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PRE-CLINICAL RESEARCH

Nitric Oxide-Loaded Echogenic Liposomes for Nitric Oxide Delivery and Inhibition of Intimal Hyperplasia

Shao-Ling Huang, MD, PhD^_*,_*, Patrick H. Kee, MD, PhD^_*, Hyunggun Kim, PhD^_*, Melanie R. Moody, MS^_*, Stephen M. Chrzanowski^_*, Robert C. MacDonald, PhD and David D. McPherson, MD^_*

^_* Division of Cardiology, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois

Manuscript received January 6, 2009; revised manuscript received March 18, 2009, accepted April 13, 2009.

^_* Reprint requests and correspondence: Dr. Shao-Ling Huang, Division of Cardiology, Department of Internal Medicine, The University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 1.246, Houston, Texas 77030 (Email: Shaoling.Huang{at}uth.tmc.edu).

Objectives: We sought to develop a new bioactive gas-delivery method by the use of echogenic liposomes (ELIP) as the gas carrier.

Background: Nitric oxide (NO) is a bioactive gas with potent therapeutic effects. The bioavailability of NO by systemic delivery is low with potential systemic effects.

Methods: Liposomes containing phospholipids and cholesterol were prepared by the use of a new method, freezing under pressure. The encapsulation and release profile of NO from NO-containing ELIP (NO-ELIP) or a mixture of NO/argon (NO/Ar-ELIP) was studied. The uptake of NO from NO-ELIP by cultured vascular smooth muscle cells (VSMCs) both in the absence and presence of hemoglobin was determined. The effect of NO-ELIP delivery to attenuate intimal hyperplasia in a balloon-injured artery was determined.

Results: Coencapsulation of NO with Ar enabled us to adjust the amount of encapsulated NO. A total of 10 µl of gas can be encapsulated into 1 mg of liposomes. The release profile of NO from NO-ELIP demonstrated an initial rapid release followed by a slower release during the course of 8 h. Sixty-eight percent of cells remained viable when incubated with 80 µg/ml of NO/Ar-ELIP for 4 h. The delivery agent of NO to VSMCs by the use of NO/Ar-ELIP was 7-fold greater than unencapsulated NO. We discovered that NO/Ar-ELIP remained an effective delivery agent of NO to VSMCs even in the presence of hemoglobin. Local NO-ELIP administration to balloon-injured carotid arteries attenuated the development of intimal hyperplasia and reduced arterial wall thickening by 41 ± 9%.

Conclusions: Liposomes can protect and deliver a bioactive gas to target tissues with the potential for both visualization of gas delivery and controlled therapeutic gas release.

Key Words: intimal hyperplasia • liposomes • nitric oxide • contrast agent

Abbreviations and Acronyms   Ar = argon   CH = cholesterol   DAF-2DA = diaminofluorescein-2 diacetate   DMEM = Dulbecco's modified Eagle medium   ELIP = echogenic liposomes   FBS = fetal bovine serum   NO = nitric oxide   NO/Ar-ELIP = nitric oxide/argon-containing liposomes   NO-ELIP = nitric oxide-containing liposomes   PBS = phosphate-buffered saline   VSMC = vascular smooth muscle cell

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