(607c) Sustained, Targeted Intraocular Delivery of Therapeutics for the Treatment of Age-Related Macular Degeneration

Authors: 
Kannan, R. M., Wayne State University
Raja Guru, B., Wayne State University
Iezzi, R., Mayo Clinic
Mishra, M. K., Johns Hopkins University School of Medicine


Neurodegenerative diseases such as retinitis pigmentosa and age related macular degeneration are due to degeneration of photoreceptor cells of retina. Though some of the neuroprotective drugs like fluocinolone acetonide (FA) are available for treatment, it is difficult to deliver therapeutic amount of drug to the outer retina for a sustained period. We have discovered that PAMAM dendrimers (generation 4) with neutral surface groups (-OH), are able to selectively localize in the cells associated with the neuroinflammation process, upon intravitreal delivery. Building on this, we have developed polyamidoamine (PAMAM) dendrimer based nanodevices for sustained delivery of neuroprotectants, such as fluocinolone acetonide. The drug release from the ester-bonded conjugates reveal that the release shows a nearly zero-order profile over a two month period. The in vivo evaluation in a RCS rat model of retinal degeneration was performed using electroretinography (ERG) measurements of the overall health of the retina, and at the tissue level using microglial and activated microglial, and outer nuclear cell counts. The dendrimer-based formulation was significantly more effective than the free drug, and a drug release implant. One injection of 0.1 microgram of the drug containing 0.7 microgram of the dendrimer was able to arrest retinal degeneration, and preserve cell counts for an entire month. The mechanism of dendrimer-based sustained intracellular delivery, results of in vivo efficacy of drug-dendrimer nanodevices, biodistribution of fluorescently-labeled dendrimers in RCS rats with the disease, and healthy rats will be presented.

Reference:

1. Dendrimer-containing particles for sustained release of compounds, R. Kannan, R. Iezzi, S. Kannan, US patent filed 10/5/07 (Application #60/997987)/International patent filed Oct 2008 (application #, PCT/US2008/078988). Regular patent filed in US, Canada, European Union, UK and India (Apr. 2010)