Large anti-HER2/neu liposomes for potential targeted intraperitoneal therapy of micrometastatic cancer.
Effective targeting and killing of intraperitoneally disseminated micrometastases remains a challenge.


OBJECTIVE
In this work, we evaluated the potential of antibody-labeled PEGylated large liposomes as vehicles for direct intraperitoneal (i.p.) drug delivery with the aim to enhance the tumor-to-normal organ ratio and to improve the bioexposure of cancer cells to the delivered therapeutics while shifting the toxicities toward the spleen. These targeted liposomes are designed to combine: (1) specific targeting to and internalization by cancer cells mediated by liposome-conjugated tumor-specific antibodies, (2) slow clearance from the peritoneal cavity, and (3) shift of normal organ toxicities from the liver to the spleen due to their relatively large size.


RESULTS
Conjugation of anti-HER2/neu antibodies to the surface of large (approximately 600 nm in diameter) PEGylated liposomes results in fast, specific binding of targeted liposomes to cancer cells in vitro, followed by considerable cellular internalization. In vivo, after i.p. administration, these liposomes exhibit fast, specific binding to i.p. cancerous tumors. Large liposomes are slowly cleared from the peritoneal cavity, and they exhibit increased uptake by the spleen relative to the liver, while targeted large liposomes demonstrate specific tumor uptake at early times. Although tissue and tumor uptake are greater for cationic liposomes, the tumor-to-liver and spleen-to-liver ratios are similar for both membrane compositions, suggesting a primary role for the liposome's size, compared to the liposome's surface charge.


CONCLUSIONS
The findings of this study suggest that large targeted liposomes administered i.p. could be a potent drug-delivery strategy for locoregional therapy of i.p. micrometastatic tumors.
Sofou
Stavroula
S
Department of Chemical and Biological Engineering, Polytechnic Institute of New York University, Brooklyn, NY 11201, USA. ssofou@poly.edu
Enmon
Richard
R
Palm
Stig
S
Kappel
Barry
B
Zanzonico
Pat
P
McDevitt
Michael R
MR
Scheinberg
David A
DA
Sgouros
George
G
D000818:Animals; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry; D008422:Materials Testing; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010316:Particle Size; D010529:Peritoneal Cavity; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*
D000912:Antibodies, Neoplasm; D001672:Biocompatible Materials; D004337:Drug Carriers; D008081:Liposomes; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human