Drug delivery system for active brain targeting - Artificial Cells, Cell Engineering and Therapy - page 408

17.2.3 Biological strategies
Biological-based brain drug delivery strategies source from an understanding of
the anatomy and physiology of the normal BBB endogenous transport process.
This process may be classified as carrier-mediated transport, receptor-mediated
transcytosis, adsorptive-mediated transcytosis and active efflux transporters.
These brain-targeted chemical delivery systems represent a general and
systematic method that can provide localized and sustained release for a variety
of therapeutic agents including neuropeptides. These vectors can be peptides,
modified proteins or monoclonal antibodies (Fig. 17.3). By using a sequential
metabolism approach, they exploit the specific trafficking properties of the BBB
and provide site-specific or site-enhanced delivery.
Carrier-mediated transport
There are some polar small molecule drugs that have a molecular structure
mimicking nutrient that normally undergoes carrier-mediated transport through
the BBB. Carrier-mediated systems include the large neutral amino acid
transporter (LAT)-1: this transporter mediates the brain uptake of various drugs
such as 1-DOPA, melphalan and baclofen. Carrier-mediated transport may be
considered by drug development focusing on structural requirements that enable
BBB transport via a carrier-mediated system.
Receptor-mediated transcytosis
The uptake of drugs by the brain can be improved by conjugation to an
endogenous compound, which uses receptor-mediated transcytosis. Examples of
endogenous receptor-mediated transcytosis include the BBB insulin receptor or
the BBB transferring receptor. For example, transferrin receptors are abundant
on the vascular endothelium of brain capillaries, and these receptors are
internalized by the endothelial cells in a process designed to deliver iron to the
brain. This allows the BBB to be bypassed using transferrin or transferrin-
receptor antibodies as carriers of proteins such as antibodies and neuropeptides.
A highly studied receptor-mediated transport vector is the OX26, a mouse
monoclonal antibody to transferrin receptor; conjugation of this transport vector
being facilitated with avidin/biodin technology.
Adsorptive-mediated transcytosis
A promising approach consisted of incorporating daunomycin in OX26
immuno-liposomes, thus greatly increasing the transport capacity of OX26.
Cationized proteins such as cationized albumin and immunoglobin G move
across the BBB by adsorption-mediated transcytosis that becomes saturated at
higher concentrations than receptor-mediated transcytosis. Doxorubicin coupled