A64: ENHANCED IN VIVO TUMOUR ACCUMULATION OF ANTIBODY-TARGETED TEMPERATURE-SENSITIVE LIPOSOMES BY LOCAL HEAT ACTIVATION
1Nanomedicine Lab, School of Medicine and National Graphene Institute, Faculty of Medical and Human Sciences, AV Hill Building, The University of Manchester, Manchester, UK,2Laboratoire dImmunologie et Chimie Thérapeutiques, CNRS, Institute de Biologie Moléculaire et Cellulaire, Strasbourg, France
One of the clinically-established methods for the advanced delivery of anticancer drugs has been to package the therapeutic molecules inside nanoscale lipid-based carrier systems, known as liposomes. This allows more effective transport and localization of the drug molecules within the tumour tissue and reduces collateral damage to healthy cells. In this study the effectiveness of these liposomes has been further improved by further engineering with targeting ligands on their surface and triggered release capabilities of the lipid vesicle bilayer to release their therapeutic drug content upon mild heating.
Targeted temperature-sensitive liposomes (TSL) were designed by surface modification with the clinically tested hCTMO1 monoclonal antibody directed towards the MUC-1 antigen. We characterized these liposomes by studying their mean diameter, surface properties, serum stability and thermal sensitivity. Receptor-mediated cellular uptake and cytotoxic efficacy of the targeted TSL were investigated using 2D and 3D cell culture techniques. Different heating and administration protocols were tested in vivo to explore the effect of local heating on the accumulation of targeted TSL into the tumor and their therapeutic efficacy.
Targeted TSL showed to be chemically and thermally stable after conjugation to anti-MUC-1 antibody. Significant enhancement in cellular uptake and cytotoxic activity after exposure to 1h of mild heating at 42°C was observed from targeted TSL compared to non-targeted TSL in MUC-1 over-expressing human melanoma cancer cells (MDA-MB-435). We observed that the actively targeted TSL in combination with mild heating showed greater uptake in tumour tissue in xenograft-bearing mice than those without targeting ability. This resulted in a moderate improvement in animal survival.
We have successfully developed combinatory heat-activated and antibody-targeted liposomes that proved to be chemically and structurally stable. This approach may open new directions to develop novel mechanistic strategies to improve targeted drug delivery and release within tumour tissue, while better sparing normal cells.