title: Triggered doxorubicin release in solid tumors from thermosensitive liposome-peptide hybrids: Critical parameters and therapeutic efficacy.
abstract: Temperature-sensitive vesicles designed by inclusion of leucine zipper peptides within a lipid bilayer (Lp-Peptide hybrids) encapsulating Doxorubicin (DOX) have been reported. Intravenous administration of these constructs prolonged blood circulation kinetics and increased tumor accumulation in vivo with local mild hyperthermia. In this study, the biological activity of the DOX-loaded Lp-Peptide hybrid vesicles was further investigated at the cellular level and in vivo compared to lysolipid-containing temperature-sensitive liposomes (LTSL) and traditional temperature-sensitive liposomes. Lp-Peptide vesicles were not toxic to cell cultures at 37°C, while effective cancer cell toxicity was observed after 1 hr of heating at 42°C. The activity of Lp-Peptide vesicles in vivo was studied using two different heating protocols to obtain tumor intravascular or interstitial drug release. Lp-Peptide vesicle treatment allowing intravascular DOX release showed equally effective tumor growth retardation and survival to that of LTSL treatment. The Lp-Peptide vesicles also offered therapeutic responses using the alternative heating protocol to maximise drug release within the tumor interstitium. Matching the drug release kinetics of temperature-sensitive vesicles with the heating protocol applied is considered the most critical factor to determine therapeutic efficacy in the clinical translation of such modalities.
authors: Nanomedicine Lab, Institute of Inflammation and Repair, Manchester Cancer Research Centre, Faculty of Medical & Human Sciences, University of Manchester, United Kingdom.|UCL School of Pharmacy, Department of Pharmaceutics, University College London, Brunswick Square, WC1N 1AX, United Kingdom.
authors: Zahraa S
authors: ZS
authors: Al-Ahmady
authors: Harwell Science and Innovation Campus, MRC Harwell, Oxfordshire, OX110RD, United Kingdom.
authors: Cheryl L
authors: CL
authors: Scudamore
authors: Nanomedicine Lab, Institute of Inflammation and Repair, Manchester Cancer Research Centre, Faculty of Medical & Human Sciences, University of Manchester, United Kingdom.|UCL School of Pharmacy, Department of Pharmaceutics, University College London, Brunswick Square, WC1N 1AX, United Kingdom.
authors: Kostas
authors: K
authors: Kostarelos
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D016350:Leucine Zippers; D008081:Liposomes / Q000737:chemistry; D008546:Melanoma, Experimental; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D010455:Peptides / Q000737:chemistry; D013696:Temperature; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D010455:Peptides; D004317:Doxorubicin
keywords: cancer therapy; chemotherapy; hyperthermia; nanoparticles; temperature-sensitive; vesicles