(557f) Dendrimer-Based Sustained Release Ocular Nanotherapeutics

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.1 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 reveals 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 efficacy was more than 50 times better than a controlled release implant. The mechanism of dendrimer-based sustained intracellular delivery, and the detailed in vivo and in vitro results will be presented.

To enable sustained delivery for 6 months from a single intravitreal injection, we encapsulated these nanodevices in to a microparticle made up of FDA approved biomaterial which can release drug-dendrimer nanodevice for longer period. In vitro release profile of the nanodevices from the microparticles at different pH conditions have been found out and the stability of the drug-dendrimer nanodevices inside the microparticles have been analyzed. We will present results of in vivo efficacy of drug-dendrimer nanodevices, biodistribution of fluorescently-labeled dendrimers in diseased rats and healthy rats, in vitro release profile of drug from dendrimer nanodevice and in vitro release profile of drug-dendrimer nanodevice from the microparticle.

(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).