Biomedical Engineering Reference
In-Depth Information
Fab
0
. To overcome this problem, they used a mixed-PEG layer formation in which
different molecular weights of PEG (2 and 5 kDa) were used for the formation of a
densely packed PEG layer. Formation of a mixed-PEG layer was originally devel-
oped by our group [
49
]. A highly dense mixed-PEG layer almost completely
prevented nonspecific protein absorption and facilitated biospecific interactions
(Fig.
10
)[
48
]. This methodology can be applied to the construction of targeted
drug delivery systems, in which a ligand is needed on the surface of nanoparticles to
bind the target molecule with high specificity and efficiency.
4 PEGylated Drugs
PEGylation technology has been applied to the development of various kinds of
drugs, including small molecules, peptides, proteins, antibody fragments, whole
antibodies, oligonucleotides, and macromolecules such as polymer micelles and
liposomes. Currently, there are ten PEGylated drugs, which utilize proteins,
enzymes, antibody fragments, and oligonucleotides, and a PEGylated nanoparticle
named Doxil available on the market (Table
1
). PEGylated small drugs are cur-
rently under investigation in clinical tests; however, there are no approved drugs
available on the market. Sections
4.1
-
4.4
describe various PEGylated drugs that
have been approved or are in clinical trials.
4.1 Small Molecules
PEGylation of small drugs has several advantages. First, PEGylation improves
pharmacokinetic properties due to the increased blood circulation time. Second,
the immunogenicity of immunogenic small drugs is reduced. Third, PEGylation
increases drug accumulation in tumors via the enhanced permeability and retention
(EPR) effect. Finally, the toxicity of the drug is reduced by the massive PEG
molecule.
Enzon pharmaceuticals have developed a PEGylated drug called SN-38
(7-ethyl-10-camptothecin) [
50
]. SN-38 is an active metabolite of irinotecan and is
produced by hydrolysis of CPT-11 [
51
]. Several problems arise in the development
of drugs using SN-38 or CPT-11. First, carboxylesterase-2 is thought to be the main
esterase that hydrolyzes CPT-11; however, the expression of this enzyme in the
blood is low. Accordingly, only 1-9% of injected CPT-11 is converted to the active
form SN-38. The second problem associated with CPT-11 is the opening reaction of
the lactone-E ring, which results in a form that is inactive against the target protein.
Finally, SN-38 cannot be used for systemic applications because of poor solubility.
This problem was solved by PEGylation of SN-38. PEGylation of SN-38 by
acylation of the 20-hydroxyl functional group improved water solubility and
preserved the active lactone form in the circulation. To increase the loading of
