title: Complete regression of local cancer using temperature-sensitive liposomes combined with ultrasound-mediated hyperthermia.
abstract: The development of treatment protocols that result in a complete response to chemotherapy has been hampered by free drug toxicity and the low bioavailability of nano-formulated drugs. Here, we explore the application of temperature-sensitive liposomes that have been formulated to enhance stability in circulation. We formed a pH-sensitive complex between doxorubicin (Dox) and copper (CuDox) in the core of lysolipid-containing temperature-sensitive liposomes (LTSLs). The complex remains associated at neutral pH but dissociates to free Dox in lower pH environments. The resulting CuDox-LTSLs were injected intravenously into a syngeneic murine breast cancer model (6 mg Dox/kg body weight) and intravascular release of the drug was triggered by ultrasound. The entire tumor was insonified for 5 min prior to drug administration and 20 min post drug injection. A single-dose administration of CuDox-LTSLs combined with insonation suppressed tumor growth. Moreover, after twice per week treatment over a period of 28 days, a complete response was achieved in which the NDL tumor cells and the tumor interstitium could no longer be detected. All mice treated with ultrasound combined with CuDox-LTSLs survived, and tumor was undetectable 8 months post treatment. Iron and copper-laden macrophages were observed at early time points following treatment with this temperature sensitive formulation. Systemic toxicity indicators, such as cardiac hypertrophy, leukopenia, and weight and hair loss were not detected with CuDox-LTSLs after the 28-day therapy.
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 Health Sciences Drive, Davis, CA 95616, USA. Electronic address: akheirolomoom@ucdavis.edu.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Kheirolomoom
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 Health Sciences Drive, Davis, CA 95616, USA. Electronic address: cylai@ucdavis.edu.
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Lai
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 Health Sciences Drive, Davis, CA 95616, USA. Electronic address: smjohns@ucdavis.edu.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Tam
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 Health Sciences Drive, Davis, CA 95616, USA. Electronic address: lmmahakian@ucdavis.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahakian
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 Health Sciences Drive, Davis, CA 95616, USA. Electronic address: esingham@ucdavis.edu.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Ingham
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 Health Sciences Drive, Davis, CA 95616, USA. Electronic address: kdwatson@ucdavis.edu.
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Watson
authors.affiliation: University of California, Davis, Department of Biomedical Engineering, 451 Health Sciences Drive, Davis, CA 95616, USA. Electronic address: kwferrar@ucdavis.edu.
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D003300:Copper / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D006863:Hydrogen-Ion Concentration; D006979:Hyperthermia, Induced / Q000379:methods; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D013696:Temperature; D014465:Ultrasonics
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D003300:Copper; D004317:Doxorubicin
keywords: Doxorubicin; Extended survival; Hyperthermia; Temperature-sensitive liposomes; Toxicity