Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 536

acid spacer to the end terminal of the peptide, resulting in an improved biodistri-
bution pattern and BBB targeting [22,61] .
Liposomes, nanoparticles, nonionized cationic gel, delivery with molecular Trojan
horses, and avidin fusion proteins expressing lentivirus vectors are widely exploited
as colloidal drug carriers to increase BBB transport of P/P drugs [64-66] . These col-
loidal carriers are discussed in detail elsewhere in this chapter.
Inhibition of proteolytic enzymes and/or efflux transporters that impede P/P drug
delivery over the BBB is one of the prime strategies for increasing the therapeutic
effectiveness of drugs [62] . Some inhibitors and their targets are as follows:

l

First-generation inhibitors of efflux transporters and their targets like verapamil (Pgp,
MRP1) and nifedipine (Pgp)

l

Second-generation inhibitors and their targets like dexverapamil (Pgp) and valspodar (Pgp,
MRP1)

l

Third-generation inhibitors and targets like zosuquidar (Pgp), tariquidar (Pgp), and laniqui-
dar (Pgp).

Many strategies related to chemical modification by one or more enzymatic and/or
chemical transformations, such as those that target a moiety like a 1,4-dihydrotrigo-
nelline system for site-specific or site-enhanced delivery/brain targeting of the P/P
drug, have been carried out to explore the maximum therapeutic benefits of the P/P
drugs [61] .
One novel approach for the targeted delivery of P/P drugs for treating neuronal
degenerative diseases is based on receptor-mediated transcytosis as it can enable
larger molecules, such as P/P, to reach the brain. A number of transcytosis recep-
tors on the BBB have been suggested and exploited in the design of formulations,
including insulin and transferrin receptors, and the transporters for low-density lipo-
proteins and insulin-like growth factors. The transferring receptors have been shown
capable of transporting vasoactive intestinal peptide, brain-derived neurotrophic fac-
tors (BDNFs), basic fibroblast growth factors (FGFs), EGF, and peptide nucleic acids
[67] . These transcytosis routes have also been recently used by applying certain pepti-
domimetic monoclonal antibodies, suggesting their use as molecular Trojan horses to
transport various proteins and peptides [65,68] .
In contrast to nutrient transporter proteins, peptide receptors are able to selectively
bind their high-molecular-weight ligands, and effect BBB transport by receptor-
mediated endocytosis at the luminal capillary membrane and exocytosis into the brain
interstitium. The addition of nontransportable drugs to these peptides did not appre-
ciably affect their transcytosis through the brain endothelium. Thus, brain delivery
of nontransportable peptides was demonstrated by Pardridge et al. [69] in the devel-
opment of BBB transport vectors and the formation of chimeric peptide neuro-
pharmaceuticals. The chimeric peptide model involves synthetic coupling of the
nontransportable peptide (e.g., -endorphin) to a transportable vector such as cation-
ized albumin [70,71] . This can be achieved by using a disulfide linkage, which can
later be cleaved in the neuropil by brain disulfide reductases. The endogenous plasma
protein transferrin is also able to bind and undergo endothelial endocytosis in the brain
capillary, and the transferrin and insulin receptors have proven to be suitable vectors.