TY - GEN
T1 - Alendronate liposomes for antitumor therapy
T2 - Activation of γδ T cells and inhibition of tumor growth
AU - Gutman, Dikla
AU - Epstein-Barash, Hila
AU - Tsuriel, Moshe
AU - Golomb, Gershon
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Liposome
KW - Monocyte
KW - TAM
KW - nBP
KW - γδ T cells
UR - http://www.scopus.com/inward/record.url?scp=84934442719&partnerID=8YFLogxK
U2 - 10.1007/978-94-7-2555-3_16
DO - 10.1007/978-94-7-2555-3_16
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C2 - 22101722
AN - SCOPUS:84934442719
SN - 9789400725546
T3 - Advances in Experimental Medicine and Biology
SP - 165
EP - 179
BT - Nano-Biotechnology for Biomedical and Diagnostic Research
PB - Springer New York LLC
ER -
