Ultrasonically Targeted Delivery into Endothelial and Smooth Muscle Cells in Ex Vivo Arteries

Overview

Journal J Control Release

Specialty Pharmacology

Date 2007 Feb 13

PMID 17291619

Citations 21

Authors

Daniel M Hallow

Anuj D Mahajan

Mark R Prausnitz

Affiliations

Soon will be listed here.

Abstract

This study tested the hypothesis that ultrasound can target intracellular uptake of drugs into vascular endothelial cells (ECs) at low to intermediate energy and into smooth muscle cells (SMCs) at high energy. Ultrasound-enhanced delivery has been shown to enhance and target intracellular drug and gene delivery in the vasculature to treat cardiovascular disease, but quantitative studies of the delivery process are lacking. Viable ex vivo porcine carotid arteries were placed in a solution containing a model drug, TO-PRO(R)-1, and Optison microbubbles. Arteries were exposed to ultrasound at 1.1 MHz and acoustic energies of 5.0, 66, or 630 J/cm(2). Using confocal microscopy and fluorescent labeling of cells, the artery endothelium and media were imaged to determine the localization and to quantify intracellular uptake and cell death. At low to intermediate ultrasound energy, ultrasound was shown to target intracellular delivery into viable cells that represented 9-24% of exposed ECs. These conditions also typically caused 7-25% EC death. At high energy, intracellular delivery was targeted to SMCs, which was associated with denuding or death of proximal ECs. This work represents the first known in-depth study to evaluate intracellular uptake into cells in tissue. We conclude that significant intracellular uptake of molecules can be targeted into ECs and SMCs by ultrasound-enhanced delivery suggesting possible applications for treatment of cardiovascular diseases and dysfunctions.

Citing Articles

Flow rate modulates focused ultrasound-mediated vascular delivery of microRNA.

He S, Singh D, Helfield B Mol Ther Nucleic Acids. 2025; 36(1):102426.

PMID: 39850318 PMC: 11754011. DOI: 10.1016/j.omtn.2024.102426.

Effect of Photo-Mediated Ultrasound Therapy on Nitric Oxide and Prostacyclin from Endothelial Cells.

Karthikesh M, Wu S, Singh R, Paulus Y, Wang X, Yang X Appl Sci (Basel). 2022; 12(5).

PMID: 35983461 PMC: 9384428. DOI: 10.3390/app12052617.

Ultrasound-Targeted Microbubble Destruction: Modulation in the Tumor Microenvironment and Application in Tumor Immunotherapy.

Han Y, Sun J, Wei H, Hao J, Liu W, Wang X Front Immunol. 2022; 13:937344.

PMID: 35844515 PMC: 9283646. DOI: 10.3389/fimmu.2022.937344.

The effect of ultrasound cavitation on endothelial cells.

Karthikesh M, Yang X Exp Biol Med (Maywood). 2021; 246(7):758-770.

PMID: 33461340 PMC: 8719027. DOI: 10.1177/1535370220982301.

High Efficiency Molecular Delivery with Sequential Low-Energy Sonoporation Bursts.

Song K, Fan A, Brlansky J, Trudeau T, Gutierrez-Hartmann A, Calvisi M Theranostics. 2015; 5(12):1419-27.

PMID: 26681986 PMC: 4672022. DOI: 10.7150/thno.13033.

References

Hwang J, Brayman A, Reidy M, Matula T, Kimmey M, Crum L . Vascular effects induced by combined 1-MHz ultrasound and microbubble contrast agent treatments in vivo. Ultrasound Med Biol. 2005; 31(4):553-64. DOI: 10.1016/j.ultrasmedbio.2004.12.014. View

Cooke J . The endothelium: a new target for therapy. Vasc Med. 2000; 5(1):49-53. DOI: 10.1177/1358836X0000500108. View

Mehier-Humbert S, Bettinger T, Yan F, Guy R . Plasma membrane poration induced by ultrasound exposure: implication for drug delivery. J Control Release. 2005; 104(1):213-22. DOI: 10.1016/j.jconrel.2005.01.007. View

Liu Y, Miyoshi H, Nakamura M . Encapsulated ultrasound microbubbles: therapeutic application in drug/gene delivery. J Control Release. 2006; 114(1):89-99. DOI: 10.1016/j.jconrel.2006.05.018. View

Melo L, Gnecchi M, Pachori A, Kong D, Wang K, Liu X . Endothelium-targeted gene and cell-based therapies for cardiovascular disease. Arterioscler Thromb Vasc Biol. 2004; 24(10):1761-74. DOI: 10.1161/01.ATV.0000142363.15113.88. View

Schlicher R, Radhakrishna H, Tolentino T, Apkarian R, Zarnitsyn V, Prausnitz M . Mechanism of intracellular delivery by acoustic cavitation. Ultrasound Med Biol. 2006; 32(6):915-24. DOI: 10.1016/j.ultrasmedbio.2006.02.1416. View

Amabile P, WAUGH J, LEWIS T, Elkins C, Janas W, Dake M . High-efficiency endovascular gene delivery via therapeutic ultrasound. J Am Coll Cardiol. 2001; 37(7):1975-80. DOI: 10.1016/s0735-1097(01)01253-0. View

Correas J, Bridal L, Lesavre A, Mejean A, Claudon M, Helenon O . Ultrasound contrast agents: properties, principles of action, tolerance, and artifacts. Eur Radiol. 2001; 11(8):1316-28. DOI: 10.1007/s003300100940. View

Hashiya N, Aoki M, Tachibana K, Taniyama Y, Yamasaki K, Hiraoka K . Local delivery of E2F decoy oligodeoxynucleotides using ultrasound with microbubble agent (Optison) inhibits intimal hyperplasia after balloon injury in rat carotid artery model. Biochem Biophys Res Commun. 2004; 317(2):508-14. DOI: 10.1016/j.bbrc.2004.03.070. View

10.

Malecki M, Kolsut P, Proczka R . Angiogenic and antiangiogenic gene therapy. Gene Ther. 2005; 12 Suppl 1:S159-69. DOI: 10.1038/sj.gt.3302621. View

11.

Unger E, Hersh E, Vannan M, Matsunaga T, McCreery T . Local drug and gene delivery through microbubbles. Prog Cardiovasc Dis. 2001; 44(1):45-54. DOI: 10.1053/pcad.2001.26443. View

12.

Ohl C, Wolfrum B . Detachment and sonoporation of adherent HeLa-cells by shock wave-induced cavitation. Biochim Biophys Acta. 2003; 1624(1-3):131-8. DOI: 10.1016/j.bbagen.2003.10.005. View

13.

Brayman A, Lizotte L, Miller M . Erosion of artificial endothelia in vitro by pulsed ultrasound: acoustic pressure, frequency, membrane orientation and microbubble contrast agent dependence. Ultrasound Med Biol. 1999; 25(8):1305-20. DOI: 10.1016/s0301-5629(99)00076-9. View

14.

Suzuki R, Takizawa T, Negishi Y, Hagisawa K, Tanaka K, Sawamura K . Gene delivery by combination of novel liposomal bubbles with perfluoropropane and ultrasound. J Control Release. 2006; 117(1):130-6. DOI: 10.1016/j.jconrel.2006.09.008. View

15.

Cines D, Pollak E, Buck C, Loscalzo J, Zimmerman G, McEver R . Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood. 1998; 91(10):3527-61. View

16.

Kipshidze N, Porter T, Dangas G, Yazdi H, Tio F, Xie F . Novel site-specific systemic delivery of Rapamycin with perfluorobutane gas microbubble carrier reduced neointimal formation in a porcine coronary restenosis model. Catheter Cardiovasc Interv. 2005; 64(3):389-94. DOI: 10.1002/ccd.20285. View

17.

Klibanov . Targeted delivery of gas-filled microspheres, contrast agents for ultrasound imaging. Adv Drug Deliv Rev. 2000; 37(1-3):139-157. DOI: 10.1016/s0169-409x(98)00104-5. View

18.

Tozer G, Kanthou C, Baguley B . Disrupting tumour blood vessels. Nat Rev Cancer. 2005; 5(6):423-35. DOI: 10.1038/nrc1628. View

19.

Ray R, Shah A . NADPH oxidase and endothelial cell function. Clin Sci (Lond). 2005; 109(3):217-26. DOI: 10.1042/CS20050067. View

20.

Taniyama Y, Tachibana K, Hiraoka K, Namba T, Yamasaki K, Hashiya N . Local delivery of plasmid DNA into rat carotid artery using ultrasound. Circulation. 2002; 105(10):1233-9. DOI: 10.1161/hc1002.105228. View