MSACL 2017 US Abstract

Application of Imaging Mass Spectrometry to Assess Ocular Drug Transit

Kerri Grove (Presenter)
Novartis Institutes for BioMedical Research

Authorship: Kerri J. Grove (1); Viral Kansara (2); Melissa Prentiss (2); Debby Long (2); Muneto Mogi (2); Sean Kim (2); Patrick J. Rudewicz (1)
(1) Novartis Institutes for BioMedical Research, Emeryville, CA; (2) Novartis Institutes for BioMedical Research, Cambridge, MA

Short Abstract

MALDI imaging mass spectrometry (IMS) is becoming an important technology to determine localization of drug compounds after dosing and has become of interest in the ophthalmology field. For this study, ocular distribution of brimonidine, a drug used to treat glaucoma, was investigated in rabbits following topical instillation. We have developed IMS methods to assess transit of topically administered brominidine from the anterior chamber to the posterior segment of rabbit eyes. The distribution of brimonidine suggests that the route of transit following topical administration is mainly through the uveal route. This study demonstrates that IMS can be applied to monitor ocular transit and distribution of topically administered drugs.

Long Abstract

Introduction

MALDI imaging mass spectrometry (IMS) is becoming an important technology to determine localization of drug compounds after dosing. IMS has become of interest in the ophthalmology field, but little work to this point has been done to investigate ocular drug transit using this technology. There are three possible local penetration routes that a drug can transit following topical administration which include the trans-vitreous route, the uvea-scleral route, and the periocular route. Information on where and how a drug is distributing through the eye is important to understand if a drug is reaching its target. For this study, ocular distribution of brimonidine was investigated in rabbits following topical instillation. Brimonidine has been shown to lower intraocular pressure and is approved to treat glaucoma, the second leading cause of blindness in the world. We have developed IMS methods to assess transit of topically administered brominidine from the anterior chamber to the posterior segment of rabbit eyes.

Methods

Rabbits were dosed topically in the right eye with 30 ul of a 3% (w/v) suspension of brimonidine. Animals were sacrificed at 15 min or 60 min. Both left and right eyes were collected and snap frozen in liquid nitrogen for storage at -80°C. Eyes were then embedded in carboxymethyl cellulose to facilitate sectioning. Twelve micron sections were cut, mounted on MALDI target plates, and coated with MALDI matrix using a TM-SprayerTM. Ion images were acquired on a 5800 AB Sciex MALDI TOF system. Co-registration of H&E images with brimonidine ion images was done to assess drug localization in specific anatomical structures including the cornea, iris, lens, vitreous humor, retina, and choroid.

Results

MALDI IMS methods were optimized for sensitivity of brimonidine in ocular tissue. Applying these methods, the transit of brimonidine through the eye after topical administration was monitored at various time points using MALDI IMS. Brimonidine signal was confirmed in the dosed tissue by examining the isotopic distribution in full scan mode and with MS/MS analysis (m/z 292-> 212). Brimonidine signal was not detected in the non-dosed contralateral eye. Imaging data showed that brimonidine (m/z 292) is located primarily in the front of the eye at 15 and 60 minutes post dose. Imaging data showed that brimonidine was detected in the cornea, aqueous chamber, iris, and reached the back of the eye. Notably, brimonidine levels were observed to increase in the iris from 15 min to 60 min indicating accumulation in pigmented structures. At these early time points, brimonidine is not distributed to a large degree in the back of the eye such as retina.

Conclusions

The MALDI imaging studies showed that brimonidine was detected in the cornea, aqueous chamber, iris, and reached the back of the eye. The distribution of brimonidine suggests that the route of transit following topical administration is mainly through the uveal route. This is consistent with other reports. This study demonstrates that IMS can be applied to monitor ocular transit and distribution of topically administered drug.


References & Acknowledgements:


Financial Disclosure

DescriptionY/NSource
Grantsno
SalaryyesNovartis Institutes for BioMedical Research
Board Memberno
Stockno
Expensesno

IP Royalty: no

Planning to mention or discuss specific products or technology of the company(ies) listed above:

no