1. Investigating in vitro and in vivo αvβ6 integrin receptor-targeting liposomal alendronate for combinatory γδ T cell immunotherapy.
- Author
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Hodgins, Naomi O., Al-Jamal, Wafa' T., Wang, Julie T.-W., Klippstein, Rebecca, Costa, Pedro M., Sosabowski, Jane K., Marshall, John F., Maher, John, and Al-Jamal, Khuloud T.
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CANCER immunotherapy , *INTEGRINS , *CANCER cells , *ALENDRONATE , *CELL-mediated cytotoxicity , *LIPOSOMES , *THERAPEUTICS - Abstract
The αvβ6 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 αvβ6 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 Vγ9Vδ2 T cells. It is hypothesised that by using the αvβ6-specific peptide A20FMDV2 as a targeting moiety for L-ALD, the therapeutic efficacy of this therapy can be increased in αvβ6 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 αvβ6 positive cells line A375Pβ6. Bio-distribution of both L and t-L were carried out in αvβ6 positive (A375Pβ6 and PANC0403) and αvβ6 negative (A375Ppuro and PANC-1) subcutaneous tumour mouse models. Immuno-compromised mice bearing A375Pβ6 experimental metastatic lung tumours were treated with L-ALD or t-L-ALD as monotherapies or in combination with ex vivo -expanded Vγ9Vδ2 T cells. In vitro , αvβ6-dependant uptake of t-L was observed, with t-L-ALD being more effective than L-ALD at sensitising A375Pβ6 to γδ 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 γδ T cells in vivo but t-L-ALD offered no added advantage compared to L-ALD. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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