This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pastorino, F. Articles by Ponzoni, M. Search for Related Content PubMed PubMed Citation Articles by Pastorino, F. Articles by Ponzoni, M.

Enhanced Antitumor Efficacy of Clinical-Grade Vasculature-Targeted Liposomal Doxorubicin

Authors' Affiliations: ¹ Experimental Therapies Unit, Laboratory of Oncology, G. Gaslini Children's Hospital; ² Animal Research Facility, ³ Gene Transfer Laboratory, and ⁴ Department of Radiology, National Cancer Institute, Genoa, Italy; ⁵ Department of Human Anatomy, University of Bari, Bari, Italy; ⁶ Ambrilia Biopharma Inc., Verdun, Quebec, Canada; ⁷ Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche; ⁸ Immunobiotechnology Unit, San Raffaele Institute, Milan, Italy; and ⁹ Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada

Requests for reprints: Fabio Pastorino, Experimental Therapies Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, 16148 Genoa, Italy. Phone: 39-10-5636342; Fax: 39-10-3779820; E-mail: fabiopastorino{at}ospedale-gaslini.ge.it.

Purpose: 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.

Experimental Design: 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.

Conclusion: TVT-DOX should be evaluated as a novel angiostatic strategy for adjuvant therapy of solid tumors.