Specific enhancement of drug delivery to AKR lymphoma by antibody-targeted small unilamellar vesicles.
Antibody targeting of drug-containing liposomes to specific cell populations provides the opportunity to improve cancer chemotherapy. We report here the efficacy of targeted liposomes containing methotrexate-gamma-aspartate against two murine T-lymphomas, AKR/J SL2 and R1.1. Both large and small unilamellar vesicles conjugated to anti-Thy-1.1 antibody associated with AKR lymphoma cells in 10-fold greater amounts than nonconjugated liposomes or liposomes conjugated to a nonspecific antibody. Cell association was inhibited by two different anti-Thy-1.1 monoclonal antibodies, but not by nonspecific antibody. Vesicle size is the critical factor determining drug delivery of targeted liposomes to both AKR and R1.1 T-lymphoma cells. Although targeted large unilamellar vesicles (mean diameter, 0.45 micron) specifically bind to lymphoma cells, they probably are not internalized, because they fail to enhance the efficacy of the drug for growth inhibition of either AKR or R1.1 cells. In contrast, drug encapsulated in targeted small unilamellar vesicles (mean diameter, 0.053 micron) is up to 22 times more effective than free drug against AKR cells, and is 40 times more effective against R1.1 cells. We have also demonstrated the efficacy of small compared to large unilamellar vesicles using two different target antigens, Thy-1.1 for AKR cells and H-2Kk for R1.1 cells. These experiments establish a system which can be used to test the antitumor efficacy of targeted liposomes against AKR/J SL2 lymphoma implanted in AKR/Cu mice.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D007518:Isoantibodies / Q000008:administration & dosage*; D007700:Kinetics; D008081:Liposomes / Q000008:administration & dosage*; D008223:Lymphoma / Q000188:drug therapy*; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains
D000970:Antineoplastic Agents; D007518:Isoantibodies; D008081:Liposomes; C035678:anti-Thy antibody; C037394:methotrexate-gamma-aspartate; D008727:Methotrexate