Abstract
Cell-based drug delivery systems have generated an increasing interest in recent years. We previously demonstrated that systemically administered macrophages deliver therapeutics to CNS, including glial cell line-derived neurotrophic factor (GDNF), and produce potent effects in Parkinson’s disease (PD) mouse models. Herein, we report fundamental changes in biodistribution and brain bioavailability of macrophage-based formulations upon different routes of administration: intravenous, intraperitoneal, or intrathecal injections. The brain accumulation of adoptively transferred macrophages was evaluated by various imaging methods in transgenic Parkin Q311(X)A mice and compared with those in healthy wild type littermates. Neuroinflammation manifested in PD mice warranted targeting macrophages to the brain for each route of administration. The maximum amount of cell-carriers in the brain, up to 8.1% ID/g, was recorded followed a single intrathecal injection. GDNF-transfected macrophages administered through intrathecal route provided significant increases of GDNF levels in different brain sub-regions, including midbrain, cerebellum, frontal cortex, and pons. No significant offsite toxicity of the cell-based formulations in mouse brain and peripheral organs was observed. Overall, intrathecal injection appeared to be the optimal administration route for genetically modified macrophages, which accomplished targeted gene delivery, and significant expression of reporter and therapeutic genes in the brain.
Highlights
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder in people over 65 years old, and one of the leading sources of disability affecting one million people in the US1
We posit that the chronic inflammation in the brain at pathological conditions provides an opportunity for site-specific delivery using inflammatory response cells as vehicles for different potent therapeutics, including genes, proteins and low molecular compounds
We have developed cell-based drug delivery systems, in which immune cells are non-virally transfected, ex vivo, with pDNA encoding therapeutic proteins, and systemically administered into mice with induced brain neurodegeneration, where they migrate to the sites of inflammation resulting in sustained expression of these therapeutics and prolonged neuroprotective e ffects[44,47]
Summary
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder in people over 65 years old, and one of the leading sources of disability affecting one million people in the US1. It is well documented that under pathological conditions, the rate of transport of immunocytes to the inflamed brain tissues is further e levated[14,15,16,19,20,21,22] These cells have shown a remarkable capability to cross an intact BBB with 80% turnover in 3 months[23,24]. Drug delivery systems based on living cells can act as “Trojan horses” carrying concealed drug cargoes across impermeable barriers, such as the BBB or blood-tumor barrier, to the disease sites. These features make immunocytes attractive candidates for the CNS drug delivery. The neuroinflammation developed in the course of disease serves as a cue for recruitment of immune cells from periphery to the brain, providing the necessary spatial, temporal, and dosage control at targeted tissues
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