An intracellular, sustained-release drug delivery system offers a new way to treat chronic, progressive retinal degeneration. In a study conducted by researchers at Mayo Clinic in Rochester, Minn., Kresge Eye Institute and the Wilmer Eye Institute at Johns Hopkins, corticosteroids attached to dendrimers were delivered to the retina to target only inflammation-causing microglial cells, leaving the rest of the eye unaffected and preserving vision.
Since the discovery of dendrimers, many studies have examined the role of their unique nanoscale architecture on the delivery of therapeutics and imaging agents. For this study, researchers used hydroxyl-terminated polyamidoamine (PAMAM) dendrimer-drug conjugate nanodevices to explore targeted drug therapy for the attenuation of neuroinflammation in the retina. The type of PAMAM dendrimers used in this study is noncytotoxic and is cleared intact through the urine.
Results showed that on intravitreal administration, PAMAM dendrimers selectively localized within activated outer retinal microglia in two rat models of retinal degeneration, but not in the retina of healthy control subjects. This pathology-dependent biodistribution was exploited for drug delivery by covalently conjugating fluocinolone acetonide (FA) to the dendrimer. The conjugates released the drug in a sustained manner over 90 days.
"Once intracellular enzymes release the steroid medication from the nanoparticle, inflammation is shut down, leaving remaining steroid medications on the particle. When the anti-inflammatory steroid effects wear off, the enzyme systems wake up and cleave off more anti-inflammatory medication from the dendrimer. It's like a sustained-release device inside the cell," says Raymond Iezzi Jr, M.D., with the Department of Ophthalmology at Mayo Clinic in Minnesota and lead author of the study, which was published in Biomaterials in 2012.
The conjugates provided significant neuroprotection, preserving photoreceptor health and outer nuclear layer thickness and attenuating neuroinflammation, over an entire month. The researchers chose FA because it has been previously shown to slow photoreceptor cell loss and dampen retinal neuroinflammation. "The use of FA may also enable eventual comparisons between dendrimer-based delivery and commercial, nonerodible intravitreal implants for the same drug," says Dr. Iezzi.
Iezzi R Jr., et al. Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration. Biomaterials. 2012;33:979.
View video of Dr. Iezzi discussing his research on YouTube.