NEI grant supports multicenter research of transscleral drug delivery

Researchers in four locations are collaborating under a $7 million NEI grant to develop and analyze novel posterior segment drug delivery devices.

NEW YORK – Now that the pharmaceutical industry has developed effective anti-angiogenic drugs to treat posterior segment eye diseases, the focus is turning to improving ways to deliver those drugs to the back of the eye.

At the OSN New York Symposium, Henry F. Edelhauser, PhD, outlined a number of sustained-release drug delivery devices and techniques that are currently under investigation with the support of a nearly $7 million multicenter grant from the National Eye Institute (NEI).

“Up until now, it has not been of interest, but now that we have these therapeutic agents, the drug delivery modality becomes an important avenue for getting the drugs to the posterior tissues of the eye,” Dr. Edelhauser told Ocular Surgery News in an interview. “Obviously, there has to be a better way to deliver these therapeutic agents.”

A multicenter initiative

Henry F. Edelhauser

The NEI grant will provide about $7 million over the course of 5 years, according to Dr. Edelhauser, director of ophthalmic research at the Emory Eye Center.

According to a press release from Emory, the grant is only the third of its kind to be awarded by the NEI.

Dr. Edelhauser said the grant will support a multidisciplinary approach with research at Emory University, the University of Nebraska, the University of Pennsylvania and the Georgia Institute of Technology.

“They all have a separate expertise. We are pulling together a number of different devices, and we also need a good tissue analysis too,” Dr. Edelhauser said. “This is something we could not solely do alone at Emory, so that is why we have all of these groups.”

Dr. Edelhauser said research began on Aug. 1. Surgeons can expect to see new drug delivery systems in the market within 5 years, he noted.

“Many pharmaceutical companies are developing various drug delivery techniques too, but this money is funded by the NEI, so the information we gather will be shared to get it out into the public domain,” Dr. Edelhauser said. “That is the advantage of this type of grant because the techniques we develop will be able to be used by a number of investigators.”

The transscleral route

Dr. Edelhauser said he and colleagues are applying their previous research on corneal physiology to the physiology of the sclera to enhance drug delivery mechanisms for the back of the eye.

“If you go back in literature, you find that Anders Bill, MD, published a paper in 1965 showing that the sclera is quite permeable to a large molecule like albumin,” Dr. Edelhauser said at the symposium. “He found that if you put albumin in the suprachoroidal space, 85% of it would diffuse back out across the sclera.”

More recently, Dr. Edelhauser said, researchers have found that scleral permeability is similar to corneal permeability without an epithelium.

“When you look at the whole eye, there is 17 cm² of sclera that we could use as a possible route for drug delivery to get a therapeutic agent to the back part of the eye,” he said, adding that the thickness of the sclera, from the limbus to the optic nerve, is 0.4 mm to 0.5 mm.

Basic studies have shown that human sclera mounted in a chamber can be analyzed to determine what size molecules can diffuse across the tissue, Dr. Edelhauser said.

“Studies have shown us that both small and large molecules can diffuse across the sclera,” he said. “This opened a door for us to say there could possibly be a transscleral route.”

Current delivery methods

Current drug delivery methods include eye drops, systemic injections, oral administration and orbital injection, but Dr. Edelhauser said novel transscleral delivery devices could reduce possible systemic side effects from systemic drugs and deliver the necessary drugs more directly to the posterior segment of the eye.

“There are a lot of new methods we are starting to look at,” he said.

Some of these methods will include the use of nanoparticles, microneedles, collagen gels or iontophoresis, Dr. Edelhauser said.

The drugs that will be used in conjunction with these novel devices include triamcinolone acetonide, methotrexate, dexamethasone, ciliary neurotrophic factor, tauroursodeoxycholic acid and cDNA, according to the Emory Eye Center.

Nanoparticles and microneedles

Size of experimental microneedle array is shown by its placement on the researcher’s finger. There are 400 needles in the array. Image used with permission from Leary S, Georgia Tech Communications Division

One delivery system uses a biodegradable collagen infused with nanoparticles of drugs, Dr. Edelhauser said.

“Nanoparticles with drugs give you a sustained release, and you could have various sustained-release particles in the collagen to deliver drugs over a long period of time,” he said.

A more recent development at Georgia Tech is the use of microneedles, Dr. Edelhauser said.

“These are tiny microneedles with biodegradable tips. They are pushed through the conjunctiva and into the sclera,” he said. “When you wiggle them a bit, the tips break off, and you can get sustained release from the drug in the biodegradable tips.”

Researchers in Nebraska are developing microparticles and nanoparticles in different sizes to investigate injections into the subconjunctival space, Dr. Edelhauser said.

“These particles will biodegrade and will be able to deliver the drug through the sclera,” he said.

Fibrin sealant delivery

Another development under investigation is the use of fibrin sealant in a subconjunctival injection to create a sustained release of drugs.

“It is biodegradable, and we are looking at adding a drug to this fibrin sealant and injecting it sub-Tenon’s space to serve as a sustained-release device,” Dr. Edelhauser said.

Another alternative being developed would use a copolymer surfactant, which is liquid at refrigerated temperatures and gel at body temperatures, injected subconjunctivally, Dr. Edelhauser said.

“The gel can be put on the surface of the sclera and could enhance diffusion across the sclera, but also, the drug will diffuse laterally within the sclera,” he said.

Chemotherapeutic agents

Dr. Edelhauser said retinoblastoma could be one of the diseases that would most benefit from a sustained-release drug delivery device.

Treatment of retinoblastoma is often limited by the difficulty of delivering adequate concentrations of chemotherapy to the back of the eye, Dr. Edelhauser said.

“We could add carboplatin to fibrin sealant and then inject it subconjunctivally to stay there for 2 to 3 weeks,” Dr. Edelhauser said. “We did this experimentally and divided the eye and found that the carboplatin does enable the drug to diffuse into the vitreous.”

Rather than injecting chemotherapeutic agents systemically, Dr. Edelhauser said, this could provide an alternative that would localize treatment and reduce the number of injections for young children with the disease.

“These are just some of the new techniques and devices that are coming along to see if we can provide alternatives to injecting directly into the vitreous once a month, thus the transscleral approach to deliver drugs may provide a sustained drug delivery mechanism for future use,” Dr. Edelhauser said.

For more information:

• Henry F. Edelhauser, PhD, can be reached at 1365 B Clifton Road, Atlanta, GA 30322; 404-778-5853; fax: 404-778-4143; e-mail: ophthfe@emory.edu.
• Daniele Cruz is an OSN Staff Writer who covers all aspects of ophthalmology.