Table 1-1.

Invasive and non-invasive strategies for delivery to the CNS

Strategies	Description and examples	References
Invasive strategies
Intracerebroventricular injection	Intracerebral infusion or implant localized to a small area in the brain, e.g. tumor site, particular failing neuron. Clinical data reported with GDNF, CTNF neurotropic factors.	[85]-88]
Intra-arterial administration and transient disruption of the BBB	Intra-arterial administration increases drugs' systemic concentration by eliminating first-pass metabolism. Hyperosmolar sugar solutions (20% mannitol) or immune adjuvants (Freund's) administration in carotid artery or application of ultrasound: shrinkage of endothelial cells, thereby causing transient opening of the tight junction (~20 min).	[86;87]
Intraventricular/Intracerebral implants	Direct injection into the CSF; Subcutaneous implant in the scalp connected to the ventricles by a catheter (Convection enhanced drug delivery (CED). Intracerebral polymeric implants for local delivery.	[88-90]
Focused Ultra sound (FUS)	Utilizes microbubbles to create an acoustic cavity and a pressure shock wave that temporarily punctures the endothelial wall to cause a transient influx of otherwise impermeable drugs. Biotherapeutics like Rituximab, an anti-CD20 mAb, have been delivered across BBB using this methodology.	[2], [91]-[92]
Non- invasive strategies
Altering the chemistry	Increasing the lipophilicity of molecules (e.g. pro-drug approach), coupling nucleic acids to cell penetrating peptides, `molecular trojan-horse' approach are some of the techniques explored to improve BBB penetration.	[76], [10]
Intranasal Delivery	Likely that intranasally delivered therapeutics reach the CNS via the olfactory region or trigeminal pathway, bypassing the BBB. E.g. evidence of delivery of insulin or nerve growth factor (NGF) via intranasal drug delivery.	[93;94]
Colloidal drug carriers	Liposomes (e.g. NGF or immunoliposomes), emulsion (e.g. nanoemulsions), solid-lipid nanoparticles (e.g. thiamine-coated nanoparticles) and polymeric nanoparticles (e.g. nerve growth factor using poly(butyl cyanoacrylate) nanoparticles) for delivery to the brain.	[95]
Co-administration with inhibitors of efflux	Combination of anticancer drugs with specific P-gp inhibitors, like valspodar, zosuquidar, etc. lead to stronger P-gp inhibition and hence, better CNS penetration.	[87]