Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 534

resistance across the endothelium. Hence, in spite of their potential, many existing
P/P drugs are rendered ineffective in the treatment of various clinical problems due to
the inability to effectively deliver and sustain them within the brain, mainly attributed
to their size (threshold of 400-500 Da) and hydrophilicity [35,36] . Except for insulin,
transferrin, neurotrophic peptides, neurotrophins and xytokines, all other classes of
proteins and peptides such as opioid peptides, hypothalamic-releasing and -inhibiting
hormones, neuropeptide-Y (NPY) and related peptides, the Vasoactive Intestinal
Peptide(VIP)-Glucagon family, ingestive peptides, and other neuropeptides present
a BBB impermeable nature after peripheral administration [35-41] . Intense research
over the last 25 years has produced a better understanding of the cellular and molec-
ular transport mechanisms across the BBB, and several strategies for enhanced P/P
drug delivery over the BBB have been developed and tested in preclinical and clini-
cal experimental research [35] .
Also, P/P drugs crossing the cell membrane are exposed to various cytosolic and
membrane-associated enzymes, such as -glutamyl transpeptidase, alkaline phospha-
tase, aromatic acid decarboxylase, dipeptidyl (amino) peptidase IV, and aminopeptidase
A and N, directed at metabolizing neuroactive blood-borne solutes [42-44] . Certain
P/P drugs may cross the BBB via free diffusion and undergo influx from the blood to
the brain compartment. However, this influx can be immediately followed by active
efflux from the brain back to the blood if the P/P drug is a substrate for one of many
different efflux systems including P-glycoprotein (Pgp) and the multidrug-resistant
protein family (MRP) localized within the brain microvasculature, as shown in
Fig. 11.1 [35,42] . Some more rate-limiting aspects to the BBB delivery of P/P drugs
are the concentration gradient, amino acid composition, lipid solubility/hydrogen
bonding, charge, aggregation, three-dimensional structure, conformation, flexibility,
folding, affinity for efflux proteins, affinity for receptors or carriers, and cellular enzy-
matic stability. The probability of cellular sequestration and the clearance rate of P/P
drugs in the brain are additional issues to be considered in drug targeting.
Proposed P/P drugs for various neurodegenerative diseases.

l

Alzheimer's disease —memantine, PACAP, ADNF-14, ADNF-9, and the neuropeptide
NAP [45]

l

Huntington's disease —neurotrophic factors such as NGF, GDNF, BDNF, NT-3, and NT-
4/5, as well as with other P/P drugs like VIP, ADNF, and EPO

l

Parkinson's disease —neurotrophic factors, particularly GDNF, BDNF, IGF, and NT-4/5,
tachykinins, mammalian tachykinins-like substance P (SP), neurokinin (NK) A, and NKB

l

Amyotrophic lateral sclerosis —P/P drugs like IGF-1, GDNF, or BDNF, which protect and
slow the disease progression, ciliary neurotrophic factor (CNTF), and vascular endothelial
growth factor (VEGF)

Several circulating peptides like LHRH, insulin, epidermal growth factor (EGF),
and TNF- are representative examples of P/P that can cross the BBB via specific
transporters and/or receptors with either long-term perfusion or intravenous injection
(saturable mechanisms). Examples of P/P that have been shown to cross the BBB with
long-term perfusion or intravenous, largely by nonsaturable mechanisms, are TRH, del-
tasleep-inducing peptide (DSIP), and leucine enkephalin (paracellular diffusion) [35] .