NEW INNOVATIONS TO DELIVER BETTER DRUGS TO OCULAR STRUCTURES

Untethered microbots, nanospheres and thermoresponsive hydrogels are among the many new innovation approaches being evaluated to better deliver drugs to ocular structures. Speaking in a mini symposium during the 2012 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), Ashim Mitra PhD, School of Pharmacy, University of Missouri, Kansas City, described increasing ocular tissue bioavailability of topically applied drugs via various chemical modifications, including creating prodrugs that target influx transporters present in the cornea and using a lipid linker to enhance cellular uptake.

“Rather than using potentially cytotoxic permeation enhancers to increase transport of impermeable drugs through the cornea, the prodrug approach takes advantage of the cells own machinery. We have shown these compounds are not cytotoxic, and in animal models, acyclovir prodrugs have demonstrated excellent activity against epithelial and stromal HSV-1 keratitis,†Dr Mitra said.

Dr Mitra and colleagues are also working to develop thermo-sensitive gel technology using novel pentablock polymers to improve the residence time of drugs both in front of and inside the eye. He described development of a dual phase polymeric delivery system comprised of a continuous biocompatible gel phase and a discontinuous nanoparticle phase that has been successful in avoiding the burst release phenomenon that has been a limitation of other nanoparticle formulations for ocular drug delivery. Jennifer Kang-Mieler PhD, Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, also discussed thermoresponsive hydrogels as a platform for ocular drug delivery. She pointed out that an advantage of this technology is that it allows for intraocular drug delivery through small gauge needles.

She described how her laboratory has synthesised thermo-responsive hydrogels as both degradable and nondegradable systems and encapsulating various ocular pharmacological agents. She also noted this platform can be developed to deliver drug at a single release rate, or when combined with nanoparticles or microspheres, at various and multilevel rates. So far, data from in vitro and in vivo biocompatibility studies indicate the synthesised thermo-responsive hydrogels are safe for injection in the eye. Dr Kang- Mieler also described results from an animal study demonstrating efficacy and safety of a nanosphere-thermo-responsive hydrogel complex encapsulating dexamethasone sodium phosphate for suppressing laserinduced choroidal neovascularisation (CNV). “We believe our thermo-responsive hydrogel has benefits as a potential drug delivery system, and we hope it will be used for various ocular pharmacological agents in the future,†she said.

Speaking at the same symposium, Peter Humphries PhD, Department of Genetics, Trinity College, Dublin, Ireland, discussed improving drug delivery to neuronal ocular tissues via barrier modulation. Explaining the rationale, he noted that about 98 per cent of systemically administered low molecular weight (LMW) anti-neovascular and neuroprotective compounds with therapeutic potential for retinal diseases do not cross an intact inner blood-retina barrier or do so with limited efficiency.

The strategy developed by Dr Humphries and colleagues enables permeability of LMW compounds (up to 1 kD) by selectively downregulating tight junctions of the inner retinal vasculature. He reviewed experiments that have been done with the development of a platform based on transient RNAimediated suppression of transcripts encoding claudin-5, which is a component of the tight junctions. In this approach, a doxycyclineinducible gene encoding claudin-5 shRNA is delivered using an adeno-associated viral vector that efficiently transduces the endothelial cells of the inner retinal vasculature. The gene is switched on in tandem with the systemically administered drug.

“So far we have shown this is a remarkably efficient way to get LMW compounds from the peripheral circulation into the eye while excluding larger, noxious molecules. In addition, all evidence from studies conducted so far indicate this is a potentially safe process for clinical use,†Dr Humphries said. Early animal experiments demonstrated efficacy in protecting against light-induced retinal degeneration, suppressing laserinduced CNV, and preventing retinal degeneration in animal models of retinitis pigmentosa. Future research aims to apply the technology to treatment of early stage AMD to prevent progression to neovascular disease using LMW compounds directed at novel molecular targets.

Justin Hanes PhD, Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University, Baltimore, focused on using nanoparticles as a platform for providing local drug delivery and timed, continuous release. He explained that each nanoparticle can be packed with hundreds of thousands of LMW drug molecules, and he discussed his group’s development of a biodegradable polymer drug conjugate technology for treating ocular neovascularisation based on an investigational, potent inhibitor of hypoxia inducible factor-1a (HIF-1a).

Results from in vivo testing generated positive safety data and showed efficacy of the HIF-1a polymer nanoparticles in models of laser-induced CNV, oxygen-induced ischemic retinopathy, and neovascular AMD. In the latter experiment, which was done in a well-accepted transgenic mouse model of ocular NV, the duration of action of the HIF- 1a polymer particle treatment was at least 2.5 times longer than that of ranibizumab.

“These are exciting results with our firstgeneration system, and we believe a system based on larger microparticles might extend the duration of action significantly. In addition, unlike anti-VEGF agents, treatment with the single-agent HIF-1a inhibitor downregulates VEGF, PDGF, their receptors and other pro-angiogenic molecules, leading to regression of CNV,†Dr Hanes said. He added that the nanotechnology platform has applicability to other drugs and is being investigated in a variety of projects, including cornea graft rejection studies and for neuroprotection of retinal ganglion cells and photoreceptors.

An engineering-driven approach

Bradley Nelson PhD, Institute of Robotics and Intelligent Systems, ETH-Zurich, Switzerland, reviewed the work his group has been doing developing microrobots for retinal drug delivery and surgical applications. Wireless control of these untethered microdevices is achieved using electromagnetic fields. So far, evaluations in in vitro and in vivo experiments show the systems provide force feedback and can be navigated with micron precision. Based on initial experience, it is expected the microrobots can be introduced into the vitreous through a sutureless site and manoeuvred without the need for vitrectomy.

As a strategy for retinal drug delivery, the group is currently focusing on using the steerable microrobots to precisely place drugloaded implants at the site of pathology. “Using the microrobot to overcome diffusion limits would dramatically decrease the amount of drug that needs to be released,†Dr Nelson explained. In addition to drug delivery, other possible applications for the technology include removing epiretinal membranes, repairing retinal tears, and hypoxia monitoring at the vitreoretinal interface.