One of the major challenges in the treatment of neuropathological conditions is getting the drug molecule to cross the blood-brain barrier. The second challenge is getting the drug to work only on the tissue/cells that are affected. With the advent of targeted drug delivery systems, much attention has been given on the subject of specifically targeting neurons. Though targeting neurons is essential, it is now becoming clear that therapeutic targeting of the non-neuronal glial cells (neuroglia) in the brain might also have important clinical benefits. Neuroglia encompass the non-neuronal cells in the brain, and have been shown to play major pathophysiological roles in almost all neurological disorders. In an article published in February 2017, Madhusudanan et al. review the current literature in “Neuroglia as targets for drug delivery systems: A review”. Nanomedicine. 2017 Feb;13(2):667-679.
Glial cells were thought to hold the nervous system together, forming the matrix that protects and facilitates the functioning of neurons. The word ‘glia’ means ‘glue’ in Greek and thereby came the name ‘neuroglia’. It was much later that different cell types were identified within the neural parenchyma. Considering their close proximity to neurons, neuroglia are now understood to be closely intertwined with the functioning of neurons, and consequently involved in the majority of neurological disorders. Neuroglia include astrocytes, oligodendrocytes, microglia, NG2-glia, and ependymal cells in the central nervous system, as well as Schwann cells and satellite glial cells in the peripheral nervous system.
Astrocytes are some of the most studied neuroglial cells, and they outnumber neurons 10 to 1. They are important for neurotransmitter reuptake and recycling, and play a critical role in mediating neuronal homeostasis. Astrocytes also communicate with the blood-brain barrier, releasing various vasoactive mediators to regulate cerebrovascular flow. They have been implicated in amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, stroke and cerebrovascular disease, as well as in epilepsy, neuropathic pain and migraine.
Microglia are resident macrophages that form the first line of defense in the brain. They play critical immunomodulatory roles in the CNS, and are responsible for clearing damaged cells and for active communication between neurons and surrounding glia. Activated microglia are implicated in Alzheimer’s disease, Parkinson’s disease, schizophrenia as well as in neuroinflammation.
Oligodendrocytes are specialized cells important for neuronal myelination and production of trophic factors important for neuronal function. They are implicated in multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease. NG-2 cells, precursor cells for oligodendrocytes, also share a close relationship with neurons. They carry Na+, K+ and Ca+ channels, in addition to GABA and glutamate receptors. However, they have not yet been fully characterized and only a few studies have been carried out for targeting them.
In the peripheral nervous system, the Schwann cells perform similar roles as the CNS-resident oligodendrocytes. They form the myelin sheath and provide trophic support to the peripheral axons. They have been implicated in the onset and development of peripheral nerve inflammatory diseases, polyneuropathies and neuropathic pain conditions.
Satellite glial cells wrap sensory neurons present within the dorsal root ganglion and become activated upon injury. They have been implicated in severe pain conditions. However, their physiological roles are yet to be completely elucidated.
Numerous drug delivery systems have been studied extensively to deliver different drugs targeting specific affected areas in case of neurological disorders. Drug delivery systems to the brain present multiple challenges. Such systems first need to cross the blood-brain barrier. Strategies involving modulation of vascular permeability, increasing endothelial fenestration and inducing selective uptake by brain endothelial cells have been used. The second challenge is selectively delivering the drug in appropriate concentrations and in a controlled manner to the affected tissue or cells. This is key to avoid adverse effects, while enhancing drug effectiveness. Common strategies in this area involve encapsulating the drug of interest in slowly degrading polymeric matrices and nanoparticles and attaching them to specific proteins that will specifically bind to certain cells. It is also key that the drug delivery systems themselves are not toxic to the cells. Several systems have been shown to be taken up by neuroglia and some can affect the survival or functional capabilities of the neuroglia. It is also known that microglia sequester nanoparticles and prevent them from reaching their target sites. To understand the true benefits of drug delivery systems, it is therefore essential to perform extensive in vivo studies in addition to starting with primary in vitro studies. Polymeric systems, nanoparticles and liposomes have been, and continue to be, investigated in vitro and in vivo as potential therapeutic options for delivering proteins, drugs and even siRNA.
Polymeric systems consisting of polymeric matrices in the form of microparticles and nanoparticles allow for both encapsulating the drug as also for their slow release. Biodegradable matrices that can specifically target non-neuronal cell types such as astrocytes may offer a targeted therapeutic option for neurological disorders in which astrocytes have been implicated. Polymers such as polylactic-co-glycolic acid (PLGA), poly(epsilon-caprolactone) (PCL) and poly(L-lactic acid) or PLLA have received regulatory approval for use in humans, and are being studied specifically for targeting astrocytes. PLGA nanoparticles coated with transferrin protein or bovine serum albumin are shown to be non-toxic to astrocytes. PCL and PLGA microspheres can diminish astrocytic response in acute traumatic brain injury. Drugs such as tacrolimus FK506, paclitaxel and resveratrol flavopiridol have been attempted to be delivered to astrocytes in this manner. Nimodipine, along with PCL and polyethylene glycol (PEG), has been delivered to microglial cells to delay ischemic neurological disorders. PEG and PCL polymersome nanoparticles with an NGF-derived peptide have been used to target neurotrophin receptors on Schwann cells and may be a potential therapeutic option for schwannoma, which causes deafness. Such biodegradable polymers are likely to have fewer long-term adverse effects. However, data is still preliminary in this area.
Drugs can be bound to metallic nanoparticles such as zinc oxide, silver, gold or titanium nanoparticles for creating effective drug delivery systems. Zinc oxide nanoparticles have been documented to be taken up by astrocytes. They, however, cause oxidative stress and dose-dependent toxicity. On the other hand, silver nanoparticles are better tolerated by astrocytes. Titanium dioxide nanoparticles activate microglia to become pro-inflammatory; silver, silicon dioxide or iron oxide nanoparticles have been reported to cause oxidative stress and induce microglia to secrete elevated pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 that play a vital role in inflammatory conditions leading to neurological disorders. However, the benefits of targeting microglia with iron oxide nanoparticles have been reported in imaging techniques for detection by MRI, especially in case of glioma. Likewise, they also accumulate in Schwann cells and can be effectively used for in vivo labeling and detected via MRI. Iron oxide nanoparticles conjugated to three neurotrophic factors – β nerve growth factor (β NGF), glial-cell derived factor (GDNF) and basic fibroblast growth factor (FGF-2) — have also been reported to promote peripheral nerve regeneration as well as myelination. Thus, metallic nanoparticles have another beneficial role in imaging, even though there are toxicity concerns associated with using them as drug delivery systems.
Liposomes are another category of drug delivery systems that have been used widely in attempts to deliver therapeutic agents to non-neuronal cells. They have been used to downregulate certain key functional pathways within astrocytes. Liposomes made ofdioleoylphosphatidylethanolamine/cholesteryl hemisuccinate (DOPE/CHEMS) have been used to deliver antisense oligonucleotides against sodium-myo-inositol co-transporter, which is upregulated in bipolar diseases. Liposomes containing sulfocerebroside, a lipid derived from the myelin sheath, have also shown promise for treating demyelinating disorders, and those made of phosphatidylserine and phosphatidylcholine have been reported to significantly decrease production of amyloid β and IFN-γ-induced pro-inflammatory cytokines and free radicals in microglial cultures, with potential to treat Alzheimer’s disease. Inhibiting colony stimulating factor-1 receptor, a surface protein found on microglia, has been reported to reduce microglial activation in an animal model of Alzheimer’s disease.
Although promising in in vitro experiments, a major challenge for neuroglia-targeted therapy has been crossing the blood-brain barrier in vivo, and several of the above drug delivery systems have not been successful in in vivo studies and several strategies may need to be combined for effectively targeting cells within the central nervous system. However, in vitro studies show the proof of concept that neuroglia can be specifically targeted, and once targeted, may be used as an effective treatment option for many neurological disorders that cause inflammation and oxidative stress to the local milieu.