Complement Activation, Immunogenicity, and Immune Suppression as Potential Side Eff ects of Liposomes - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 324

mice, of partial RES blockage by liposomal doxorubicin was the dose-
dependent pharmacokinetics of Doxil, resulting in slower clearance
and disproportional increase of tumor uptake at higher doses (in the
2.5 to 20 mg/kg range) [37]. The clearance slow-down eff ect was
not seen with free doxorubicin administration at a similar dose or
after doxorubicin-free liposomes were co-administered with free
doxorubicin [37].
Although interference with innate antibacterial defense was
not found in Doxil-treated patients to date (by now more humans
have been injected with Doxil than mice), clinical signs of partial
macrophage suppression do seem to be present in cancer patients
treated with Doxil. Evidence for this includes the rise of circulation
T 1/2 of Doxil after repeated administrations [35], and the inhibition
of HSRs to carboplatin by co-administered Doxil [1]. The implications
of partial immune suppression by Doxil remains to be evaluated,
including two potential clinical benefits. One is that tumor uptake
of Doxil might increase upon repeated doses (as seen with dose
escalation in mice [37]), resulting in increased therapeutic efficacy
by the same dose, or allowing dose reduction without loss of efficacy.
The second is that Doxil may provide therapeutic advantage over
paclitaxel or gemcitabine in combination chemotherapies with
carboplatin, as HSRs to carboplatin have become dose-limiting
during treatment of platinum sensitive recurrent cancer [1].

11.7 Conclusions and Outlook

Immunosafety may become a key issue in current and future R&D of
liposomes and other nanomedicines. Its significance is emphasized
by examples of postmarketing drug recalls, industry guidelines on
immunotoxicity testing and recent calls for collaborative research in
the fields of nanotoxicology and immunogenicity [29, 31, 46]. Clearly,
the currently used immunotoxicology endpoints (e.g. lymphoid
organ weight and histology, lymphocyte proliferation, cytotoxicity
and antibody production tests, cytokine assays, skin irritation test)
have little, or no predictive value in assessing the risk of HSRs, nor
do they predict the immunogenicity of complex liposomes or other
nano-bio-hybrid drugs. An almost insurmountable difficulty in this
regard is the high complexity and species and individual variability
of the immune processes involved in the latter phenomena.