Genetically modified macrophages accomplish targeted gene delivery to the inflamed brain in transgenic Parkin Q311X(A) mice: importance of administration routes

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.

Biodistribution of Biomimetic Drug Carriers, Mononuclear Cells, and Extracellular Vesicles, in Nonhuman Primates

“…As seen in the figure, the amount of 64 Cu-PBMCs retained in monkeys' brains depended on route of administration: IP < IV < IT. Thus, similar to the mouse models, [20] the highest accumulation of the cells was recorded in animal brain after IT injection (Figure 1C). Using IV (Figure 1B) and IP (Figure 1A) routes resulted in substantially lower cell-carriers accumulation in the brain, and higher accumulation in peripheral organs, liver, and kidney.…”

“…This study was designed to determine the suitability of these natural carriers, monocytes, and EVs released by monocytes for drug delivery to the brain in NHPs. We previously demonstrated in mouse models of neurodegenerative disorders that EVs [13,15,17,19] and living cells [7][8][9][10][11][12]20,22] can reach brain tissues in substantial amounts and deliver therapeutic doses of drugs. However, development of therapeutic interventions, especially for neurodegenerative disorders in humans, requires NHP models.…”

“…Thus, autologous macrophages were shown to improve pharmacokinetics and protect drugs against degradation and rapid clearance in mouse models of neurodegeneration. [7,8,[10][11][12]20] Next, the standardized uptake values SUV mean and SUV max in the main organs for 64 Cu-PBMCs were assessed at 24 h and 48 h post injection using three routes of administration (Figure 2). SUV was calculated as decay-volume per injected radiotracer activity per body mass ((kBq mL −1 )/(kBq g −1 )).…”

“…Moreover, immunocytes, in particular, monocytes/ macrophages and EVs released by these cells selectively accumulate in therapeutically relevant numbers in regions of inflammation and neurodegeneration and can deliver therapeutics to inflamed brain. [8,13,15] We reported earlier [7,[9][10][11][12]20,22] multiple lines of evidence for therapeutic efficacy of cell-based drug delivery systems, including significant neuroprotection, decreased brain inflammation, and improved locomotor functions in mouse models of Parkinson's disease (PD). Furthermore, our previous investigations demonstrated a remarkable ability of macrophage derived EVs to communicate with recipient cells [23][24][25] in inflamed mouse brain tissues via the lymphocyte function associated antigen-1 (LFA1)/intercellular Discovery of novel drug delivery systems to the brain remains a key task for successful treatment of neurodegenerative disorders.…”

A novel method for producing functionalized vesicles that efficiently deliver oligonucleotides in vitro in cancer cells and in vivo in mice

“…6A). Because of their small physical size, IP administration to mice was easier and more reliable than intravenous (IV) administration [90][91][92][93][94]. Also, vesicles administered by IP injection distribute broadly to the organs and the visceral adipose tissue because of the lymphatic system [90][91][92][93][94], which was preferred for testing our modified vesicles.…”