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Peptide drug delivery into the central nervous system

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Progress in Drug Research

Part of the book series: Progress in Drug Research ((PDR,volume 51))

Summary

The microvasculature of the central nervous system (CNS) is characterized by tight junctions between the endothelial cells and, thus, behaves as a continuous lipid bilayer that prevents the passage of polar and lipid-insoluble substances such as peptides. Highly active enzymes expressed in the morphological compontents of the microcirculation also represent a metabolic component that contributes to the homeostatic balance of the CNS. Peptides generally cannot enter the brain and spinal cord from the circulating blood because they are highly polar and lipid insoluble, metabolically unstable, and active transport systems only exist for very few of them in this membraneous barrier separating the systemic circulation from the interstitital fluid of the CNS. This blood-brain barrier is, therefore, the major obstacle to peptide-based drugs that are potentially useful for combating diseases affecting the brain and spinal cord. This review discusses and critically evaluates invasive, chemical-enzymatic (prodrug and chemical delivery/targeting system) and biological carrier-based approaches to overcome the blood-brain barrier for these highly active and versatile molecules that are very attractive as a future generation of neuropharmaceuticals.

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Abbreviations

BBB:

blood-brain barrier

CDS:

chemical delivery system

CNS:

central nervous system

CSF:

cerebrospinal fluid

CVO:

circumventricular organ

DPDPE:

[D-Pen2, D-Pen5]enkephalin

EC:

enzyme commission

GLUT:

glucose transporter

i.c.v.:

intracerebroventricular

IGF:

insulin-like growth factor

IgG:

immunoglobulin

i.t.:

intratechal

i.v.:

intravenous

Lpf:

lipophilic functional group

MAb:

monoclonal antibody

NGF:

nerve-growth factor

NAD+ :

nicotinamide adenine dinucleotide (phosphate)

NAD(P)H:

nicotinamide adenine dinucleotide (phosphate), reduced form

OX26 (TfRMAb):

murine monoclonal antibody toothe rat transferrin receptor

Pgp:

P-glycoprotein

RMP:

receptor-mediated permeabilizer

S:

spacer amino acid residue(s)

T:

redox targetor

T+ :

redox targetor, oxidized

TRH:

thryrotropin-releasing hormone

VIPa:

vasoactive intestinal peptide analogue

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  1. Center for Drug Discovery, College of Pharmacy, University of Florida, J. Hillis Miller Health Center, Gainesville, FL, 32610-0497, USA

    Laszlo Prokai

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  1. Steinweg 28, CH-4107, Ettingen, Switzerland

    Ernst Jucker

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Prokai, L. (1998). Peptide drug delivery into the central nervous system. In: Jucker, E. (eds) Progress in Drug Research. Progress in Drug Research, vol 51. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8845-5_3

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