(656f) Dendrimer-Based Nanodevices for the Treatment of Neuroinflammation in Cerebral Palsy

Kannan, R. M., Wayne State University
Navath, R., Wayne State University
Dai, H., Wayne State University
Balakrishnan, B., Wayne State University
Romero, R., Wayne State University
Kannan, S., Wayne State University

Maternal intrauterine inflammation resulting in microglial activation has been implicated in the development of periventricular leukomalacia and cerebral palsy. N-acetyl cysteine (NAC) is a drug that is currently being explored for the treatment of neuroinflammation in neonatal and perinatal applications. However, plasma binding of NAC significantly reduces the bioavailability requiring very high doses (100-300 mg/kg in animal models). We have developed neutral PAMAM dendrimer-based nanodevices where a disulfide linker is used to link the drug to the dendrimer. This enables tailored intracellular release of the drug in a manner sensitive to the glutathione levels (low in blood circulation, high inside the cells). When this is combined with the ability of dendrimers to selectively localize in activated microglial cells, significant improvements in vivo performance is achieved. The nanodevices are evaluated extensively in a rabbit model of cerebral palsy. The biodistribution and efficacy of intravenously administered dendrimer-drug conjugates are compared with those of the free drug using a combination of tools. The biodistribution is studied using microPET imaging and tissue confocal microscopy. The efficacy is evaluated using a combination of neurobehavioral analysis, assessment of brain tissue level inflammatory cytokine analysis. Our studies show that dendrimer-drug conjugates are 10-100 times more efficacious that free drug, suggesting that these conjugates (~ 18000 Da) are able to cross the blood brain barrier and deliver the drug significantly better than free drug. The dramatic improvements in motor deficits of dendrimer-drug treated animals suggest that targeted and timely treatment of neuroinflammation can lead to significant improvements in therapeutic outcomes in this disease with no known cure. Detailed mechanistic and efficacy studies will be presented.

(1) ?Drug release mechanisms and kinetics from dendrimer-drug conjugates with glutathione sensitive linkers', Emre, YK, R. Navath, B. Wang, R. Romero, S. Kannan, RM Kannan*, Biomaterials, 30, 2112-2121 (2009) (2) ?Dendrimer-drug conjugates for tailored intracellular drug release based on glutathione levels', Navath, R; E. Turkoglu; B. Wang; S. Kannan;R. Romero; R.M. Kannan*, Bioconjugate Chemistry, 19, 2446-2455 (2008) (3) Intrinsic targeting of neuroinflammation by polyamidoamine dendrimers in a rabbit model of cerebral palsy' H.Dai, R.Navath, B.Balakrishnan, B.Raja Guru, M.Mishra, R.Romero, R.M.Kannan*, S.Kannan*, revised and submitted, Future Medicine:Nanomedicine, Apr. (2010) (4) Dendrimer-based therapeutic nanodevices for therapeutic and imaging applications, R. Kannan, S. Kannan, R.Romero, R. Navath, H. Dai, Y. Kurtoglu, B.Wang, A. Menjoge, Provisional patent filed # 61/187263, 5/09, and additional provisional patent filed, #61/319285, 3/10