fourth the patients treated with Doxil
® (PEGylated liposomal doxorubicin).
Chanan-Khan et al. [79] also reported that Doxil
® therapy activated complement in
the majority of patients and elicited moderate to severe hypersensitivity reactions in
about 50% of cancer patients infused with Doxil
® for the first time. Furthermore,
CARPA reactions have been elicited with other liposomal formulations regardless
their structure or the presence/absence of PEG surface modification [70, 75, 80].
Currently, CARPA phenomenon is considered one of the safety issues for
nanomedicines, including radionanomedicines, that to be evaluated prior the clinical approval of generic intravenous liposomal formulations.
20.9 Alternative Approaches to PEGylation
An emerging body of literature has been proposed to avert the immunogenicity of
PEGylated therapeutics [81–84]. Among them, the application of alternative
polymers to PEG has gained increased attention. Zhang et al. [83] have emphasized
the utility of liposome surface coating with hyaluronic acid (HA), instead of PEG,
to improve pharmacokinetics and to reduce immune response of administered
liposomes while preserving their long circulating characteristics. They demonstrated that HA-liposomes showed good stealth properties without inducing neither
anti-polymer antibodies nor the ABC phenomenon. Moreover, HA-liposomes did
not trigger complement activation neither in human serum in vitro nor in rat blood
in vivo. On the other hand, PEGylated liposomes could elicit complement activation and consequent ABC phenomenon accompanied by an enhanced accumulation
of PEGylated liposomes in the liver. In the same context, we have employed a
polyglycerol (PG)-derived lipid, as an alternative to PEG, to mitigate the immune
response against injected liposomes [81, 82]. We demonstrated that surface decoration with PG potentially attenuated the anti-polymer immune response. The
hydroxymethyl side group in the repeating –(O–CH 2 –CH(CH 2 OH)) n – subunit of
PG was reported to sterically hinder the interaction and effective binding to surface
immunoglobulins on reactive splenic B-cells, and thus, prevents the direct stimulation of splenic B cells and the production of anti-polymer IgM (Fig. 20.2). In a
subsequent study, surface modification of pDNA-lipoplex with PG, instead of PEG,
was also confirmed to efficiently attenuate the immunogenicity of PEGylated
lipoplex, and thereby, enhanced the accumulation of the PG-modified lipoplexes in
the tumor tissue upon repeated administration (Fig. 20.3) [81]. More recently, we
examined the potential of incorporating porcine ganglioside into the membrane of
PEGylated liposome in alleviating/abrogating the anti-PEG IgM response against
PEGylated liposomes (PL). Insertion of ganglioside into PEGylated liposomes
significantly mitigated the anti-PEG IgM immune response and alleviated the
incidence of the accelerated clearance of subsequently injected PEGylated liposomes, presumably via inducing B cell tolerance. These findings emphasize the
feasibility of liposomal surface decoration with ganglioside in attenuating the
immunogenicity of PEGylated nanocarriers upon repeated administration [84].
380
A. S. Abu Lila and T. Ishida
® (PEGylated liposomal doxorubicin).
Chanan-Khan et al. [79] also reported that Doxil
® therapy activated complement in
the majority of patients and elicited moderate to severe hypersensitivity reactions in
about 50% of cancer patients infused with Doxil
® for the first time. Furthermore,
CARPA reactions have been elicited with other liposomal formulations regardless
their structure or the presence/absence of PEG surface modification [70, 75, 80].
Currently, CARPA phenomenon is considered one of the safety issues for
nanomedicines, including radionanomedicines, that to be evaluated prior the clinical approval of generic intravenous liposomal formulations.
20.9 Alternative Approaches to PEGylation
An emerging body of literature has been proposed to avert the immunogenicity of
PEGylated therapeutics [81–84]. Among them, the application of alternative
polymers to PEG has gained increased attention. Zhang et al. [83] have emphasized
the utility of liposome surface coating with hyaluronic acid (HA), instead of PEG,
to improve pharmacokinetics and to reduce immune response of administered
liposomes while preserving their long circulating characteristics. They demonstrated that HA-liposomes showed good stealth properties without inducing neither
anti-polymer antibodies nor the ABC phenomenon. Moreover, HA-liposomes did
not trigger complement activation neither in human serum in vitro nor in rat blood
in vivo. On the other hand, PEGylated liposomes could elicit complement activation and consequent ABC phenomenon accompanied by an enhanced accumulation
of PEGylated liposomes in the liver. In the same context, we have employed a
polyglycerol (PG)-derived lipid, as an alternative to PEG, to mitigate the immune
response against injected liposomes [81, 82]. We demonstrated that surface decoration with PG potentially attenuated the anti-polymer immune response. The
hydroxymethyl side group in the repeating –(O–CH 2 –CH(CH 2 OH)) n – subunit of
PG was reported to sterically hinder the interaction and effective binding to surface
immunoglobulins on reactive splenic B-cells, and thus, prevents the direct stimulation of splenic B cells and the production of anti-polymer IgM (Fig. 20.2). In a
subsequent study, surface modification of pDNA-lipoplex with PG, instead of PEG,
was also confirmed to efficiently attenuate the immunogenicity of PEGylated
lipoplex, and thereby, enhanced the accumulation of the PG-modified lipoplexes in
the tumor tissue upon repeated administration (Fig. 20.3) [81]. More recently, we
examined the potential of incorporating porcine ganglioside into the membrane of
PEGylated liposome in alleviating/abrogating the anti-PEG IgM response against
PEGylated liposomes (PL). Insertion of ganglioside into PEGylated liposomes
significantly mitigated the anti-PEG IgM immune response and alleviated the
incidence of the accelerated clearance of subsequently injected PEGylated liposomes, presumably via inducing B cell tolerance. These findings emphasize the
feasibility of liposomal surface decoration with ganglioside in attenuating the
immunogenicity of PEGylated nanocarriers upon repeated administration [84].
380
A. S. Abu Lila and T. Ishida