title: 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.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Via delle Messi d'oro, Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Porru
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via Costantinopoli, Naples, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zappavigna
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Montesano, Naples, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Salzano
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via Costantinopoli, Naples, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Luce
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Via delle Messi d'oro, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Stoppacciaro
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via Costantinopoli, Naples, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Balestrieri
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Via delle Messi d'oro, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Artuso
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Montesano, Naples, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lusa
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Montesano, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Rosa
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Via delle Messi d'oro, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via Costantinopoli, Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004164:Diphosphonates / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009607:Nitrosourea Compounds / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D000077204:Temozolomide; D014168:Transferrin / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D014168:Transferrin; D000077211:Zoledronic Acid; D003606:Dacarbazine; C054368:fotemustine; D000077204:Temozolomide