(448b) Dendrimer-Based Nanotherapeutics for Targeted Post-Natal Therapy In Cerebral Palsy: Chemistry, Mechanism and In Vivo Efficacy | AIChE

(448b) Dendrimer-Based Nanotherapeutics for Targeted Post-Natal Therapy In Cerebral Palsy: Chemistry, Mechanism and In Vivo Efficacy


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

Neuroinflammation plays a key role in the pathogenesis of a wide range of neurodegenerative diseases such as cerebral palsy, autism, and Alzheimer’s.  Developing therapeutic approaches to treat inflammation in the central nervous system is a challenge, because: (1) inflammation and injury are often diffuse, precluding local delivery mechanisms (2) transport of nanoscale drug delivery vehicles, and even small drugs across the blood-brain-barrier is difficult to achieve (3) postnatal treatment of a prenatal injury to the brain is not expected to result in improvement in motor deficits. We hypothesized that a therapeutic strategy targeting activated microglia and astrocytes for sustained attenuation of ongoing neuroinflammation would improve outcomes in the post-natal period.

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). Our translational research effort is focused on the preparation, in vitro, and in vivo evaluation of PAMAM dendrimer-based nanodevices for the delivery of therapeutics in general, and NAC in particular.

We have shown that PAMAM dendrimers, without any targeting ligands, can target neuroinflammation even upon intravenous administration. These dendrimers localize in activated microglia and astrocytes only in animals with cerebral palsy, but not in age-matched controls.

The nanodevices were 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 efficacy is evaluated using a combination of neurobehavioral analysis, assessment of brain injury at the neuronal level, and at the DNA and RNA levels. Our studies show that dendrimer-drug conjugates are able to produce a dramatic improvement in motor deficits, in contrast to expectations that such improvements are not possible upon post-natal treatment.  The dendrimer nanodevices were significantly better than even 100-fold higher free drug treatments, suggesting that these conjugates (~ 18000 Da) are able to cross the blood brain barrier and deliver the drug significantly better than free drug. Detailed mechanistic and efficacy studies will be presented.