Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models.
We describe evidence for a novel mechanism of monoclonal antibody (MAb)-directed nanoparticle (immunoliposome) targeting to solid tumors in vivo. Long-circulating immunoliposomes targeted to HER2 (ErbB2, Neu) were prepared by the conjugation of anti-HER2 MAb fragments (Fab' or single chain Fv) to liposome-grafted polyethylene glycol chains. MAb fragment conjugation did not affect the biodistribution or long-circulating properties of i.v.-administered liposomes. However, antibody-directed targeting also did not increase the tumor localization of immunoliposomes, as both targeted and nontargeted liposomes achieved similarly high levels (7-8% injected dose/g tumor tissue) of tumor tissue accumulation in HER2-overexpressing breast cancer xenografts (BT-474). Studies using colloidal gold-labeled liposomes showed the accumulation of anti-HER2 immunoliposomes within cancer cells, whereas matched nontargeted liposomes were located predominantly in extracellular stroma or within macrophages. A similar pattern of stromal accumulation without cancer cell internalization was observed for anti-HER2 immunoliposomes in non-HER2-overexpressing breast cancer xenografts (MCF-7). Flow cytometry of disaggregated tumors posttreatment with either liposomes or immunoliposomes showed up to 6-fold greater intracellular uptake in cancer cells due to targeting. Thus, in contrast to nontargeted liposomes, anti-HER2 immunoliposomes achieved intracellular drug delivery via MAb-mediated endocytosis, and this, rather than increased uptake in tumor tissue, was correlated with superior antitumor activity. Immunoliposomes capable of selective internalization in cancer cells in vivo may provide new opportunities for drug delivery.
Kirpotin
Dmitri B
DB
Hermes Biosciences Inc., South San Francisco, CA, USA.
Drummond
Daryl C
DC
Shao
Yi
Y
Shalaby
M Refaat
MR
Hong
Keelung
K
Nielsen
Ulrik B
UB
Marks
James D
JD
Benz
Christopher C
CC
Park
John W
JW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000276:immunology* / Q000493:pharmacokinetics*; D051379:Mice; D049329:Nanostructures; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology*; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D008081:Liposomes; D018719:Erb-b2 Receptor Tyrosine Kinases