Medical treatment of orthotopic glioblastoma with transferrin-conjugated nanoparticles encapsulating zoledronic acid.

Abstract

Glioblastomas are highly aggressive adult brain tumors with poor clinical outcome. In the central nervous system (CNS) the blood-brain barrier (BBB) is the most important limiting factor for both development of new drugs and drug delivery. Here, we propose a new strategy to treat glioblastoma based on transferrin (Tf)-targeted self-assembled nanoparticles (NPs) incorporating zoledronic acid (ZOL) (NPs-ZOL-Tf). NPs-ZOL-Tf have been assessed on the glioblastoma cell line U373MG-LUC that showed a refractoriness in vitro to temozolomide (TMZ) and fotemustine (FTM). NPs-ZOL-Tf treatment resulted in higher in vitro cytotoxic activity than free ZOL. However, the potentiation of anti-proliferative activity of NPs-ZOL-Tf was superimposable to that one induced by NPs-ZOL (not armed with Tf). On the other hand, NPs-ZOL-Tf showed a higher antitumor efficacy if compared with that one caused by NPs-ZOL in immunosuppressed mice intramuscularly bearing U373MG-LUC xenografts, inducing a significant tumor weight inhibition (TWI). The experiments performed on mice with intracranial U373MG-LUC xenografts confirmed the efficacy of NPs-ZOL-Tf. These effects were paralleled by a higher intratumour localization of fluorescently-labeled-NPs-Tf both in intramuscular and intracranial xenografts. In conclusion, our results demonstrate that the encapsulation of ZOL increases the antitumor efficacy of this drug in glioblastoma through the acquisition of ability to cross the BBB.

• Authors: Manuela Porru, Silvia Zappavigna, Giuseppina Salzano, Amalia Luce, Antonella Stoppacciaro, Maria Luisa Balestrieri, Simona Artuso, Sara Lusa, Giuseppe De Rosa, Carlo Leonetti, Michele Caraglia
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 21 Pg. 10446-59 (Nov 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25431953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Diphosphonates
• Imidazoles
• Nitrosourea Compounds
• Organophosphorus Compounds
• Transferrin
• Zoledronic Acid
• Dacarbazine
• fotemustine
• Temozolomide

Topics

• Animals
• Apoptosis (drug effects)
• Blood-Brain Barrier (drug effects)
• Brain Neoplasms (drug therapy)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Dacarbazine (analogs & derivatives, therapeutic use)
• Diphosphonates (administration & dosage, chemistry)
• Drug Delivery Systems (methods)
• Drug Resistance, Neoplasm
• Glioblastoma (drug therapy, immunology)
• Humans
• Imidazoles (administration & dosage, chemistry)
• Male
• Mice
• Mice, Inbred Strains
• Nanoparticles (administration & dosage, chemistry)
• Nitrosourea Compounds (therapeutic use)
• Organophosphorus Compounds (therapeutic use)
• Temozolomide
• Transferrin (chemistry)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays
• Zoledronic Acid