title: Focused ultrasound and interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in glioblastoma multiforme.
abstract: The clinical application of chemotherapy to brain tumors has been severely limited because the blood-brain barrier (BBB) often prevents therapeutic levels from being achieved. Here we show that pulsed HIFU and human atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes containing doxorubicin (AP-1 Lipo-Dox) act synergistically in an experimental brain tumor model. We developed an intracranial brain-tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM) 8401 cells. Pulsed HIFU was used to transcranially disrupt the BBB in these mouse brains by delivering ultrasound waves in the presence of microbubbles. Prior to each sonication, AP-1 Lipo-Dox or unconjugated Lipo-Dox was administered intravenously, and the concentration in the brains was quantified by fluorometer. Compared to control animals treated with injections of AP-1 Lipo-Dox or unconjugated Lipo-Dox, animals receiving the drug followed by pulsed HIFU exhibited enhanced accumulation of the drug in tumor cells. Drug injection with sonication increased the tumor-to-normal brain doxorubicin ratio of the target tumors by about twofold compared with the control tumors. Moreover, the tumor-to-normal brain ratio was highest after the injection of AP-1 Lipo-Dox with sonication. Combining sonication with AP-1 Lipo-Dox also significantly inhibited tumor growth compared with chemotherapy alone. There was a modest but significant increase in the median survival time in mice treated with AP-1 Lipo-Dox followed by pulsed HIFU, compared to those treated with AP-1 Lipo-Dox without sonication. The use of AP-1-conjugated liposomes carrying cytotoxic agents followed by pulsed HIFU represents a feasible approach for enhanced targeted drug delivery in brain tumor therapies.
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan. fyyang@ym.edu.tw
authors.forename: Feng-Yi
authors.initials: FY
authors.lastname: Yang
authors.forename: Tai-Tong
authors.initials: TT
authors.lastname: Wong
authors.forename: Ming-Che
authors.initials: MC
authors.lastname: Teng
authors.forename: Ren-Shyan
authors.initials: RS
authors.lastname: Liu
authors.forename: Maggie
authors.initials: M
authors.lastname: Lu
authors.forename: Hsiang-Fa
authors.initials: HF
authors.lastname: Liang
authors.forename: Ming-Cheng
authors.initials: MC
authors.lastname: Wei
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage*; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D057086:High-Intensity Focused Ultrasound Ablation; D006801:Humans; D008081:Liposomes; D051379:Mice; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry; D019948:Receptors, Interleukin-4 / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D014463:Ultrasonography; D023041:Xenograft Model Antitumor Assays
chemical_list: C513345:AP1 peptide; D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D010455:Peptides; D019948:Receptors, Interleukin-4; D004317:Doxorubicin