Inflammatory Cells for Transport of Therapeutic Polypeptides Across the BBB

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): 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.