Medical treatment of orthotopic glioblastoma with transferrin-conjugated nanoparticles encapsulating zoledronic acid
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Manuela Porru1, Silvia Zappavigna2, Giuseppina Salzano3, Amalia Luce2, Antonella Stoppacciaro1, Maria Luisa Balestrieri2, Simona Artuso1, Sara Lusa3, Giuseppe De Rosa3, Carlo Leonetti1 and Michele Caraglia2
1 Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Via delle Messi d’oro, Rome, Italy
2 Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via Costantinopoli, Naples, Italy
3 Department of Pharmacy, University of Naples Federico II, Via Montesano, Naples, Italy
Carlo Leonetti , email:
Michele Caraglia, email:
Keywords: Glioblastoma, intracranial xenografts, zoledronic acid, transferrin, delivery, calcium phosphate self-assembly nanoparticles.
Received: May 28, 2014 Accepted: July 8, 2014 Published: July 9, 2014
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.
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