A65: TRIGGERED DOXORUBICIN RELEASE IN SOLID TUMOURS IN VIVO FROM LIPID-ZIPPER PEPTIDE HYBRID THERMOSENSITIVE VESICLES
1 Nanomedicine Lab, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK,2Mary Lyons Centre, MRC Harwell, Harwell Science and Innovations Campus, Oxfordshire, UK
A promising development in liposomal anticancer treatment is to enclose the drug inside temperature-sensitive vesicles that can travel to the tumour site and release their contents on-demand when heated. Recently, we described a new type of such thermosensitive vesicles, based on the hybrid membrane formation between lipids and leucine zipper temperature-responsive peptides (Lp-Peptide hybrids) encapsulating doxorubicin (DOX). These constructs prolonged blood circulation kinetics and increased tumour accumulation in vivo on application of localised mild heating. Here, the biological activities of the doxorubicin-loaded Lp-Peptide hybrids were further investigated in comparison to other clinically-relevant thermosensitive liposomes along with the critical conditions that could elicit the most efficient tumour-killing in mice bearing human colorectal carcinoma xenografts.
Lp-Peptide hybrids therapeutic activities were investigated by looking at comparative tumour accumulation of DOX with live optical imaging, tumour growth retardation and survival using a human colorectal adenocarcinoma (SW480) xenograft model. Two heating protocols were applied to assess tumour tissue intravascular or interstitial drug release.
In vivo studies showed that Lp-Peptide hybrid treatment with the intravascular release protocol achieved significant tumour growth retardation compared to control mice and no accompanying signs of toxicity. The therapeutic effect of Lp-Peptide hybrids with this protocol was also identical to the effect observed from the clinically tested lysolipid-containing thermosensitive liposomes (ThermoDOX®). When the heating protocol was changed to release DOX interstitially, the best tumour growth retardation was obtained from Lp-Peptide hybrids because of their longer blood circulation that resulted in good tumour accumulation. Similar findings were observed in survival rates that agreed with the tumour growth delay and DOX accumulation data observed in the two heating protocols.
Novel temperature-sensitive Lp-Peptide hybrid vesicles were shown to triggerably release doxorubicin in vivo using different heating and administration protocols that can maximise treatment options without compromising therapeutic efficacy.