Nanosized Drug Delivery Vectors and the Reticuloendothelial System - Intracellular Delivery: Fundamentals and Applications - page 172

4.2 PEGylation

Polyethylene glycol (Fig. 10 ) was identified in the 1970s to be a highly biocompatible
polymer. Since then, its use in improving the pharmacokinetic and biodistribution
properties of nanomedicines has become widespread. The structure is composed
of multiple repeating units of ethylene glycol that complex many water molecules
resulting in the biological 'masking' properties of the polymer. The polymer is
also relatively non-toxic; the administration of several grams per kg of body
weight is required before toxicity becomes evident. Although it is slowly metabo-
lized in the body, metabolism of PEG is not considered a major mechanism in the
clearance of conjugated nanomedicines. However, for very large, long circulating
systems, gradual metabolism of PEG chains with a resulting reduction in particle
size and exposure of surface groups may eventually alter the biodistribution of the
particles.
In the pharmaceutical industry, PEGylation has been used to increase the circu-
lation times of proteins and liposomes, reduce RES uptake by liposomes and reduce
the susceptibility of proteins to enzymatic degradation. Although PEGylation of
proteins masks key receptor binding sites and therefore decreases in vitro activity
compared to the native protein, in vivo therapeutic efficacy is generally increased
as a result of the increased exposure of target receptors to the protein due to
improved residence time in circulation. PEGylation works in a similar manner to
mask biologically incompatible surface properties on nanomedicines, thus reducing
both opsonisation and uptake via macrophages of the RES.
Although increasing particle size generally acts to increase RES targeting, con-
jugation of PEG, resulting in increased particle molecular weight and hydrody-
namic size, does not have a similar effect. Increasing the size of conjugated
nanomedicines via PEGylation instead acts to increase circulation times and reduce
excretion via the urine. Increased eventual uptake by the RES (in particular the liver
and spleen) for large PEGylated materials is more a consequence of increased
exposure to macrophages that slowly phagocytose the material rather than increased
uptake of larger materials. This is demonstrated by data showing that increasing the
extent of PEGylation on polylysine dendrimers (resulting in increasing dendrimer
sizes due to increased PEG molecular weight) results in slow uptake of the particles
by the liver and spleen, such that approximately 12% of the injected dose of 68 kDa
dendrimers with terminal plasma half lives of 3 days are recovered in the liver and
spleen after 1 week (Kaminskas et al. 2008 ).

O

R n OR'

R - nanoparticle
R' - H (hydroxy PEG)

CH 3 (methoxy PEG)

unctional group attachment point

Fig. 10 Polyethylene glycol