title: Pulsed-high intensity focused ultrasound and low temperature-sensitive liposomes for enhanced targeted drug delivery and antitumor effect.
abstract: OBJECTIVE
  To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors.
  
  
  METHODS
  Comparisons in vitro and in vivo were carried out between non-thermosensitive liposomes (NTSL) and low temperature-sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors.
  
  
  RESULTS
  In vitro incubations simulating the pulsed-HIFU thermal dose (42 degrees C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups.
  
  
  CONCLUSIONS
  Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.
authors.affiliation: Diagnostic Radiology Department, Clinical Center, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Dromi
authors.forename: Victor
authors.initials: V
authors.lastname: Frenkel
authors.forename: Alfred
authors.initials: A
authors.lastname: Luk
authors.forename: Bryan
authors.initials: B
authors.lastname: Traughber
authors.forename: Mary
authors.initials: M
authors.lastname: Angstadt
authors.forename: Monica
authors.initials: M
authors.lastname: Bur
authors.forename: Jason
authors.initials: J
authors.lastname: Poff
authors.forename: Jianwu
authors.initials: J
authors.lastname: Xie
authors.forename: Steven K
authors.initials: SK
authors.lastname: Libutti
authors.forename: King C P
authors.initials: KC
authors.lastname: Li
authors.forename: Bradford J
authors.initials: BJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods*; D006979:Hyperthermia, Induced / Q000379:methods*; D008081:Liposomes; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D013696:Temperature; D014465:Ultrasonics
chemical_list: D008081:Liposomes; D004317:Doxorubicin