Efficacy of interleukin-13 receptor-targeted liposomal doxorubicin in the intracranial brain tumor model.
Human glioblastoma tumors selectively express receptors for interleukin 13 (IL-13). In a previous study, we showed that liposomes, when conjugated with IL-13, will deliver chemotherapeutics to a subcutaneous glioma tumor model in mice much more effectively than conventional unconjugated liposomes. Based on this observation, we developed an intracranial brain tumor model in nude mice using human U87 glioma cells. Mice receiving weekly i.p. injections of 15 mg/kg of doxorubicin encapsulated in IL-13-conjugated liposomes had a 5-fold reduction in the intracranial tumor volume over 6 weeks and four of seven animals survived >200 days after tumor implantation. In contrast, the animals receiving unconjugated liposomes with the same doxorubicin concentration did not survive beyond 35 days and there was no evidence of tumor size reduction. The presence of liposomes with doxorubicin in the tumor was shown by taking advantage of the selective expression of IL-13 receptors on the tumor cells and the endogenous fluorescence of doxorubicin. There was no increase in the indices of toxicity in animals receiving the doxorubicin-containing liposomes. Finally, a model of the blood-brain barrier was used to show that the nanovesicles do not harm the endothelial cells yet maintain their toxicity to astrocytoma cells. This approach is necessary to show the efficacy of this targeting platform for tumors in which the blood-brain barrier is not compromised and as a potential use of the nanovesicle system as a surveillance mechanism to prevent recurrence. These data show that IL-13 targeted nanovesicles are a viable option for the treatment of brain tumors.
Madhankumar
Achuthamangalam B
AB
Department of Neurosurgery (H110), G.M. Leader Family Laboratory, Penn State University, College of Medicine, M.S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033-0850, USA.
Slagle-Webb
Becky
B
Wang
Xinsheng
X
Yang
Qing X
QX
Antonetti
David A
DA
Miller
Patti A
PA
Sheehan
Jonas M
JM
Connor
James R
JR
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods; D004355:Drug Stability; D005260:Female; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D010316:Particle Size; D053660:Receptors, Interleukin-13 / Q000037:antagonists & inhibitors*; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D053660:Receptors, Interleukin-13; D004317:Doxorubicin