Microbubble-Assisted Ultrasound for Drug Delivery to the Retina in an Ex Vivo Eye Model
Charis Rousou,
Nicky van Kronenburg,
Andreas F. P. Sonnen,
Marijke van Dijk,
Chrit Moonen,
Gert Storm,
Enrico Mastrobattista,
Roel Deckers
Affiliations
Charis Rousou
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Heidelberglaan 8, 3584 CS Utrecht, The Netherlands
Nicky van Kronenburg
Department of Translational Neuroscience, Brain Center, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
Andreas F. P. Sonnen
Department of Pathology, Division of Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
Marijke van Dijk
Department of Pathology, Division of Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
Chrit Moonen
Imaging and Oncology Division, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
Gert Storm
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Heidelberglaan 8, 3584 CS Utrecht, The Netherlands
Enrico Mastrobattista
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Heidelberglaan 8, 3584 CS Utrecht, The Netherlands
Roel Deckers
Imaging and Oncology Division, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
Drug delivery to the retina is one of the major challenges in ophthalmology due to the biological barriers that protect it from harmful substances in the body. Despite the advancement in ocular therapeutics, there are many unmet needs for the treatment of retinal diseases. Ultrasound combined with microbubbles (USMB) was proposed as a minimally invasive method for improving delivery of drugs in the retina from the blood circulation. This study aimed to investigate the applicability of USMB for the delivery of model drugs (molecular weight varying from 600 Da to 20 kDa) in the retina of ex vivo porcine eyes. A clinical ultrasound system, in combination with microbubbles approved for clinical ultrasound imaging, was used for the treatment. Intracellular accumulation of model drugs was observed in the cells lining blood vessels in the retina and choroid of eyes treated with USMB but not in eyes that received ultrasound only. Specifically, 25.6 ± 2.9% of cells had intracellular uptake at mechanical index (MI) 0.2 and 34.5 ± 6.0% at MI 0.4. Histological examination of retinal and choroid tissues revealed that at these USMB conditions, no irreversible alterations were induced at the USMB conditions used. These results indicate that USMB can be used as a minimally invasive targeted means to induce intracellular accumulation of drugs for the treatment of retinal diseases.
