In vitro potency, in vitro and in vivo efficacy of liposomal alendronate in combination with γδ T cell immunotherapy in mice

• Published in: Journal of controlled release Vol. 241; pp. 229 - 241
• Main Authors: Hodgins, Naomi O., Al-Jamal, Wafa' T., Wang, Julie T-W., Parente-Pereira, Ana C., Liu, Mao, Maher, John, Al-Jamal, Khuloud T.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.11.2016; Elsevier Science Publishers
• Subjects: Alendronate - administration & dosage; Alendronate - therapeutic use; Alendronate - toxicity; Animals; Bisphosphonates; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - immunology; Coculture Techniques; Cytotoxicity, Immunologic; Humans; Immunotherapy; Immunotherapy, Adoptive - methods; Interferon-gamma - blood; Liposomes; Male; Mice, SCID; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - therapy; Receptors, Antigen, T-Cell, gamma-delta - immunology; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Sensitiser; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Xenograft Model Antitumor Assays; γδ T cells; γδ T cells; Liposomes; Bisphosphonates; Immunotherapy; Sensitiser
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2016.09.023

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. [Display omitted]