Investigating in vitro and in vivo alpha v beta 6 integrin receptor-targeting liposomal alendronate for combinatory gamma delta T cell immunotherapy

摘要

The alpha v beta 6 integrin receptor has been shown to be overexpressed on many types of cancer cells, resulting in a more pro-invasive and aggressive phenotype, this makes it an attractive target for selective drug delivery. In tumours that over-express the alpha v beta 6 receptor, cellular uptake of liposomes can be enhanced using ligand-targeted liposomes. It has previously been shown in both in vitro and in vivo studies that liposomal alendronate (L-ALD) can sensitise cancer cells to destruction by V gamma 9V delta 2 T cells. It is hypothesised that by using the alpha v beta 6-specific peptide A20FMDV2 as a targeting moiety for L-ALD, the therapeutic efficacy of this therapy can be increased in alpha v beta 6 positive tumours. Targeted liposomes (t-L) were formulated and the targeting efficacy of targeted liposomes (t-L) was assessed by cell uptake and cytotoxicity studies in the alpha v beta 6 positive cells line A375P beta 6. Bio-distribution of both L and t-L were carried out in alpha v beta 6 positive (A375P beta 6 and PANC0403) and alpha v beta 6 negative (A375Ppuro and PANC-1) subcutaneous tumour mouse models. Immuno-compromised mice bearing A375P beta 6 experimental metastatic lung tumours were treated with L-ALD or t-L-ALD as monotherapies or in combination with ex vivo-expanded V gamma 9V delta 2 T cells. In vitro, alpha v beta 6-dependant uptake of t-L was observed, with t-L-ALD being more effective than L-ALD at sensitising A375P beta 6 to gamma delta T cells. Interestingly, t-L-ALD led to slightly higher but not significant reduction in tumour growth compared to L-ALD, when used as monotherapy in vivo. Moreover, both L-ALD and t-L-ALD led to significant reductions in tumour growth when used in combination with gamma delta T cells in vivo but t-L-ALD offered no added advantage compared to L-ALD.