title: Lipid-peptide vesicle nanoscale hybrids for triggered drug release by mild hyperthermia in vitro and in vivo.
abstract: The present study describes leucine zipper peptide-lipid hybrid nanoscale vesicles engineered by self-assembled anchoring of the amphiphilic peptide within the lipid bilayer. These hybrid vesicles aim to combine the advantages of traditional temperature-sensitive liposomes (TSL) with the dissociative, unfolding properties of a temperature-sensitive peptide to optimize drug release under mild hyperthermia, while improving in vivo drug retention. The secondary structure of the peptide and its thermal responsiveness after anchoring onto liposomes were studied with circular dichroism. In addition, the lipid-peptide vesicles (Lp-peptide) showed a reduction in bilayer fluidity at the inner core, as observed with DPH anisotropy studies, while the opposite effect was observed with an ANS probe, indicating peptide interactions with both the headgroup region and the hydrophobic core. A model drug molecule, doxorubicin, was successfully encapsulated in the Lp-peptide vesicles at higher than 90% efficiency following the remote loading, pH-gradient methodology. The release of doxorubicin from Lp-peptide hybrids in vitro indicated superior serum stability at physiological temperatures compared to lysolipid-containing temperature-sensitive liposomes (LTSL) without affecting the overall thermo-responsive nature of the vesicles at 42 °C. A similar stabilizing effect was observed in vivo after intravenous administration of the Lp-peptide vesicles by measuring (14)C-doxorubicin blood kinetics that also led to increased tumor accumulation after 24 h. We conclude that Lp-peptide hybrid vesicles present a promising new class of TSL that can offer previously unexplored opportunities for the development of clinically relevant mild hyperthermia-triggered therapeutic modalities.
authors.affiliation: Nanomedicine Lab, Centre for Drug Delivery Research, UCL School of Pharmacy, University College London, London WC1N 1AX, United Kingdom.
authors.forename: Zahraa S
authors.initials: ZS
authors.lastname: Al-Ahmady
authors.forename: Wafa' T
authors.initials: WT
authors.lastname: Al-Jamal
authors.forename: Jeroen V
authors.initials: JV
authors.lastname: Bossche
authors.forename: Tam T
authors.initials: TT
authors.lastname: Bui
authors.forename: Alex F
authors.initials: AF
authors.lastname: Drake
authors.forename: A James
authors.initials: AJ
authors.lastname: Mason
authors.forename: Kostas
authors.initials: K
authors.lastname: Kostarelos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D006358:Hot Temperature; D008081:Liposomes / Q000737:chemistry*; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D010455:Peptides / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D008081:Liposomes; D053769:Nanocapsules; D010455:Peptides; D004317:Doxorubicin