title: Enhanced antitumor efficacy of clinical-grade vasculature-targeted liposomal doxorubicin.
abstract: OBJECTIVE
  In vivo evaluation of good manufacturing practice-grade targeted liposomal doxorubicin (TVT-DOX), bound to a CD13 isoform expressed on the vasculature of solid tumors, in human tumor xenografts of neuroblastoma, ovarian cancer, and lung cancer.
  
  
  METHODS
  Mice were implanted with lung, ovarian, or neuroblastoma tumor cells via the pulmonary, peritoneal, or orthotopic (adrenal gland) routes, respectively, and treated, at different days post inoculation, with multiple doses of doxorubicin, administered either free or encapsulated in untargeted liposomes (Caelyx) or in TVT-DOX. The effect of TVT-DOX treatment on tumor cell proliferation, viability, apoptosis, and angiogenesis was studied by immunohistochemical analyses of neoplastic tissues and using the chick embryo chorioallantoic membrane assay.
  
  
  RESULTS
  Compared with the three control groups (no doxorubicin, free doxorubicin, or Caelyx), statistically significant improvements in survival was seen in all three animal models following treatment with 5 mg/kg (maximum tolerated dose) of TVT-DOX, with long-term survivors occurring in the neuroblastoma group; increased survival was also seen at a dose of 1.7 mg/kg in mice bearing neuroblastoma or ovarian cancer. Minimal residual disease after surgical removal of neuroblastoma primary mass, and the enhanced response to TVT-DOX, was visualized and quantified by bioluminescence imaging and with magnetic resonance imaging. When treated with TVT-DOX, compared with Caelyx, all three tumor models, as assayed by immunohistochemistry and chorioallantoic membrane, showed statistically significant reductions in cell proliferation, blood vessel density, and microvessel area, showing increased cell apoptosis.
  
  
  CONCLUSIONS
  TVT-DOX should be evaluated as a novel angiostatic strategy for adjuvant therapy of solid tumors.
authors.affiliation: Experimental Therapies Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy. fabiopastorino@ospedale-gaslini.ge.it
authors.forename: Fabio
authors.initials: F
authors.lastname: Pastorino
authors.forename: Daniela
authors.initials: D
authors.lastname: Di Paolo
authors.forename: Federica
authors.initials: F
authors.lastname: Piccardi
authors.forename: Beatrice
authors.initials: B
authors.lastname: Nico
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Antonio
authors.initials: A
authors.lastname: Daga
authors.forename: Gabriella
authors.initials: G
authors.lastname: Baio
authors.forename: Carlo E
authors.initials: CE
authors.lastname: Neumaier
authors.forename: Chiara
authors.initials: C
authors.lastname: Brignole
authors.forename: Monica
authors.initials: M
authors.lastname: Loi
authors.forename: Danilo
authors.initials: D
authors.lastname: Marimpietri
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pagnan
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Lepekhin
authors.forename: Seema V
authors.initials: SV
authors.lastname: Garde
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Allen
authors.forename: Jinzi J
authors.initials: JJ
authors.lastname: Wu
authors.forename: Mirco
authors.initials: M
authors.lastname: Ponzoni
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D018826:CD13 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D004317:Doxorubicin; D018826:CD13 Antigens