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Alendronate Liposomes for Antitumor Therapy: Activation of γδ T Cells and Inhibition of Tumor Growth

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Nano-Biotechnology for Biomedical and Diagnostic Research

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 733))

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.

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Abbreviations

DSPC:

1,2-Distearoyl-sn-glycero-3-phosphocholine

ALN-L:

Alendronate liposomes

nBP:

Amino-bisphosphonate

APC:

Antigen presenting cells

BSA:

Bovine serum albumin

CLOD-L:

Clodronate liposomes

DCs:

Dendritic cells

DSPG:

Distearoyl-phosphatidylglycerol

MHC:

Histocompatibility complex

h-PBMCs:

Human peripheral blood mononuclear cells

imDC:

Immature DC

IPP:

Isopentenyl pyrophosphate

mAbs:

Monoclonal antibodies

MPS:

Mononuclear phagocytic system

TAM:

Tissue associated macrophages

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Authors and Affiliations

  1. Faculty of Medicine, Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, 12065, Jerusalem, 91120, Israel

    Dikla Gutman, Hila Epstein-Barash, Moshe Tsuriel & Gershon Golomb

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  1. Dikla Gutman
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  2. Hila Epstein-Barash
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  3. Moshe Tsuriel
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  4. Gershon Golomb
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Correspondence to Dikla Gutman .

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Editors and Affiliations

  1. Israel Institute for Biological Research, P.O. Box 19, Ness-Ziona, 74100, Israel

    Eran Zahavy

  2. Israel Institute for Biological Research, P.O. Box 19, Ness-Ziona, 74100, Israel

    Arie Ordentlich

  3. Israel Institute for Biological Research, P.O. Box 19, Ness-Ziona, Israel

    Shmuel Yitzhaki

  4. Israel Institute for Biological Research, P.O. Box 19, Ness-Ziona, 74100, Israel

    Avigdor Shafferman

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Gutman, D., Epstein-Barash, H., Tsuriel, M., Golomb, G. (2012). Alendronate Liposomes for Antitumor Therapy: Activation of γδ T Cells and Inhibition of Tumor Growth. In: Zahavy, E., Ordentlich, A., Yitzhaki, S., Shafferman, A. (eds) Nano-Biotechnology for Biomedical and Diagnostic Research. Advances in Experimental Medicine and Biology, vol 733. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2555-3_16

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