Chapter V: Overall Summary and Conclusions
1.3 Current Methods of Drug Delivery to the CNS
The vast majority of drugs currently used to treat neurological diseases are small and lipophilic, reaching the CNS through PTD. This includes benzodiazepines, many anti- psychotics and anti-depressants, and the AD treatments in Fig 1.2. Not coincidentally, most diseases that can be treated with these drugs, such as depression, anxiety, and psychosis, have significantly better prognoses than diseases where small, lipophilic drugs are unavailable.
Invasive methods that physically bypass the BBB have been investigated for several decades to treat CNS diseases that are poorly treated systemically. Three similar techniques that involve direct introduction of drug to the parenchyma have been developed with varying, but overall limited, degrees of success: (i) intracerebral implantation (ICI), (ii) intracerebroventricular infusion (ICV), and (iii) convection enhanced diffusion (CED) (13).
Two other methods, hyperosmotic shrinkage (HOS) and focused ultrasound (FUS), involve transient disruption of BBB tight junctions to allow circulating drugs to enter the CNS (14).
ICI involves direct implantation of drugs into the CNS parenchyma. It was first crudely applied in patients with gliomas, where a chemotherapeutic-soaked sponge was placed in the resulting cavity after sub-total tumor resection. This technique was further refined to incorporate external cannulas allowing multiple chemotherapy doses to be introduced directly into the glioma site or implantation of drug-loaded, biodegradable devices (15). ICV introduces drugs directly into the ventricular system to take advantage of cerebrospinal fluid (CSF) circulation to deliver drug to a large brain area while avoiding
uptake into systemic circulation. This method has been applied in a variety of conditions, including AD (16) and chronic pain (17).
Clinically, these two techniques have shown limited to no improvement over systemic treatments. The main reason for this failure is the poor drug diffusion from the site of introduction. Solute diffusion in the brain decreases by the square of the distance from its origin, leading to logarithmic decay in drug concentration. In practical applications, the concentration of small molecule drugs introduced by ICV to Rhesus monkeys was found to decrease by 98% only 1-2mm from the ependymal surface (contact point between the CNS parenchyma and CSF) (13). The extremely limited diffusional capacity of drugs introduced by these methods and their failure to significantly improve outcomes for focal diseases like primary neoplasm bodes poorly for their application in diffuse conditions such as AD where neurons throughout the brain are affected.
CED attempts to improve upon the diffusional limitations of ICI and ICV through use of an infusion pump. This produces a small positive pressure gradient to drive bulk flow of drug into the CNS parenchyma, leading to delivery of therapeutic concentrations over a much larger volume than previously possible. Two CED treatments have reached Phase III clinical trials for glioblastoma multiforme (GBM) but failed to show statistically significant survival benefit as monotherapy compared to conventional therapy, though there is some evidence they may have a role in combination therapies. Research is ongoing with CED devices to improve biocompatibility and technical reproducibility as well as deliver novel therapeutics (18).
An alternative method to physically bypass the BBB is to temporarily disrupt the tight junctions between endothelial cells, allowing for transient permeability to systemic drug molecules. This is done commonly in the clinical through arterial injection of a hyperosmotic solution, such as mannitol. The high salt concentration in the blood causes BBB endothelial cells to shrink and stretch the tight junctions (19,20). Expansion of the tight junctions creates space in between cells for circulating drug molecules to cross and enter the CNS. HOS suffers, however, from difficult administration and significant side effects, including seizures and hypotension (14). These problems are likely due to the widespread, nonspecific nature of BBB disruption in HOS, allowing toxic substances to enter the brain.
Similar to the development of CED in response to ICI and ICV’s shortcomings, FUS was investigated as a method to safely disrupt the BBB. In FUS, microbubbles are administered systemically, followed by focal application of ultrasound waves. The microbubbles oscillate within the ultrasound field allowing them to interact with endothelial cells. At the BBB, the exact mechanism that leads to BBB disruption is unclear. Current understanding is that the microbubbles either physically stretch the endothelium similar to HOS or trigger a physiologic response that temporarily increases permeability. Regardless of the true biological cascade leading to BBB disruption, FUS has garnered considerable attention due to the abilities to both control the magnitude of disruption and spatially locate disruption by controlled application of the ultrasound. It is also reproducible, capable of delivering a wide variety of therapeutic agents, and has not shown significant side effects in animal models (14). Concerns persist regarding the long-term safety of FUS and its efficacy in humans. The technique has very recently begun investigation in a pilot clinical trial to deliver doxorubicin to GBM patients (21). Of particular concern is whether this method will cause similar neurological side effects as HOS by non-specifically regulating what crosses the BBB.
One final aspect affecting small molecule drug delivery to the CNS—either systemically or by invasively bypassing the BBB—is the presence of efflux pumps on the basal side of BBB endothelial cells. Similar to the influx SCP’s on the apical cell membrane, specific efflux transporters exists to clear neurotoxins from the CNS. There are numerous different ATP Binding-Cassette (ABC) transporters expressed for this purpose, including P- glycoprotein, Multidrug Resistance-associated Proteins, and Breast Cancer Resistance Protein (10). These proteins can actively transport a diverse array of molecules out of the CNS, including a large number of prescribed medications. In fact, many drugs that showed promise in vitro have failed either in animal models or during clinical trials because they are cleared from the CNS by ABC transporters (22). Novel therapeutics that not only diffuse through significant portions of the brain but can also avoid rapid efflux by ABC proteins are needed to improve on these current paradigms.