ovalbumin (OVA) [24–26]. These findings potentially contradict the basic
assumption that PEG is a bio-inert and non-immunogenic substance. In 1983,
Richter and Akerblom [26] firstly reported the elicitation of PEG-specific antibodies
following either subcutaneous or intramuscular injections of different
PEG-modified proteins in complete Freund’s adjuvant. By contrary, under similar
experimental conditions, free PEG showed little or no immunogenicity. Similarly,
we have confirmed the induction of an anti-PEG antibody response (mainly
anti-PEG IgM) following a single intravenous injection of either PEGylated OVA
or PEGylated bovine serum albumin (BSA), despite the fact that a single injection
does not induce specific neutralizing antibodies to either OVA or BSA [27]. These
results support the scenario that the elicitation of anti-PEG immune response only
occurs against PEG conjugates in a manner wherein PEG acts as a hapten. A hapten
is a non-immunogenic small molecule that triggers antibody response only when
attached to an immunogenic protein that can provide CD4
+ T cell epitopes, which
are required to initiate the antibody response. This haptenic characteristic of PEG
has been revealed to be dependent on the molecular weight and the immunogenicity
of the carrier protein and/or the presence of adjuvants [21, 28, 29]. This explains
why PEGylated proteins such as uricase, asparaginase and OVA could harmfully
elicit anti-PEG antibody response, whereas others are relatively safer [30–33].
20.3 Anti-PEG Response to PEGylated Nanocarriers
Nanocarriers are currently explored extensively as a vehicle of various medicinal
agents in biomedical fields including targeted drug delivery systems, medical
imaging and diagnosis [34–36]. Surface decoration of nanocarrier systems with
PEG is reported to prevent the uptake of nanocarriers by the cells of MPS and
improve their in vivo fate following intravenous administration [37, 38].
Nonetheless, in spite of the usefulness and importance of PEGylation, surface
decoration of nanocarriers with PEG has been reported to elicit an immunogenic
response against PEGylated nanocarriers [10, 14, 39, 40].
While single dose of PEGylated nanocarriers often demonstrates in vivo
extended blood circulation time, some PEGylated nanocarriers exhibit rapid systemic clearance upon repeated administration. In 1997, Moghimi and Gray [41]
demonstrated that a single intravenous dose of particles coated with the amphiphilic
polymer poloxamine 908 (a PEG-containing surfactant) triggered enhanced clearance of subsequently administered doses in rats. Similarly, we and other research
groups have demonstrated that empty PEGylated liposomes could also trigger a
strong immune response that significantly compromise circulation time in the blood
of the subsequent dose via enhancing its hepatic clearance [10, 11, 14, 42, 43]. Such
unexpected pharmacokinetic alteration of PEGylated nanocarriers upon repeated
administration is now well recognized as the “accelerated blood clearance (ABC)”
20 Immune Response to PEGylated Nanomedicines …
373
assumption that PEG is a bio-inert and non-immunogenic substance. In 1983,
Richter and Akerblom [26] firstly reported the elicitation of PEG-specific antibodies
following either subcutaneous or intramuscular injections of different
PEG-modified proteins in complete Freund’s adjuvant. By contrary, under similar
experimental conditions, free PEG showed little or no immunogenicity. Similarly,
we have confirmed the induction of an anti-PEG antibody response (mainly
anti-PEG IgM) following a single intravenous injection of either PEGylated OVA
or PEGylated bovine serum albumin (BSA), despite the fact that a single injection
does not induce specific neutralizing antibodies to either OVA or BSA [27]. These
results support the scenario that the elicitation of anti-PEG immune response only
occurs against PEG conjugates in a manner wherein PEG acts as a hapten. A hapten
is a non-immunogenic small molecule that triggers antibody response only when
attached to an immunogenic protein that can provide CD4
+ T cell epitopes, which
are required to initiate the antibody response. This haptenic characteristic of PEG
has been revealed to be dependent on the molecular weight and the immunogenicity
of the carrier protein and/or the presence of adjuvants [21, 28, 29]. This explains
why PEGylated proteins such as uricase, asparaginase and OVA could harmfully
elicit anti-PEG antibody response, whereas others are relatively safer [30–33].
20.3 Anti-PEG Response to PEGylated Nanocarriers
Nanocarriers are currently explored extensively as a vehicle of various medicinal
agents in biomedical fields including targeted drug delivery systems, medical
imaging and diagnosis [34–36]. Surface decoration of nanocarrier systems with
PEG is reported to prevent the uptake of nanocarriers by the cells of MPS and
improve their in vivo fate following intravenous administration [37, 38].
Nonetheless, in spite of the usefulness and importance of PEGylation, surface
decoration of nanocarriers with PEG has been reported to elicit an immunogenic
response against PEGylated nanocarriers [10, 14, 39, 40].
While single dose of PEGylated nanocarriers often demonstrates in vivo
extended blood circulation time, some PEGylated nanocarriers exhibit rapid systemic clearance upon repeated administration. In 1997, Moghimi and Gray [41]
demonstrated that a single intravenous dose of particles coated with the amphiphilic
polymer poloxamine 908 (a PEG-containing surfactant) triggered enhanced clearance of subsequently administered doses in rats. Similarly, we and other research
groups have demonstrated that empty PEGylated liposomes could also trigger a
strong immune response that significantly compromise circulation time in the blood
of the subsequent dose via enhancing its hepatic clearance [10, 11, 14, 42, 43]. Such
unexpected pharmacokinetic alteration of PEGylated nanocarriers upon repeated
administration is now well recognized as the “accelerated blood clearance (ABC)”
20 Immune Response to PEGylated Nanomedicines …
373