Currently, there are no curative or interdictive therapies available for Parkinson's disease (PD), and only palliative therapies such as replacement strategies for missing neurotransmitters exist. The main obstacle is the blood brain barrier (BBB) that severely limits the brain penetration of therapeutics, which can be successfully used for PD therapy. In particular, BBB is practically impermeable for polypeptides involved in anti-inflammatory neuroprotection. Nevertheless, there is a class of inflammatory response cells that have extraordinary ability to cross the BBB due to their increased margination and extravasation. A long-term objective of this proposal is to develop a targeted cell-mediated delivery of therapeutic polypeptides to the brain to attenuate neuroinflammation and produce neuroprotection in patients with PD. Specifically, we aimed to load mouse bone-marrow derived monocytes (BMM) ex vivo with an anti-inflammatory polypeptide, catalase, and administer these cells into the blood stream. To protect the enzyme against degradation inside the host cells, catalase will be coupled with a synthetic polyelectrolyte of opposite charge. The drug-loaded BMM will migrate across the BBB in vivo toward the inflammation signal and release the nanoparticles that attenuate inflammation. We hypothesize that 1) catalase-incorporated nanoparticles will be taken by BMM through the accelerated endocytosis;2) loaded BMM will migrate across the BBB toward the inflammation signal, and 3) the nanoparticles will be discharged by exocytosis from the carrier cells in the brain, where catalase will produce its neuroprotection effect. Incorporation of catalase into nanoparticles will preserve its activity inside BMM, while using cell-mediated delivery will reduce its immunogenecity and target the therapeutic polypeptide to the brain. To test this hypothesis, first, we will synthesize series of block copolymers to obtain catalase/polymer nanoparticles that protect enzymatic activity of catalase inside the cells, and optimize their composition with maximal loading efficiency and sustained release of the polypeptide from BMM. Second, we will characterize the biodistribution and therapeutic efficacy of catalase nanoparticles delivered by BMM in the PD in vivo model. It is anticipated that these studies will lead to the developing a new technology based on cell- mediated active delivery of therapeutic polypeptides that attenuate neuroinflammation and produce neuroprotection in patients with PD. Public Health Relevance: It is anticipated that these studies will lead to the developing a new technology based on cell-mediated active delivery of therapeutic polypeptides that attenuate neuroinflammation and produce neuroprotection in patients with PD.

Public Health Relevance

It is anticipated that these studies will lead to the developing a new technology based on cell-mediated active delivery of therapeutic polypeptides that attenuate neuroinflammation and produce neuroprotection in patients with PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS057748-05
Application #
8329677
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Sutherland, Margaret L
Project Start
2008-09-29
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$293,266
Indirect Cost
$100,328
Name
University of North Carolina Chapel Hill
Department
None
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Zhao, Yuling; Haney, Matthew J; Gupta, Richa et al. (2014) GDNF-transfected macrophages produce potent neuroprotective effects in Parkinson's disease mouse model. PLoS One 9:e106867
Klyachko, Natalia L; Haney, Matthew J; Zhao, Yuling et al. (2014) Macrophages offer a paradigm switch for CNS delivery of therapeutic proteins. Nanomedicine (Lond) 9:1403-22
Haney, Matthew J; Zhao, Yuling; Harrison, Emily B et al. (2013) Specific transfection of inflamed brain by macrophages: a new therapeutic strategy for neurodegenerative diseases. PLoS One 8:e61852
Klyachko, Natalia L; Manickam, Devika S; Brynskikh, Anna M et al. (2012) Cross-linked antioxidant nanozymes for improved delivery to CNS. Nanomedicine 8:119-29
Haney, Matthew J; Suresh, Poornima; Zhao, Yuling et al. (2012) Blood-borne macrophage-neural cell interactions hitchhike on endosome networks for cell-based nanozyme brain delivery. Nanomedicine (Lond) 7:815-33
Haney, Matthew J; Zhao, Yuling; Li, Shu et al. (2011) Cell-mediated transfer of catalase nanoparticles from macrophages to brain endothelial, glial and neuronal cells. Nanomedicine (Lond) 6:1215-30
Batrakova, Elena V; Gendelman, Howard E; Kabanov, Alexander V (2011) Cell-mediated drug delivery. Expert Opin Drug Deliv 8:415-33
Zhao, Yuling; Haney, Matthew J; Klyachko, Natalia L et al. (2011) Polyelectrolyte complex optimization for macrophage delivery of redox enzyme nanoparticles. Nanomedicine (Lond) 6:25-42
McMillan, JoEllyn; Batrakova, Elena; Gendelman, Howard E (2011) Cell delivery of therapeutic nanoparticles. Prog Mol Biol Transl Sci 104:563-601
Banks, W A; Gertler, A; Solomon, G et al. (2011) Principles of strategic drug delivery to the brain (SDDB): development of anorectic and orexigenic analogs of leptin. Physiol Behav 105:145-9

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