This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long-term objective of this proposal is to develop delivery system of free-radical scavengers, RedOx enzymes, to the brain to attenuate neuroinflammation and increase neuroprotection in patients with ischemic stroke. Initial treatment for stroke involves removing the blockage and restoring blood flow. When acute phase is over, the treatment focused on restoration of brain function and cell survival. At this stage, delivery of RedOx enzymes to the brain to decrease inflammation is of great importance. However, the blood brain barrier (BBB) severely limits the delivery of therapeutic polypeptides to the brain and is a major obstacle to the successful treatment of many devastating central nervous system (CNS) diseases. To improve the therapeutic polypeptide transport to the brain, preserve enzyme activity, and reduce immunogenecity, the therapeutic RedOx enzymes will be cross-linked with a synthetic polyelectrolyte of opposite charge to form a stable polyion complex micelle, """"""""nanozyme"""""""". We hypothesize that 1) enzyme incorporated nanocontainers will be stable at physiological conditions, 2) will enhance permeability of the enzyme across the in vitro BBB, 3) will increase circulation time and/or permeability across the BBB in vivo, and 4) will improve biological activity in in vitro brain hypoxia and in vivo stroke models.
Specific Aims are 1) to assemble RedOx nanozymes (SOD, catalase) and tailor the composition for increased stability, circulation time and/or permeability across the BBB, 2) to determine permeability and transport mechanisms of the nanozymes synthesized in SA1 across the brain microvascular endothelial cells (BMVEC) in vitro and in vivo, 3) to determine whether the most promising nanozymes selected in SA2 can attenuate neuroinflammation and provide neuroprotection in an in vitro brain hypoxia and in vivo stroke models. It is anticipated that these studies will provide a novel platform for the delivery of therapeutic proteins across the BBB for regenerative therapy.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR021937-04
Application #
8360237
Study Section
Special Emphasis Panel (ZRR1-RI-2 (01))
Project Start
2011-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$223,081
Indirect Cost
Name
University of Nebraska Medical Center
Department
Other Basic Sciences
Type
Schools of Pharmacy
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Karuturi, Bala V K; Tallapaka, Shailendra B; Yeapuri, Pravin et al. (2017) Encapsulation of an EP67-Conjugated CTL Peptide Vaccine in Nanoscale Biodegradable Particles Increases the Efficacy of Respiratory Immunization and Affects the Magnitude and Memory Subsets of Vaccine-Generated Mucosal and Systemic CD8+ T Cells in a Diamet Mol Pharm 14:1469-1481
Mahajan, Vivek; Gaymalov, Zagit; Alakhova, Daria et al. (2016) Data on macrophage mediated muscle transfection upon delivery of naked plasmid DNA with block copolymers. Data Brief 7:1269-82
Kim, Myung Soo; Haney, Matthew J; Zhao, Yuling et al. (2016) Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine 12:655-664
Karuturi, Bala Vamsi K; Tallapaka, Shailendra B; Phillips, Joy A et al. (2015) Preliminary evidence that the novel host-derived immunostimulant EP67 can act as a mucosal adjuvant. Clin Immunol 161:251-9
Wakaskar, Rajesh R; Bathena, Sai Praneeth R; Tallapaka, Shailendra B et al. (2015) Peripherally cross-linking the shell of core-shell polymer micelles decreases premature release of physically loaded combretastatin A4 in whole blood and increases its mean residence time and subsequent potency against primary murine breast tumors after I Pharm Res 32:1028-44
Golovin, Yuri I; Gribanovsky, Sergey L; Golovin, Dmitry Y et al. (2015) Towards nanomedicines of the future: Remote magneto-mechanical actuation of nanomedicines by alternating magnetic fields. J Control Release 219:43-60
Sharma, Bhawna; Nannuru, Kalyan C; Varney, Michelle L et al. (2015) Host Cxcr2-dependent regulation of mammary tumor growth and metastasis. Clin Exp Metastasis 32:65-72
Macha, M A; Rachagani, S; Pai, P et al. (2015) MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. Oncogene 34:1698-708
Zhu, Yu; Li, Jing; Kanvinde, Shrey et al. (2015) Self-immolative polycations as gene delivery vectors and prodrugs targeting polyamine metabolism in cancer. Mol Pharm 12:332-41
Haney, Matthew J; Klyachko, Natalia L; Zhao, Yuling et al. (2015) Exosomes as drug delivery vehicles for Parkinson's disease therapy. J Control Release 207:18-30

Showing the most recent 10 out of 76 publications