Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 535

11.2.6.1 St�at��i�s to Enhan�� P/P D�﻽iv��y ���oss th� BBB
A study conducted by Jeffrey et al. investigated an integrated model for the assess-
ment of BBB. It emphasized the correct balance of permeability, a low potential for
active efflux, and the appropriate physicochemical properties that allow for drug par-
titioning and distribution into brain tissue [46] .
Several strategies for enhanced P/P drug delivery over the BBB have been deve-
loped and tested in preclinical and clinical experimental research. Alternative routes of
administration that target the brain use less invasive techniques such as nasal drug deliv-
ery, and more invasive drug delivery techniques including neurosurgery-based intra-
cerebroventricular/intracerebral/intrathecal infusion of drugs using catheters, pumps,
and reservoirs; manipulation of the BBB; efflux pumps and/or proteolytic enzymes;
enhancing BBB permeability by modulating the efficacy of the tight junctions between
the cerebral endothelial cells [47,48] ; direct delivery of gene, cell, and antisense thera-
pies; use of viral and nonviral vectors [49-53] ; technology-based approaches (compri-
sing functionalized nanocarriers and liposomes); pharmacological strategies (such as
the use of carrier systems and chimeric peptide technology); and peptide analogues
with increased plasma half-life and increased stability in brain extracellular fluid.
Similarly, the affinity of the peptide for the plasma membrane can be enhanced by
manipulating the molecular structure to enhance lipid solubility, for example, by attach-
ment of cholesterol at one end and a redox targetor at the other end of a peptide [54] ,
provided the central activity of the analogue is retained [55,56] . Several in vitro and in
vivo models, coupled with sensitive analytical techniques, are available to study drug
transport to the brain [55,57-62] .
A study has suggested that the permeability of peptides across the BBB may
be related to their hydrogen-bonding potential rather than their lipophilicity [63] .
Methylation can reduce the overall hydrogen-bonding potential of peptides.
Halogenation of P/P drugs can also enhance lipophilicity and BBB permeability.
Glycosylation of protein with various sugar moieties modulates hydrophilic-lipophilic
properties. The lipidization of molecules generally increases the volume of distribu-
tion, mainly due to the modification of plasma protein binding, which affects all other
pharmacokinetic parameters. In addition, increased lipophilicity increases the rate of
sequestration by cytochrome P450 and other enzymes, which should also be consid-
ered while making the modification.
Prodrug results from transient chemical modifications of biologically active spe-
cies and prodrugs for P/P drugs can be obtained by esterification or amidation of
hydroxyl-, amino-, or carboxylic acid containing P/P drugs. However, when the pro-
drug is developed by coupling the P/P drug to a lipid moiety, such as fatty acids,
glyceride, or phospholipids, the increased lipophilicity is paralleled by an undesir-
able increase of uptake into other tissues. The disadvantages are poor selectivity, poor
retention, and increased probability of the formation of reactive metabolites, often
contributing to the decreased therapeutic index of P/P drugs masked as prodrugs.
Bodor described another approach to target peptides to the CNS by using a chem-
ical delivery system. In this system, an enkephalin analogue was “packaged” with a
lipophilic function (cholesterol) at one end and a redox targetor linked via an amino