Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 532

Besides size, charge also plays a key role in the pharmacokinetics of proteins,
as proven by the renal disposition profiles for BSA versus cationized BSA (cBSA).
Hence, another improvement in chemical alteration of proteins includes their conjuga-
tion with charged polymers such as anionic carboxymethyl-dextran (CM-dex) or cat-
ionic diethylaminoethyl-dextran (DEAE-dex) to introduce or modify electrical charges
on the protein-polymer conjugate. Proteins with altered charge, such as cBSA, can
also be synthesized directly. Furthermore, proteins can still be amended with galac-
tose (Gal) and mannose (Man) to confer an affinity for receptor-mediated endocytosis
in cells [30,31] .
In one study, it was observed that SOD, which is generally reabsorbed in the renal
tubules after glomerular filtration, showed significantly reduced urinary excretion
compared to native SOD, after chemically modifying it to prepare SOD-PEG and
SOD-CM-dex conjugates that have higher molecular size and altered charge. However,
the other conjugates, Gal-SOD and Man-SOD, showed decreased tubular reabsorp-
tion and thus enhanced the exposure of the luminal surface to SOD [31] . Sialylation
prolongs the effect of P/P drugs. Sialylation/desialylation of many P/P drugs, such as
adeponectin, insulin, apolipoprotein, rEPO, and rGM-CSF, have shown altered phar-
macokinetic parameters like hepatic uptake/metabolism, distribution, and clearance
[33] . Aconitylated and succinylated IFN-2b may be useful antiproliferative agents for
cancer treatment [34] . The targeting of proteins to a particular organ showing specific
receptors has also been explored by chemically modifying the proteins. The presence
of scavenger receptors for polyanionic macromolecules in the liver sinusoidal cells has
been beneficially utilized for targeting protein drugs to the liver nonparenchymal cells
by direct succinylation to form the Suc-SOD (34 kDa) protein. This modification has
shown clinical significance for the treatment of hepatic diseases mediated by reactive
oxygen species [31] . Several attempts using protein engineering have been made to
investigate chimeric peptides as a tool to enhance the pharmacokinetic profile of thera-
peutic P/P. Chimeric peptide is discussed in Section 11.6.5, and PEGylated proteins,
with their remarkable role in enhancing PK/PD of P/P drugs, are discussed in detail in
Section 11.6.1.
The studies mentioned earlier concluded that the in vivo disposition features of
proteins can be extensively changed by chemically modifying them favorably.
11.2.6 P/P Drug Delivery Across the Blood-Brain Barrier
P/P drugs have been identified as showing great promise for treating various neurode-
generative diseases, ischemia, inflammatory CNS diseases, Alzheimer's disease (AD),
Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis
(ALS), multiple sclerosis (MS), stroke, brain and spinal cord injury, brain cancer, the
neurological symptoms of AIDS, childhood inborn genetic errors affecting the brain,
and acute and chronic pain syndromes.
The pharmacokinetic aspects of peptides in the plasma and CNS will be influenced
by the factors that influence the transport of a peptide across the blood-brain barrier
(BBB). These include molecular weight, charge, degree of protein binding, peptide
aggregation status, and, perhaps most important, lipophilicity. A large volume of dis-