title: Chitosan-clodronate nanoparticles loaded in poloxamer gel for intra-articular administration.
abstract: This work was based on the study of an intra-articular delivery system constituted by a poloxamer gel vehiculating clodronate in chitosan nanoparticles. This system has been conceived to obtain a specific and controlled release of clodronate in the joints to reduce the arthritis rheumatoid degenerative effect. Clodronate (CLO) is a first-generation bisphosphonate with anti-inflammatory properties, inhibiting the cytokine and NO secretion from macrophages, therefore causing apoptosis in these cells. This is related to its ability to be metabolized by cells and converted into a cytotoxic intermediate as a non-hydrolysable analogue of ATP. Chitosan (CHI) was used to develop nanosystems, by ionotropic gelation induced by clodronate itself. A fractional factorial experimental design allowed us to obtain nanoparticles, the diameter of which ranged from 200 to 300nm. Glutaraldehyde was used to increase nanoparticle stability and modify the drug release profile. The zeta potential value of crosslinked nanopaparticles was 21.0mV±1.3, while drug loading was 31.0%±5.4 w/w; nanoparticle yield was 18.2%±1.8 w/w, the encapsulation efficiency was 48.8%±9.9 w/w. Nanoparticles were homogenously loaded in a poloxamer sol, and the drug delivery system is produced in-situ after local administration, when sol become gel at physiological temperature. The properties of poloxamer gels containing CHI-CLO nanoparticles, such as viscosity, gelation temperature and drug release properties, were evaluated. In vitro studies were conducted to evaluate the effects of these nanoparticles on a human monocytic cell line (THP1). The results showed that this drug delivery system is more efficient, with respect to the free drug, to counteract the inflammatory process characteristic of several degenerative diseases.
authors.affiliation: Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148 Genova, Italy. Electronic address: russo@difar.unige.it.
authors.forename: E
authors.initials: E
authors.lastname: Russo
authors.affiliation: Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148 Genova, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Gaglianone
authors.affiliation: Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148 Genova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Baldassari
authors.affiliation: Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148 Genova, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Parodi
authors.affiliation: Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148 Genova, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Croce
authors.affiliation: Department of Experimental Medicine, General Pathology, University of Genova, Via L.B. Alberti 2, 16132 Genova, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Bassi
authors.affiliation: Department of Experimental Medicine, General Pathology, University of Genova, Via L.B. Alberti 2, 16132 Genova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Vernazza
authors.affiliation: Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148 Genova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Caviglioli
mesh_terms: D050071:Bone Density Conservation Agents / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004002:Clodronic Acid / Q000737:chemistry* / Q000494:pharmacology; D003094:Collagen / Q000737:chemistry* / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems; D065546:Drug Liberation; D017886:Durapatite / Q000737:chemistry* / Q000494:pharmacology; D005163:Factor Analysis, Statistical; D015870:Gene Expression; D005976:Glutaral / Q000737:chemistry; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D044367:Phase Transition; D020442:Poloxamer / Q000737:chemistry; D014783:Viscosity
chemical_list: D050071:Bone Density Conservation Agents; D003432:Cross-Linking Reagents; C508585:IL1B protein, human; D053583:Interleukin-1beta; D016209:Interleukin-8; D004002:Clodronic Acid; D020442:Poloxamer; D003094:Collagen; D017886:Durapatite; D005976:Glutaral
keywords: Clodronate; Controlled release; IL-1β and IL-8 gene expression; Nanoparticles; Poloxamer gels; Rheumatoid arthritis; THP1 cells