title: Stealth liposomes encapsulating zoledronic acid: a new opportunity to treat neuropathic pain.
abstract: In the pathogenesis of neuropathic pain, the conversion of astrocytes in the reactive state and the ras-dependent Erk-mediated pathway play an important role. Zoledronic acid (ZOL) is a potent inhibitor of the latter pathway, but its activity in neurological diseases is hampered by its biodistribution that is almost exclusively limited to the bone. We have developed nanotechnological devices able to increase the accumulation of ZOL in extra bone sites. In this work, we have evaluated the effects of ZOL-encapsulating PEGylated liposomes (LipoZOL) on an animal model of neuropathic pain. We have found that 2 iv administrations (10 μg of ZOL, either as free or encapsulated into liposomes) at days 2 and 4 after the injury markedly reduced mechanical hypersensitivity at 3 and 7 days after nerve injury. On the other hand, free ZOL did not exert any significant alteration of the mechanical threshold. Immunohistochemical analysis of spinal cord revealed that GFAP-labeled astrocytes appeared hypertrophic activated cells in the ispilateral dorsal horn of spinal cord 7 days after SNI. LipoZOL significantly changed astrocyte morphology, by inducing a protective phenotype, without changing the total cell number. Moreover, the astrocytes of the spinal cord of LipoZOL-treated mice were positive for interleukin-10. Delivery of ZOL into the CNS was confirmed by biodistribution of fluorescently labeled liposomes. In particular, liposomes accumulated in the liver and kidney in both groups of normal and neuropathic animals; on the other hand, only in the case of neuropathic animals, a fluorescence increase in the brain and spinal cord occurred only in neuropathic animals at 30 min and 1 h. These data demonstrate that ZOL, only by using a delivery system able to cross the altered BBB, could be a new opportunity to treat neuropathic pain.
authors: Department of Biochemistry and Biophysics "F. Cedrangolo", Second University of Naples , Via Costantinopoli, 16 80138 Naples, Italy.
authors: Michele
authors: M
authors: Caraglia
authors: Livio
authors: L
authors: Luongo
authors: Giuseppina
authors: G
authors: Salzano
authors: Silvia
authors: S
authors: Zappavigna
authors: Monica
authors: M
authors: Marra
authors: Francesca
authors: F
authors: Guida
authors: Sara
authors: S
authors: Lusa
authors: Catia
authors: C
authors: Giordano
authors: Vito
authors: V
authors: De Novellis
authors: Francesco
authors: F
authors: Rossi
authors: Alberto
authors: A
authors: Abbruzzese Saccardi
authors: Giuseppe
authors: G
authors: De Rosa
authors: Sabatino
authors: S
authors: Maione
mesh_terms: D000818:Animals; D004164:Diphosphonates / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D005434:Flow Cytometry; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry*; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D008081:Liposomes; D000077211:Zoledronic Acid