title: Busulfan loading into poly(alkyl cyanoacrylate) nanoparticles: physico-chemistry and molecular modeling.
abstract: The busulfan is an alkylating agent widely used for the treatment of haematological malignancies and nonmalignant disorders. For a long time, it has been available only in an oral form. This treatment leads to a wide variability in bioavailability and side effects such as the veino-occlusive disease. Thus, an intravenous formulation of busulfan-loaded nanoparticles may be considered as a major progress. This study deals with busulfan entrapment by nanoprecipitation into five different types of poly(alkyl cyanoacrylate) polymers. The polymers leading to the highest busulfan loading efficiencies were poly(isobutyl cyanoacrylate) (PIBCA) and poly(ethyl cyanoacrylate). Molecular modeling along with energy minimization process was employed to identify the nature of the interactions occurring between busulfan and PIBCA. Further, optimization studies enabled to obtain PIBCA nanoparticles displaying busulfan loading ratios equal to 5.9% (w/w) together with nanoparticle yields of 71% (w/w). Since busulfan is a highly reactive molecule, we performed (1)H-NMR spectroscopy experiments showing that chemical integrity of the drug was preserved after loading into nanoparticles. The in vitro release studies under sink conditions, in water, or in rat plasma showed a fast release in the first 10 min followed by a slower one over 6 h. This phenomenon could be explained by the semi-polar characteristics of busulfan.
authors.affiliation: UMR CNRS 8612, Faculty of Pharmacy, Paris-Sud University, Chātenay-Malabry, France.
authors.forename: Anne-Magali
authors.initials: AM
authors.lastname: Layre
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
authors.forename: Hélène
authors.initials: H
authors.lastname: Chacun
authors.forename: Caroline
authors.initials: C
authors.lastname: Aymes-Chodur
authors.forename: Nour-Eddine
authors.initials: NE
authors.lastname: Ghermani
authors.forename: Jacques
authors.initials: J
authors.lastname: Poupaert
authors.forename: Joël
authors.initials: J
authors.lastname: Richard
authors.forename: Denis
authors.initials: D
authors.lastname: Requier
authors.forename: Ruxandra
authors.initials: R
authors.lastname: Gref
mesh_terms: D000477:Alkylating Agents / Q000008:administration & dosage* / Q000737:chemistry; D002066:Busulfan / Q000008:administration & dosage* / Q000737:chemistry; D002850:Chromatography, Gel; D003487:Cyanoacrylates / Q000138:chemical synthesis / Q000737:chemistry; D016503:Drug Delivery Systems; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology
chemical_list: D000477:Alkylating Agents; D003487:Cyanoacrylates; D002066:Busulfan