Ultrasound-mediated ocular delivery of therapeutic agents: a review

Abstract

Introduction: Due to numerous anatomical and physiological barriers, ocular drug delivery remains a major limitation in the treatment of diseases such as glaucoma, macular degeneration or inflammatory diseases. To date, only invasive approaches provide clinically effective results. Ultrasound can be defined as the propagation of a high-frequency sound wave exposing the propagation media to mechanical and thermal effects. Ultrasound has been proposed as a non-invasive physical agent for increasing therapeutic agent delivery in various fields of medicine.Areas Covered: An update on recent advances in transscleral and transcorneal ultrasoundmediated drug delivery is presented. Efficient drug delivery is achieved in vitro, ex vivo and in vivo for various types of materials. Numerous studies indicate that efficacy is related to Downloaded by [University of Lethbridge] at 02:55 18 June 2016 2 cavitation. Although slight reversible effects can be observed on the corneal epithelium, efficient drug delivery can be performed without causing damage to the cornea. Expert Opinion: Recent developments prove the potential of ultrasound-mediated ocular drug delivery. Cavitation appears to be a preponderant mechanism, opening a way to treatment monitoring by cavitation measurement. Even if no clinical studies have yet been performed, the promising results summarized here are promoting developments toward clinical applications, particularly in assessing the safety of the technique. Article highlights box• Ocular drug delivery limits the treatment of numerous diseases because of anatomical and physiological barriers so that current techniques are either inefficient (5% of the dose reaching the interior of the eye) or invasive (intravitreal injections, implants).• Ultrasound offers the possibility of acting noninvasively on the sclera or cornea.• Both in vitro and in vivo experiments report an increase in transscleral and transcorneal drug delivery by applying ultrasound which could suggest an increased treatment efficacy.• The mechanism of enhanced drug delivery is attributable to cavitation, producing slight, reversible changes in tissues.• Slight reversible damages attributable could be found. Thus, with an efficient cavitation monitoring procedure, translation to the clinic should be encouraged, as no severe damage has been observed. Downloaded by [University of Lethbridge] at 02:55 18 June 2016 3• The strategy of dosing the ultrasound exposure on measured cavitation activity in relation with its calibrated bioeffects in terms of damages and efficacy is proposed.Also, future developments shall benefit from the experience of sonophoresis.

Nucleation, mapping and control of cavitation for drug delivery

“…4a). Enhancements in drug delivery have also been achieved with inertial cavitation from endogenous nuclei 128,129,130 , but at the cost of microvascular rupture inside the tumour and extensive haemorrhage in treated areas. Cavitation agents provide a safer and more effective method of intratumoral drug delivery.…”

Ultrasound-Responsive Materials for Drug/Gene Delivery

“…Ultrasound-responsive material-based drug/gene delivery has been explored widely in treating cancer (Khokhlova et al, 2015;Qin et al, 2016;Fan et al, 2017;Yue et al, 2018;Jing et al, 2019), cardiovascular diseases (Hua et al, 2014;Dixon et al, 2015;Castle and Feinstein, 2016), orthopedic diseases (Le et al, 2016;Pullan et al, 2017;Kuo et al, 2019), ocular diseases (Aptel and Lafon, 2012;Wan et al, 2015a;Wan et al, 2015b;Lafond et al, 2017) and brain diseases (Timbie et al, 2015;Song et al, 2018a), and also applied in vaccine immunization (Tachibana et al, 1997;Escoffre et al, 2016). However, application of ultrasound-responsive materials in drug/gene delivery faces certain challenges.…”

<p>Comparative Assessment of Distribution Characteristics and Ocular Pharmacokinetics of Norvancomycin Between Continuous Topical Ocular Instillation and Hourly Administration of Eye Drop</p>

“…However, these devices were limited to a certain total drug dosage, not controllable, with a limited time of action and accidental loss. 15 In addition, microneedles that can be inserted into the cornea, [34][35][36] trans-corneal ultrasound-media drug delivery, 37 and trans-corneal iontophoresis techniques have been reported. [38][39][40] Even though these methods are non-invasive or minimally invasive, to increase the ability of the drug to travel across the biological barrier, and further research is required to confirm their safety and efficacy.…”