Stroke is the leading cause of disability and the fourth leading cause of death amongst adults in the United States. Plasminogen activator remains the only food and drug administration (FDA)-approved drug for stroke treatment. However this treatment has significant limitations in efficacy, safety, and the window of effectiveness. The lack of any effective restorative pharmacological approaches indicates the urgent need of stem cell-based therapies. A new class of autologous neural stem cells (NSCs) known as induced pluripotent stem cell derived NSCs (iNSCs) with abilities to differentiate into neurons, astrocytes and oligodendrocytes and to integrate into damaged brain tissue represents an exciting regenerative therapeutic population. However, these cells show significant variability in efficacy due to their survival issues under the cytotoxic environment after stroke with high levels of reactive oxygen species (ROS) and inflammatory cytokines. This suggests that pre-treatment of the damaged brain with anti-oxidant and anti-inflammatory agents appropriately delivered to the target tissue would significantly improve survival of transplants and ultimately tissue and functional outcomes. We recently developed a highly lipophilic biodegradable nanoparticle (NP) delivery platform with ability to cross the blood brain barrier (BBB) and deliver anti-oxidant insie the mitochondrial matrix rich in ROS and anti-inflammatory agent in the white matter of the brain where inflammation is diffused. With this success, we hypothesized that development of therapeutic options based on combined NP delivered neuroprotectant-stem cell therapy after stroke in a large animal model such as pig with brains similar to human can be extremely beneficial. To construct this NP platform and to demonstrate its potential, we have defined the following Specific Aims: (1) Construction and in vitro optimization of a BBB penetrating targeted biodegradable NP containing mitochondria acting anti-oxidant and anti-inflammatory agents; (2) Safety, toxicity, distribution in normal piglet and therapeutic efficacy in a pig middle cerebral artery occlusion (MCAO) ischemic injury model; (3) Combined therapeutic NP-stem cell therapy in a pig MCAO stroke model. This study will provide a potential nanomedicine platform for combined neuroprotectant-stem cell therapy after stroke. The targeted NPs are simple in composition and constructed from a well characterized biodegradable targeting moiety appended polymer which will be extremely beneficial for clinical translation.

Public Health Relevance

Stroke is a major public health problem due to the unavailability of medication; the magnitude of stroke can be reduced by effective prevention and treatment. Therapeutic evaluation of a blood brain barrier penetrating nanoparticle containing neuroprotectants followed by stem cell therapy using a pig model with brain similar to human has the potential to provide a combined nanomedicine-stem cell platform to improve outcome after stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS093314-05
Application #
9743236
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Bosetti, Francesca
Project Start
2015-09-30
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Georgia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Lau, Vivian W; Platt, Simon R; Grace, Harrison E et al. (2018) Human iNPC therapy leads to improvement in functional neurologic outcomes in a pig ischemic stroke model. Brain Behav 8:e00972
Jiang, Wen; Delahunty, Ian Michael; Xie, Jin (2018) Oxygenating the way for enhanced chemophototherapy. Theranostics 8:3870-3871
Zhang, Weizhong; Liu, Lin; Chen, Hongmin et al. (2018) Surface impact on nanoparticle-based magnetic resonance imaging contrast agents. Theranostics 8:2521-2548
Webb, Robin L; Kaiser, Erin E; Jurgielewicz, Brian J et al. (2018) Human Neural Stem Cell Extracellular Vesicles Improve Recovery in a Porcine Model of Ischemic Stroke. Stroke 49:1248-1256
Apsite, Indra; Stoychev, Georgi; Zhang, Weizhong et al. (2017) Porous Stimuli-Responsive Self-Folding Electrospun Mats for 4D Biofabrication. Biomacromolecules 18:3178-3184
Baker, Emily W; Platt, Simon R; Lau, Vivian W et al. (2017) Induced Pluripotent Stem Cell-Derived Neural Stem Cell Therapy Enhances Recovery in an Ischemic Stroke Pig Model. Sci Rep 7:10075
Webb, Robin L; Gallegos-Cárdenas, Amalia; Miller, Colette N et al. (2017) Pig Induced Pluripotent Stem Cell-Derived Neural Rosettes Parallel Human Differentiation Into Sensory Neural Subtypes. Cell Reprogram 19:88-94
Chen, Hongmin; Zhang, Weizhong; Zhu, Guizhi et al. (2017) Rethinking cancer nanotheranostics. Nat Rev Mater 2:
Wen, Ru; Banik, Bhabatosh; Pathak, Rakesh K et al. (2016) Nanotechnology inspired tools for mitochondrial dysfunction related diseases. Adv Drug Deliv Rev 99:52-69
Kalathil, Akil A; Kumar, Anil; Banik, Bhabatosh et al. (2016) New formulation of old aspirin for better delivery. Chem Commun (Camb) 52:140-3

Showing the most recent 10 out of 12 publications