Strategies for drug delivery to the central nervous system by systemic route

Figures & data

Table 1. Properties of a drug molecule to enter brain.

Properties	Explanation
Nature of the compound	Unionized
Basicity	As the cell membrane is negatively charged, basic molecules are preferred over acidic substances.
Lipophilicity	Lipid solubility has a direct effect on transport across BBB. Ideally, the molecule should possess a log p value (octanol:water partition coefficient) near to 2 (1.5–2.7)
Size	Molecular weight: <400–500 Da
Hydrogen bonding	For each pair of hydrogen bonds or polar functional groups added, the permeability of molecule across BBB decreases by one log unit. Cumulative number of hydrogen bonds: <8–10

Table 2. Various mechanisms involved in transportation of a molecule across blood–brain barrier.

Transport pathways	Mechanism	Features
Paracellular pathway	Presence of tight junctions prevent transport of water soluble substances	Ideal for molecules less than 20 nm in size
Transcellular diffusion	Transcytosis of lipophilic molecules of molecular weight less than 500 Da	Molecules move along concentration gradient, no energy required
Carrier-mediated transport	Takes place through facilitated diffusion or active transport	Modulates the entry of various endogenous substances such as glucose, aminoacids and purines
Adsorptive-mediated transcytosis	Based on electrostatic interaction between positively charged molecules to negatively charged cell membrane	Internalization of molecules into vesicles to reach the cell
Receptor-mediated transcytosis	(a) Endocytosis at the luminal side after receptor- ligand binding (b) Movement through the endothelial cytoplasm (c) Exocytosis of the drug or ligand attached drug at the abluminal side	The different receptors expressed on endothelial cells include insulin, insulin-like growth-factors, Tf, leptin, diphtheria toxin, dopaminergic GABAB, amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA), lipoprotein receptors, scavenger receptors class B type I and glutathione transporter
Efflux pumps	Rejects the entry of molecules	Pgp, OAT and MRP efflux pumps that expels drugs and xenobiotics.

Table 3. Advantages and limitations of various delivery systems for drug delivery to brain.

Type of delivery system	Advantages	Limitations
Focused ultrasound	Target specific	Self administration not possible. Practical application in humans is limited
Lipidization	Enhances permeability	Increases the volume of distribution
Inhibition of efflux transporters	Increases drug availability within brain	Entry of toxins
Carrier-mediated transport	Useful in delivering wide range of molecules	Requires complete understanding. Could be sometime non-specific
Peptidomimetics	Enhanced permeability	Cannot be applied for all the molecules
Nanoparticulate delivery	Target specific Useful in delivering wide range of molecules Reduces the therapeutic concentration of drugs	Distribution and rate elimination not understood completely. Role of protein corona not understood completely
Prodrug	Improved permeability	Not target specific. Cannot be applied for all the drug molecules