title: Lipid nanocarriers containing a levodopa prodrug with potential antiparkinsonian activity.
abstract: This paper describes the production, characterization and in vivo activity of lipid nanocarriers (LN) containing a levodopa prodrug (LD-PD) with therapeutic potential in Parkinson's disease. LD is the mainstay of the pharmacotherapy of Parkinson's disease. However, after a good initial response, motor fluctuations, dyskinesia and loss of efficacy, develop over time, partly due to oscillations in plasma and brain levels of the drug. LD-PD was produced with the aim of prolonging the pharmacological activity of LD. To improve solubility, and simultaneously provide a long lasting release and therapeutic efficacy, the prodrug was formulated in tristearin/lecithin LN. The obtained formulation was homogeneous in particle size and remained stable for up to 2months from preparation. For the three different tested LD concentrations, namely 1.25, 2.5 and 5.0mg/ml, the morphological characterization revealed no substantial differences between unloaded and LD-PD loaded LN. The calorimetric test showed an interaction between the lipid phase and the loaded prodrug. In vitro studies using the dialysis method and enzymatic degradation procedure showed that the LD-PD loaded LN provided a controlled prodrug release. Finally, two behavioural tests specific to akinesia (bar test) or akinesia/bradykinesia (drag test) performed in 6-hydroxydopamine hemilesioned mice (a model of Parkinson's disease) demonstrated that the LD-PD loaded LN attenuated parkinsonian disabilities, showing a slightly reduced maximal efficacy but a longer lasting action (up to 24h) than an equal dose of LD. We conclude that LD-PD loaded LN may represent a future LD formulation useful in Parkinson's disease therapy.
authors.affiliation: Department of Life Sciences & Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ravani
authors.affiliation: Department of Drug Sciences, University of Catania, Catania, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Sarpietro
authors.affiliation: Department of Life Sciences & Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Esposito
authors.affiliation: Department of Pharmaceutical Sciences, University of "G. D'Annunzio", Chieti, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Stefano
authors.affiliation: Department of Pharmaceutical Sciences, University of "G. D'Annunzio", Chieti, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Sozio
authors.affiliation: Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Centre for Neuroscience, National Institute for Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Calcagno
authors.affiliation: Macromolecular Chemistry II, University of Bayreuth, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Drechsler
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Catia
authors.initials: C
authors.lastname: Contado
authors.affiliation: Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Centre for Neuroscience, National Institute for Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Longo
authors.affiliation: Department of Drug Sciences, University of Catania, Catania, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Giuffrida
authors.affiliation: Department of Drug Sciences, University of Catania, Catania, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Castelli
authors.affiliation: Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Centre for Neuroscience, National Institute for Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
authors.affiliation: Department of Life Sciences & Biotechnology, University of Ferrara, Ferrara, Italy. Electronic address: crt@unife.it.
authors.forename: Rita
authors.initials: R
authors.lastname: Cortesi
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D020285:Cryoelectron Microscopy; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D054709:Lecithins / Q000737:chemistry; D007980:Levodopa / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008055:Lipids / Q000737:chemistry*; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000188:drug therapy; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D014280:Triglycerides / Q000737:chemistry
chemical_list: D000978:Antiparkinson Agents; D004337:Drug Carriers; D054709:Lecithins; D008055:Lipids; D011355:Prodrugs; D014280:Triglycerides; D007980:Levodopa; C022618:tristearin