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Collaborations with practicing ophthalmologists have been crucial to nanotechnology discoveries pertaining to eye diseases, and in which drug can be delivered to the eye.
Take-home message: Collaborations with practicing ophthalmologists have been crucial to nanotechnology discoveries pertaining to eye diseases, and in which drug can be delivered to the eye.
Listen as Laura Ensign, PhD, discusses some of the cutting-edge nanomedicine taking place with regard to the eye during the 2014 meeting of Current Concepts in Ophthalmology at the Wilmer Eye Institute, Johns Hopkins University School of Medicine.
By Stephanie Skernivitz; Reviewed by Laura Ensign, PhD
Baltimore-Nanotechnology is proving a powerful resource for the current and future treatment of eye diseases-including ocular neovascularization (NV), age-related macular degeneration (AMD), glaucoma, and corneal grafts.
And these are just several eye-related conditions being impacted by the intricacies of the science of manipulating small matter.
Laura Ensign, PhD, of Johns Hopkins University School of Medicine, Baltimore, presented some of the research in regard to nanomedicine for the eye. Dr. Ensign is affiliated with the Center for Nanomedicine at Johns Hopkins University, directed by Justin Hanes, PhD. Research conducted in the Center for Nanomedicine has led to the launch several companies and generated more than $75 million in grants to date.
Dr. Ensign outlined several relevant and current nanotechnology projects related to the eye under way at the center.
The first project involved AMD. In collaboration with Peter Campochiaro, MD, and Jie Fu, PhD, Wilmer Eye Institute, Johns Hopkins University School of Medicine, the center is using polymerized anthracycline particles loaded with HIF-1 inhibitor for ocular NV.
“Everyone is familiar with the VEGF antibodies typically used for AMD,” Dr. Ensign said. “Here we are using HIF-1 inhibition, which actually leads to down-regulation of many key proangiogenic factors.”
These factors include VEGF, PDGF-BB, and SDF-1.
According to Dr. Ensign, their formulations achieve high loading (up to 23.6%) of the HIF-1 inhibitors. She also noted a significant polyethylene glycol (PEG) coating on the surface of these particles.
“This is important in that it actually attenuates inflammatory responses when injecting particles into the eye,” Dr. Ensign explained. “These particles provide sustained release, which is really the advantage of using nanomedicine for eye indications because we are getting drug release over weeks to even months. So you can get much longer duration of therapy with one treatment.”
As she pointed out, the HIF-1 inhibitor polymer nanoparticles suppress and actually cause regression of NV in the eye.
Next: More neovascularization and AMD
In a study example of 2 different mouse models, one model was a humanized VEGF-expressing transgenic mouse. At 4 and 5 weeks, they observed suppression of retinal NV and, importantly, in contrast, Lucentis (Genentech) only lasted for 2 weeks in this mouse model.
In another mouse laser-induced model, they observed regression of choroidal neovascularization (CNV) with the HIF-1 inhibitor polymer nanoparticle. Dr. Hanes launched Graybug LLC in 2011 to develop the technology based on these findings.
She relayed a second example of work involving NV and AMD, led by Rangaramanujam Kannan, PhD, co-director of the Center for Nanomedicine. Dr. Kannan works with dendrimers-a different type of nanoparticle.
These very small particles-roughly 5 nm in size-have “interesting properties,” according to Dr. Ensign. In collaboration with Gerard Lutty, MD, Wilmer Eye Institute, they’ve found that systemic dendrimer therapy caused CNV regression.
“From systemic circulation, they are able to accumulate in activated microglia,” Dr. Ensign said. “This is very advantageous because you can administer systemically and they’ll accumulate in inflamed cells in the eye.”
The researchers have been administering two drugs. One is N-acetylcysteine, which has advantages for dry AMD symptoms, and triamcinolone, which has anti-neovascular properties for wet AMD symptoms.
In a rat model, there was suppression of the CNV and regression.
In yet another project, Dr. Ensign addresses mucus-penetrating particle (MPP) technology, another type of nanoparticle.
In this technology, the particle surfaces are protected so they penetrate the mucus barriers that are coating epithelial surfaces. Similar work has been conducted in the GI tract and vagina.
“Recently, we began translating that work to the surface of the eye, a mucosal surface,” she added.
With conventional nanoparticles, Dr. Ensign explained that most polymers are hydrophobic, so they stick to the mucus in the tear film or on the epithelial surface.
Next: Corneal NV/sustained drug release
“What we do to make the mucus penetrating is we put a hydrophilic coating on top of these nanoparticles so that their surface does not interact with the mucins that are in the tear film,” said Dr. Ensign. “The drug that is contained within these particles is able to rapidly penetrate and be absorbed by the epithelium. With that, the improved penetration should give you improved drug delivery to the surface of the eye.”
With the results of this work, Dr. Hanes also launched Kala Pharmaceuticals in 2009. Kala is evaluating loteprednol MPPs, which have this coating so the drug can penetrate through the tear film and into the corneal surface.
“Compared to standard eye drops at the same drug concentration, you see much higher corneal drug levels over time,” said Dr. Ensign. “This LE-MPP system is being tested in about five clinical trials for various indications.”
The next project-in collaboration with Walter Stark, MD, Peter J. McDonnell, MD, and Qingguo Xu, PhD, all of the Wilmer Eye Institute-involves corneal NV and corneal transplant rejection. Particles are loaded with a steroid and provide sustained steroid release over a week. These particles are injected subconjuctivally where they continuously release the drug.
In a rat model, the cornea was transplanted from 1 species of rat to another. With the saline treatment, the team observed NV and graft rejection within 2 weeks in all rats. With the placebo nanoparticle (a nanoparticle without drug), they observed complete rejection within 2 weeks. With the free drugs, which is a steroid injected into the subconjunctival space, they saw complete rejection within 4 weeks.
“With the drug-loaded nanoparticles, we saw 100% survival for greater than 9 weeks with a weekly injection,” Dr. Ensign explained. “At this point, we have particles that can release the steroid for a month, so we are initiating studies for monthly injection. This can be very advantageous for immediately after surgery, getting a subconjunctival injection and not having to use steroid eye drops for a month.”
Next: Glaucoma and microparticles
The final project is involves the treatment of glaucoma with microparticles, where a kinase inhibitor is loaded into microparticles that provide release for greater than 2 months in infinite sink conditions. This work is in collaboration with Donald Zack, MD, PhD; Harry Quigley, MD; Derek Welsbie, MD, PhD; and Dr. Fu, all of the Wilmer Eye Institute.
“The reason we highlight infinite sink conditions is we found that releasing the drug in vitro in infinite sink conditions lasts for much longer when you inject it into the eye,” Dr. Ensign said. “We expect that the drug release would last for much longer than 2 months in the eye. One month after laser-induced elevated IOP, you can see that with the drug-loaded microparticles, you get increased retinal ganglion cell survival and increased axon counts.”
In summary, Dr. Ensign said the center is actively working on discoveries pertaining to eye diseases, and about anything in which drug can be delivered to the eye. For this work, collaborations with practicing ophthalmologists have been crucial, she added.
Laura Ensign, PhD
This article was adapted from Dr. Ensign’s presentation at the 2014 meeting of Wilmer Eye Institute’s Current Concepts in Ophthalmology. Dr. Ensign did not indicate any proprietary interest in the subject matter.