The Blood-brain Barrier: Principles for Targeting Peptides and Drugs to the Central Nervous System

Abstract

The presence of the blood-brain barrier (BBB), reduces the brain uptake of many drugs, peptides and other solutes from blood. Strategies for increasing the uptake of drugs and peptide-based drugs include; structural modifications to increase plasma half-life; improving passive penetration of the BBB by increasing the lipophilicity of the molecule; designing drugs which react with transporters present in the BBB; and reducing turnover and efflux from the central nervous system (CNS).

Glucose-targeted niosomes deliver vasoactive intestinal peptide (VIP) to the brain

“…VIP may have interesting applications in the treatment of various neurological disorders: a lipophilic VIP analogue was proposed as a therapy against Alzheimer's disease (Gozes et al, 1996). However, like most endogenous peptides, its potential therapeutic applications are limited by its failure to cross the blood-brain barrier (BBB) which strictly controls the access of solutes to the brain (Begley, 1996) and by its rapid elimination after intravenous administration. Its blood half-life is less than 1 min in rat (Hassan et al, 1994) and approximately 1 min in man (Domschke et al, 1978).…”

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

“…Some relatively lipophilic and low molecular weight substances can transport across the BMVEC by passive diffusion. However, a large number of lipophilic compounds are rapidly effluxed from the brain into the blood by extremely effective drug efflux systems expressed in the BBB [85][86][87][88]. These efflux systems include Pglycoprotein (Pgp), multi-drug resistance proteins (MRPs), breast cancer resistance protein (BCRP), and the multi-specific organic anion transporter (MOAT).…”

“…By first restricting and then selectively transporting circulating substances the BBB acts as a regulatory membrane, which largely defines the homeostatic and nutritive CNS environment. The BBB also has a role in brain and peripheral tissue communication by allowing some peptides and regulatory proteins into the CNS [85,[91][92][93][94]. The polypeptides, such as wheatgerm agglutinin, leptin, and insulin cross the BBB by adsorptive transcytosis [95,96].…”

Pharmacological Approaches to Antitrypanosomal Chemotherapy

“…This high level of control of access has clear implications for delivery of drugs to the brain. However, the BBB is not an inert barrier; there are special transport systems that enable access of amino acids, glucose and specific macromolecules into the brain (Begley 1996). In addition passive diffusion of low molecular weight lipophilic compounds, for example melarsoprol, is possible.…”

“…Two such examples for HIV infections of the brain include the design of lipophilic nucleoside derivatives (Ford et al 1995) and the conjugation of zidothymidine to a lipophilic carrier that crosses the BBB to become more hydrophilic and trapped in the brain (Brewster et al 1997). Peptides, for example somastatin analogues, have also been designed with enhanced permeability (see Begley 1996). There are many paradigms that could be included in the design of new drugs for HAT.…”