Ultrasound-Responsive Nanobubbles for Enhanced Intravitreal Drug Migration: An Ex Vivo Evaluation

Sachin S Thakur, Ying-Shan Chen, Zachary H Houston, Nicholas Fletcher, Nigel L Barnett, Kristofer J Thurecht, Ilva D Rupenthal, Harendra S Parekh

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

The intravitreal route faces many challenges in rapidly and effectively reaching posterior eye pathology, with administered therapeutics experiencing non-specific distribution around and premature clearance from ocular tissues. Nanobubbles and ultrasound may improve outcomes of intravitreally administered drugs by influencing the directionality of drug-containing particle migration. In this study, we assessed the impact of trans-scleral or corneal ultrasound application on the distribution of intravitreally-injected nanobubbles. Rhodamine-tagged gas entrapped nanobubble formulations were prepared and injected into ex vivo bovine and porcine eyes and subjected to ultrasound (1 MHz, 0-2.5 W/cm2, 50-100% duty, 60 s). Bovine eyes were partially dissected to visualize the vitreous humor and particle migration was evaluated via optical fluorescence spectroscopy. Directional migration in porcine eyes was evaluated using a snap freezing protocol complemented by quantification of regional fluorescence. The impact on nanobubble migration following pars-plana injection and sequential ultrasound cycle application from scleral or corneal-surface positions was also assessed. Administration of ultrasound significantly enhanced the directional migration of nanobubbles in both ex vivo models, with multiple corneal ultrasound cycles promoting greater migration of dye-filled nanobubbles to posterior regions of the vitreous. Moreover, particles moved in a directional manner away from the ultrasound wave source demonstrating an ability to effectively control the rate and path of nanobubble migration. These findings establish an encouraging new and safe modality enabling rapid distribution of intravitreally-injected therapeutics where expeditious therapeutic intervention is warranted.

Original languageEnglish
Pages (from-to)102-107
Number of pages6
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume136
Issue number136
Early online date17 Jan 2019
DOIs
Publication statusPublished - 1 Mar 2019

Fingerprint

Pharmaceutical Preparations
Swine
Vitreous Body
Rhodamines
Temazepam
Fluorescence Spectrometry
Freezing
Coloring Agents
Therapeutics
Fluorescence
Gases
Pathology
Injections
Ultrasonic Waves

Cite this

Thakur, Sachin S ; Chen, Ying-Shan ; Houston, Zachary H ; Fletcher, Nicholas ; Barnett, Nigel L ; Thurecht, Kristofer J ; Rupenthal, Ilva D ; Parekh, Harendra S. / Ultrasound-Responsive Nanobubbles for Enhanced Intravitreal Drug Migration: An Ex Vivo Evaluation. In: European Journal of Pharmaceutics and Biopharmaceutics. 2019 ; Vol. 136, No. 136. pp. 102-107.
@article{e7493eeacdfa46f7ab769773f601f891,
title = "Ultrasound-Responsive Nanobubbles for Enhanced Intravitreal Drug Migration: An Ex Vivo Evaluation",
abstract = "The intravitreal route faces many challenges in rapidly and effectively reaching posterior eye pathology, with administered therapeutics experiencing non-specific distribution around and premature clearance from ocular tissues. Nanobubbles and ultrasound may improve outcomes of intravitreally administered drugs by influencing the directionality of drug-containing particle migration. In this study, we assessed the impact of trans-scleral or corneal ultrasound application on the distribution of intravitreally-injected nanobubbles. Rhodamine-tagged gas entrapped nanobubble formulations were prepared and injected into ex vivo bovine and porcine eyes and subjected to ultrasound (1 MHz, 0-2.5 W/cm2, 50-100{\%} duty, 60 s). Bovine eyes were partially dissected to visualize the vitreous humor and particle migration was evaluated via optical fluorescence spectroscopy. Directional migration in porcine eyes was evaluated using a snap freezing protocol complemented by quantification of regional fluorescence. The impact on nanobubble migration following pars-plana injection and sequential ultrasound cycle application from scleral or corneal-surface positions was also assessed. Administration of ultrasound significantly enhanced the directional migration of nanobubbles in both ex vivo models, with multiple corneal ultrasound cycles promoting greater migration of dye-filled nanobubbles to posterior regions of the vitreous. Moreover, particles moved in a directional manner away from the ultrasound wave source demonstrating an ability to effectively control the rate and path of nanobubble migration. These findings establish an encouraging new and safe modality enabling rapid distribution of intravitreally-injected therapeutics where expeditious therapeutic intervention is warranted.",
author = "Thakur, {Sachin S} and Ying-Shan Chen and Houston, {Zachary H} and Nicholas Fletcher and Barnett, {Nigel L} and Thurecht, {Kristofer J} and Rupenthal, {Ilva D} and Parekh, {Harendra S}",
note = "Copyright {\circledC} 2019. Published by Elsevier B.V.",
year = "2019",
month = "3",
day = "1",
doi = "10.1016/j.ejpb.2019.01.014",
language = "English",
volume = "136",
pages = "102--107",
journal = "Acta Pharmaceutica Technologica",
issn = "0939-6411",
publisher = "Elsevier",
number = "136",

}

Ultrasound-Responsive Nanobubbles for Enhanced Intravitreal Drug Migration: An Ex Vivo Evaluation. / Thakur, Sachin S; Chen, Ying-Shan; Houston, Zachary H; Fletcher, Nicholas; Barnett, Nigel L; Thurecht, Kristofer J; Rupenthal, Ilva D; Parekh, Harendra S.

In: European Journal of Pharmaceutics and Biopharmaceutics, Vol. 136, No. 136, 01.03.2019, p. 102-107.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Ultrasound-Responsive Nanobubbles for Enhanced Intravitreal Drug Migration: An Ex Vivo Evaluation

AU - Thakur, Sachin S

AU - Chen, Ying-Shan

AU - Houston, Zachary H

AU - Fletcher, Nicholas

AU - Barnett, Nigel L

AU - Thurecht, Kristofer J

AU - Rupenthal, Ilva D

AU - Parekh, Harendra S

N1 - Copyright © 2019. Published by Elsevier B.V.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - The intravitreal route faces many challenges in rapidly and effectively reaching posterior eye pathology, with administered therapeutics experiencing non-specific distribution around and premature clearance from ocular tissues. Nanobubbles and ultrasound may improve outcomes of intravitreally administered drugs by influencing the directionality of drug-containing particle migration. In this study, we assessed the impact of trans-scleral or corneal ultrasound application on the distribution of intravitreally-injected nanobubbles. Rhodamine-tagged gas entrapped nanobubble formulations were prepared and injected into ex vivo bovine and porcine eyes and subjected to ultrasound (1 MHz, 0-2.5 W/cm2, 50-100% duty, 60 s). Bovine eyes were partially dissected to visualize the vitreous humor and particle migration was evaluated via optical fluorescence spectroscopy. Directional migration in porcine eyes was evaluated using a snap freezing protocol complemented by quantification of regional fluorescence. The impact on nanobubble migration following pars-plana injection and sequential ultrasound cycle application from scleral or corneal-surface positions was also assessed. Administration of ultrasound significantly enhanced the directional migration of nanobubbles in both ex vivo models, with multiple corneal ultrasound cycles promoting greater migration of dye-filled nanobubbles to posterior regions of the vitreous. Moreover, particles moved in a directional manner away from the ultrasound wave source demonstrating an ability to effectively control the rate and path of nanobubble migration. These findings establish an encouraging new and safe modality enabling rapid distribution of intravitreally-injected therapeutics where expeditious therapeutic intervention is warranted.

AB - The intravitreal route faces many challenges in rapidly and effectively reaching posterior eye pathology, with administered therapeutics experiencing non-specific distribution around and premature clearance from ocular tissues. Nanobubbles and ultrasound may improve outcomes of intravitreally administered drugs by influencing the directionality of drug-containing particle migration. In this study, we assessed the impact of trans-scleral or corneal ultrasound application on the distribution of intravitreally-injected nanobubbles. Rhodamine-tagged gas entrapped nanobubble formulations were prepared and injected into ex vivo bovine and porcine eyes and subjected to ultrasound (1 MHz, 0-2.5 W/cm2, 50-100% duty, 60 s). Bovine eyes were partially dissected to visualize the vitreous humor and particle migration was evaluated via optical fluorescence spectroscopy. Directional migration in porcine eyes was evaluated using a snap freezing protocol complemented by quantification of regional fluorescence. The impact on nanobubble migration following pars-plana injection and sequential ultrasound cycle application from scleral or corneal-surface positions was also assessed. Administration of ultrasound significantly enhanced the directional migration of nanobubbles in both ex vivo models, with multiple corneal ultrasound cycles promoting greater migration of dye-filled nanobubbles to posterior regions of the vitreous. Moreover, particles moved in a directional manner away from the ultrasound wave source demonstrating an ability to effectively control the rate and path of nanobubble migration. These findings establish an encouraging new and safe modality enabling rapid distribution of intravitreally-injected therapeutics where expeditious therapeutic intervention is warranted.

UR - http://www.scopus.com/inward/record.url?scp=85060184925&partnerID=8YFLogxK

U2 - 10.1016/j.ejpb.2019.01.014

DO - 10.1016/j.ejpb.2019.01.014

M3 - Article

VL - 136

SP - 102

EP - 107

JO - Acta Pharmaceutica Technologica

JF - Acta Pharmaceutica Technologica

SN - 0939-6411

IS - 136

ER -