Immunoliposomes bearing polyethyleneglycol-coupled Fab' fragment show prolonged circulation time and high extravasation into targeted solid tumors in vivo.
We have developed a new type of long-circulating immunoliposome (Fab'-PEG immunoliposomes) which is efficiently extravasated into the targeted solid tumor in vivo. Small unilamellar liposomes (100-130 nm in diameter) were prepared from distearoylphosphatidylcholine (DSPC), cholesterol (CHOL) and a dipalmitoylphosphatidylethanolamine derivative of PEG with a terminal maleimidyl group (DPPE-PEG-Mal), and conjugated Fab' fragment of antibody. Inclusion of DPPE-PEG-Mal and linkage of the Fab' fragment instead of intact antibody to PEG terminals allowed the liposomes to evade RES uptake and remain in the circulation for a long time, resulting in enhanced accumulation of the liposomes in the solid tumor. Because of the ability of such Fab'-PEG immunoliposomes to target solid tumors, they appear highly attractive as carriers of not only chemotherapeutic agents, but also of macromolecular drugs.
Maruyama
K
K
Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan. maruyama@pharm.teikyo-u.ac.jp
Takahashi
N
N
Tagawa
T
T
Nagaike
K
K
Iwatsuru
M
M
D000818:Animals; D002272:Carcinoembryonic Antigen / Q000276:immunology; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D008081:Liposomes / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D008301:Maleimides / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D013274:Stomach Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D002272:Carcinoembryonic Antigen; D007140:Immunoglobulin Fab Fragments; D008081:Liposomes; D008301:Maleimides; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; C043592:maleimide; C007510:1,2-dipalmitoyl-3-phosphatidylethanolamine; D011092:Polyethylene Glycols; D002784:Cholesterol; C010942:1,2-distearoyllecithin