Novel chemotherapy delivery options rely on either direct injection to the brain or bypassing the blood-brain barrier through chemical or physical changes made to it.

We discuss intracerebroventricular injection of substances in the main article. The problem with using CSF to deliver medication is the high drop of concentration. The further from the place of contact with CSF, as CSF is dominantly around the surface of the brain.[1]

Possibly a better approach is to provide medicaments through blood, somehow passing the BBB. We discuss some ways to achieve this.

Disruption of the BBB

There are several ways to disrupt the tight junctions between endothelial cells that block osmosis in the cerebral capilaries. This causes leakiness around the BBB which helps deliver treatment but also allows entry of foreign bodies into and out of the brain.[1][3]

• MRI-guided focused ultrasound - ultrasound has been shown to be capable of BBB disruption. A focused US burst disrupts the endothelial cells and create gaps in the tight junctions. [2]

• Osmotic disruption - an osmotic shock causes endothelial cells to shrink, thereby disrupting the tight junctions. 

There are severe limitations to applicability of these approaches, as there is the risk of pathogens from blood infecting the brain. This may cause permanent damage to neurons or cause possible swelling of the brain.[1]

Chemical optimization of the drug

Another way to allow a drug to pass to the brain is to optimize its chemical composition to make it more permissible through the barrier. This approach is based on observation which structures make some particles able to passively penetrate the BBB, like alcohol and nicotine.[1][3]

• Lipid carriers - bind the active molecules to a lipidous structure
• Using small molecules → better penetrability
• Binding to alcohol-, nicotine- or benzodiazepine -derivatives (among others)
  
  

The limitation in this approach is the fact that changes to the molecular structure often change the properties of the original agent and may completely negate therapeutical effects. Also there are possible toxic effects of the carrier itself

Physiological approaches

Physiological approaches use the fact that the brain requires certain nutrients and hormones to function, for example glucose, insulin and growth hormones.

These substances are recognized by specific receptors in the BBB resulting in active specific transport into the brain.

Drugs are bound to "nutrients" and they are actively supplied to a cell requiring the given nutrient. Uses the brain's support glia for transporting nutrients to cells.[1]

• Transporter-mediated delivery - e.g. Peptide Masking

• Transferrin receptor (TR) 
• Liposomes coated with targeting molecules such as antibodies or Trojan Horses Liposomes (THL)
• Nanoparticles coated with transferrin or transferrin receptor antibodies
• Low-density lipoprotein receptor related proteins 1 and 2 (LRP-1 and 2)

Bibliography

1) Reinhard Gabathuler (2009) Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases, Neurobiology of Disease

2) Manabu Kinoshita et al. (2006) Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood–brain barrier disruption 

3) Benjamin K. Hendricks, BS, Aaron A. Cohen-Gadol, MD, MSc, and James C. Miller., (2015), Novel delivery methods bypassing the blood-brain and blood-tumor barriers