized medicine in ciliopathy patients.

KEYWORDS:

calcium; chemosensor; ciliopathy; cilium; mechanosensor; nanotherapy

PMID:
30860808
DOI:
10.1021/acsnano.9b00033

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