Maternal inflammation-induced perinatal brain injury has been implicated in neurodevelopmental disorders such as cerebral palsy (CP) and autism spectrum disorders. CP is a chronic childhood disability with no effective cure, resulting in significant personal, social and economic burden. Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP. Targeting these cells may enable sustained therapies till adulthood. Our preliminary studies suggest that intravenous administration of a hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimer (~4 nm) results in its selective accumulation in activated microglia and astrocytes in the brain of newborn rabbits with neuroinflammation and CP, but not in age-matched healthy controls. More importantly, a single 10 mg/kg drug dose in the form of dendrimer-N-acetyl cysteine conjugate (D-NAC) intravenously administered on the day of birth (3 days after injury) to rabbit kits with CP, resultd in a significant improvement in motor function and myelination, attenuation of activated microglia, and decrease in neuronal injury by 5 days. Building on these promising findings, our long-term goal is to develop targeted nanotherapeutic approaches for the sustained, post-natal treatment of CP, where improvements persist till adulthood (~1 month in the rabbit model). We propose using a cocktail of dendrimer-NAC and dendrimer-minocycline (D-NAC+D-Mino) for a multipronged approach to attenuate the injury. Our overall hypothesis is that the combination therapy will provide targeted intracellular release of NAC (fast release) and minocycline (sustained release).
The first aim relates to the preparation and characterization of (D-NAC+D-Mino) conjugates, while the second aim focuses on the toxicity, pharmacokinetics and biodistribution of NAC and minocycline delivered through the conjugate, in the brain, plasma, and other major organs.
Aim 3 will focus on the longitudinal evaluation of the sustained efficacy achieved through this postnatal, combination therapy up to 30 day (when development of major neurologic functions has occurred in rabbits). This study is significant, because it explores applications of nanotechnology for the first time to a debilitating childhood disease, building on positive preliminary results/ This proposal is responsive to the formulations RFA since it directly relates to areas of nanotechnology in pediatrics, delivery to target tissues/cells, sustained delivery, combination therapy, and reducing side effects.
The proposed research is relevant to public health because it explores the use of nanotechnology-based combination therapy approaches for sustained postnatal treatment of neuroinflammation in cerebral palsy. The research project utilizes selective localization of dendrimers in cells associated with neuroinflammation in animal models of CP. Designing targeted therapy using this knowledge will benefit a large number of affected children, a typically overlooked population when it comes to novel developments.
|Lei, Jun; Rosenzweig, Jason M; Mishra, Manoj K et al. (2017) Maternal dendrimer-based therapy for inflammation-induced preterm birth and perinatal brain injury. Sci Rep 7:6106|
|Zhang, Fan; Trent Magruder, J; Lin, Yi-An et al. (2017) Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model. J Control Release 249:173-182|
|Sharma, Rishi; Kim, Soo-Young; Sharma, Anjali et al. (2017) Activated Microglia Targeting Dendrimer-Minocycline Conjugate as Therapeutics for Neuroinflammation. Bioconjug Chem 28:2874-2886|
|Zhang, Fan; Nance, Elizabeth; Zhang, Zhi et al. (2016) Surface functionality affects the biodistribution and microglia-targeting of intra-amniotically delivered dendrimers. J Control Release 237:61-70|
|Nance, Elizabeth; Zhang, Fan; Mishra, Manoj K et al. (2016) Nanoscale effects in dendrimer-mediated targeting of neuroinflammation. Biomaterials 101:96-107|