title: Novel temperature-triggered liposome with high stability: formulation, in vitro evaluation, and in vivo study combined with high-intensity focused ultrasound (HIFU).
abstract: We developed a novel temperature-sensitive liposome, STL composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG-2000), cholesterol, and a fatty acid conjugated elastin-like polypeptide (ELP). The STL had a unilamellar spherical shape with a mean diameter of 160 nm. Doxorubicin (DOX) was encapsulated by the STL using an ammonium sulfate gradient method with a lipid to drug ratio of 1:0.2 (w/w), resulting in 95% loading efficiency. The STL exhibited better stability than conventional low temperature sensitive liposome (LTSL-lysolipid-based temperature sensitive liposomes; DPPC:MSPC:DSPE-PEG-2000=90:10:4) at 37 °C in the presence of serum; there was rapid release of doxorubicin in the range of 39-42 °C (≥95% release at 42 °C within 10s). A confocal microscope revealed that DOX encapsulated in STL (STL-DOX) was taken up much better by cell nuclei at 42 °C than at 37 °C. The difference in cell viability between 37 and 42 °C was 63% relative to STL-DOX and 18% for LTSL-DOX. The pharmacokinetics (PK) and antitumor effect of STL-DOX combined with high-intensity focused ultrasound (HIFU) were studied, and compared with LTSL. An in vivo study demonstrated that STL-DOX is highly stable, with a long circulating property (half life=2.03±0.77 h) in HIFU-untreated mice, and resulted in significant tumor regression for 2 days after intravenous injection of STL-DOX at 5 mg DOX/kg in combination with HIFU. These results are better than conventional LTSL, for which the blood circulation time is short (0.92±0.17 h) and inhibition of tumor growth is weak. These results indicate that the properties of stability at 37 °C and burst release at 42 °C of STL-DOX act synergistically against tumors.
authors.affiliation: DDS Group, Bio Research Center, Samsung Advanced Institute of Technology-SAIT, Samsung Electronics Co., Ltd., Yongin 446-712, South Korea.
authors.forename: Sun Min
authors.initials: SM
authors.lastname: Park
authors.forename: Min Sang
authors.initials: MS
authors.lastname: Kim
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Park
authors.forename: Eun Sung
authors.initials: ES
authors.lastname: Park
authors.forename: Kyu-Sil
authors.initials: KS
authors.lastname: Choi
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Hyun Ryoung
authors.initials: HR
authors.lastname: Kim
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006367:HeLa Cells; D057086:High-Intensity Focused Ultrasound Ablation; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D013696:Temperature; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D008055:Lipids; D008081:Liposomes; D004317:Doxorubicin
keywords: Drug delivery system; Elastin-like polypeptide; Heat-triggered drug release; Mild hyperthermia; Thermosensitive liposome