title: Alendronate liposomes for antitumor therapy: activation of γδ T cells and inhibition of tumor growth.
abstract: Circulating γδ T cells are cytotoxic lymphocytes that are unique to primates. Recent -studies have shown that amino-bisphosphonates (nBP) activate γδ T cells to kill tumor cells in an indirect mechanism, which requires antigen presenting cells (APC). We hypothesized that selective targeting of nBP to monocytes would result in a more potent γδ T cells activation in circulation, and in tissue associated macrophages (TAM) following monocytes-laden drug extravasation and liposomes accumulation at the tumor site. In addition, inhibition of TAM by alendronate liposomes (ALN-L) is expected. ALN was targeted exclusively to monocytes, but not to lymphocytes, by encapsulating it in negatively-charged liposomes. The proportion of human γd-T cells in the CD3(+) population following treatment with ALN-L or the free drug was increased, from 5.6 ± 0.4% to 50.9 ;± 12.2% and 49.5 ± 12.9%, respectively. ALN solution and liposomes treatments resulted in an increased, and in a dose dependent manner, TNFα secretion from h-PBMC. Preliminary results showed that ALN-L inhibited tumor growth in a nude mouse breast tumor model. It is suggested that enhanced activation of γδ T cells could be obtained due to interaction with circulating monocytes as well as by TAM endocytosing liposomal nBP leading to a potentiated anti-tumor effect of nBP. It should be noted that this could be validated only in primates/humans since γδ T cells are unique in these species.
authors.affiliation: Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel. diklag@ekmd.huji.ac.il
authors.forename: Dikla
authors.initials: D
authors.lastname: Gutman
authors.forename: Hila
authors.initials: H
authors.lastname: Epstein-Barash
authors.forename: Moshe
authors.initials: M
authors.lastname: Tsuriel
authors.forename: Gershon
authors.initials: G
authors.lastname: Golomb
mesh_terms: D019386:Alendronate / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D019386:Alendronate