In vitro potency, in vitro and in vivo efficacy of liposomal alendronate in combination with γδ T cell immunotherapy in mice.
Nitrogen-containing bisphosphonates (N-BP), including zoledronic acid (ZOL) and alendronate (ALD), have been proposed as sensitisers in γδ T cell immunotherapy in pre-clinical and clinical studies. Therapeutic efficacy of N-BPs is hampered by their rapid renal excretion and high affinity for bone. Liposomal formulations of N-BP have been proposed to improve accumulation in solid tumours. Liposomal ALD (L-ALD) has been suggested as a suitable alternative to liposomal ZOL (L-ZOL), due to unexpected mice death experienced in pre-clinical studies with the latter. Only one study so far has proven the therapeutic efficacy of L-ALD, in combination with γδ T cell immunotherapy, after intraperitoneal administration of γδ T cell resulting in delayed growth of ovarian cancer in mice. This study aims to assess the in vitro efficacy of L-ALD, in combination with γδ T cell immunotherapy, in a range of cancerous cell lines, using L-ZOL as a comparator. The therapeutic efficacy was tested in a pseudo-metastatic lung mouse model, following intravenous injection of γδ T cell, L-ALD or the combination. In vivo biocompatibility and organ biodistribution studies of L-N-BPs were undertaken simultaneously. Higher concentrations of L-ALD (40-60μM) than L-ZOL (3-10μM) were required to produce a comparative reduction in cell viability in vitro, when used in combination with γδ T cells. Significant inhibition of tumour growth was observed after treatment with both L-ALD and γδ T cells in pseudo-metastatic lung melanoma tumour-bearing mice after tail vein injection of both treatments, suggesting that therapeutically relevant concentrations of L-ALD and γδ T cell could be achieved in the tumour sites, resulting in significant delay in tumour growth.
King's College London, 150 Stamford Street, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
Naomi O
NO
Hodgins
School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.
Wafa' T
WT
Al-Jamal
King's College London, 150 Stamford Street, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
Julie T-W
JT
Wang
King's College London, Division of Cancer Studies, Guy's Hospital, London SE1 9RT, UK.
Ana C
AC
Parente-Pereira
King's College London, 150 Stamford Street, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
Mao
M
Liu
King's College London, Division of Cancer Studies, Guy's Hospital, London SE1 9RT, UK. Electronic address: john.maher@kcl.ac.uk.
John
J
Maher
King's College London, 150 Stamford Street, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK. Electronic address: khuloud.al-jamal@kcl.ac.uk.
Khuloud T
KT
Al-Jamal
D019386:Alendronate / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000097:blood; D008081:Liposomes; D008297:Male; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000628:therapy*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D008081:Liposomes; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma; D019386:Alendronate
Bisphosphonates; Immunotherapy; Liposomes; Sensitiser; γδ T cells
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