Biomedical Engineering Reference
In-Depth Information
therapeutic oligonucleotides, several issues must be addressed [ 60 ]. These issues
include the instability of native oligonucleotides and their rapid clearance from the
blood. To overcome these problems, PEGylation of the oligonucleotide is very
useful. For example, Macugen, which is used for the treatment of the wet form of
age-related macular degeneration (ARMD), is an aptamer drug modified with
branched 40-kDa PEG at the 5 0 -terminus [ 26 ]. A number of PEGylated
oligonucleotides are now at various stages of clinical trials.
4.4 PEGylated Nanoparticles
Precise design of the surface of nanoparticles is very important for the efficient and
specific delivery of the drug by the nanocarrier. Surface modification of
nanoparticles, such as micelles and liposomes, with PEG represents an essential
strategy for reducing nonspecific interactions with serum proteins and endothelial
cells in the blood stream, as well as avoiding recognition by immune system
components such as the reticuloendothelial system (RES) [ 61 ]. Thus, stabilized
nanocarriers tend to yield long blood circulation times and facilitate accumulation
in the tumor tissue through the effects of EPR. Tamura et al. reported the influence
of the surface PEG density on nanoparticles in the blood circulation [ 62 ] by using a
nanogel composed of chemically crosslinked poly[2- N , N -(diethylamino)ethyl
methacrylate] (PEAMA) gel cores surrounded by PEG palisade layers [ 63 ].
Because of their chemically crosslinked polyamine gel core, the PEGylated
nanogels show higher stability against extremely dilute and high salt conditions
than self-assembled nanocarriers such as liposomes and micelles. This stable
nanoparticle is suitable for studying the influence of the physicochemical properties
of nanoparticles on pharmacokinetics. The density of PEG on the surface of the
nanogels was controlled by the post-PEGylation method. It was clearly
demonstrated that the blood circulation time of the post-PEGylated nanogels was
definitely prolonged as the PEG content was increased [ 62 ].
4.4.1 PEGylated Liposomes
Several liposome-based drugs have been approved for clinical application [ 64 ]. One
of the clinically approved liposomes is Doxil, a PEGylated liposome containing
doxorubicin (DOX), which is used for the treatment of a number of diseases [ 65 ].
As shown in this case, in the field of liposome drug development, PEG is widely
used to protect the liposome from recognition by opsonins, thereby reducing
liposome clearance.
A number of PEGylation reactions with liposomes have been developed [ 66 ].
One of the methods utilizes lipophilic compounds that possess reactive groups such
as amino and carboxyl groups. By incorporating these components into the bilayer
membrane, 500-2,000 functional groups can be introduced onto the liposome
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