A growth factor antagonist as a targeting agent for sterically stabilized liposomes in human small cell lung cancer.
The ability of a growth factor antagonist, [D-Arg(6),D-Trp(7,9)-N(me)Phe(8)]-substance P(6-11), named antagonist G, to selectively target polyethylene glycol-grafted liposomes (known as sterically stabilized liposomes) to a human classical small cell lung cancer (SCLC) cell line, H69, was examined. Our results showed that radiolabeled antagonist G-targeted sterically stabilized liposomes (SLG) bound to H69 cells with higher avidity than free antagonist G and were internalized (reaching a maximum of 13000 SLG/cell), mainly through a receptor-mediated process, likely involving clathrin-coated pits. This interaction was confirmed by confocal microscopy to be peptide- and cell-specific. Moreover, it was shown that SLG significantly improved the nuclear delivery of encapsulated doxorubicin to the target cells, increasing the cytotoxic activity of the drug over non-targeted liposomes. In mice, [(125)I]tyraminylinulin-containing SLG were long circulating, with a half-life of 13 h. Use of peptides like antagonist G to promote binding and internalization of sterically stabilized liposomes, with their accompanying drug loads, i.e., anticancer drugs, genes or antisense oligonucleotides, into target cells has the potential to improve therapy of SCLC.
Moreira
J N
JN
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Hansen
C B
CB
Gaspar
R
R
Allen
T M
TM
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D018288:Carcinoma, Small Cell / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D004317:Doxorubicin / Q000032:analysis / Q000494:pharmacology; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004705:Endocytosis; D006207:Half-Life; D006801:Humans; D007457:Iodine Radioisotopes; D008081:Liposomes / Q000737:chemistry* / Q000493:pharmacokinetics; D008175:Lung Neoplasms / Q000737:chemistry*; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011955:Receptors, Drug / Q000737:chemistry; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004337:Drug Carriers; D007457:Iodine Radioisotopes; D008081:Liposomes; D009842:Oligopeptides; D011955:Receptors, Drug; C095573:arginyl-tryptophyl-N-methylphenylalanyl-tryptophyl-leucyl-methioninamide; D004317:Doxorubicin