Enhanced antitumor efficacy of clinical-grade vasculature-targeted liposomal doxorubicin.
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.
Pastorino
Fabio
F
Experimental Therapies Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy. fabiopastorino@ospedale-gaslini.ge.it
Di Paolo
Daniela
D
Piccardi
Federica
F
Nico
Beatrice
B
Ribatti
Domenico
D
Daga
Antonio
A
Baio
Gabriella
G
Neumaier
Carlo E
CE
Brignole
Chiara
C
Loi
Monica
M
Marimpietri
Danilo
D
Pagnan
Gabriella
G
Cilli
Michele
M
Lepekhin
Eugene A
EA
Garde
Seema V
SV
Longhi
Renato
R
Corti
Angelo
A
Allen
Theresa M
TM
Wu
Jinzi J
JJ
Ponzoni
Mirco
M
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
D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D004317:Doxorubicin; D018826:CD13 Antigens