title: Characterization of alkanoyl-10-O-minocyclines in micellar dispersions as potential agents for treatment of human neurodegenerative disorders.
abstract: Minocycline is a widely used antibacterial agent. Moreover, it is also demonstrated to be effective in several neurodegenerative disorders, due to its antioxidant and anti-inflammatory activities. However, the last activity is only apparent at very high doses. In fact, minocycline poorly crosses the blood-brain barrier (BBB) due to its low lipophilicity and half-life. The present work details the physicochemical characterization of a series of alkanoyl-10-O-minocycline derivatives (2-6), which are able to produce self-assembled aggregates in aqueous solution. The n-octanol/aqueous phase lipophilicity of minocycline and its derivatives were assessed by theoretical calculation, by shake-flask method, and by reversed-phase HPLC. Moreover, we determined their affinity for membrane phospholipids measuring their HPLC retention on phospholipid-based stationary phases, the so-called "Immobilized Artificial Membranes" (IAMs). Our results indicate high lipophilicity values for the minocycline derivatives (compounds 2-6); these values and the corresponding phospholipid affinities increase with the length of the hydrocarbon moiety substituent. Furthermore, the ability of the investigated alkanoyl-10-O-minocycline derivatives to self-assemble could allow a direct administration by oral and intraperitoneal routes as supramolecular systems. The advantages are an enhancement of drug solubilization, a sustained release, and the consequent less frequent drug administration. Moreover, we can hypothesize the potential solubilization in the micellar core of other poorly water soluble drugs which could improve the therapeutic effects of the pharmaceutical formulation in a combined therapy. Given the high lipophilicity of the title derivatives, they can be supposed to offer higher half-life and a better BBB penetration than minocycline. Since the new derivatives retain the structural features related to the antioxidant and anti-inflammatory effects of minocycline, they can be regarded not only as long-acting antimicrobial agents but also as candidate drugs for a targeted treatment of mental illness.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università G. D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy. adistefano@unich.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Stefano
authors.forename: Piera
authors.initials: P
authors.lastname: Sozio
authors.forename: Antonio
authors.initials: A
authors.lastname: Iannitelli
authors.forename: Laura Serafina
authors.initials: LS
authors.lastname: Cerasa
authors.forename: Antonella
authors.initials: A
authors.lastname: Fontana
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Biase
authors.forename: Guglielmo
authors.initials: G
authors.lastname: D'Amico
authors.forename: Mara
authors.initials: M
authors.lastname: Di Giulio
authors.forename: Carmen
authors.initials: C
authors.lastname: Carpentiero
authors.forename: Lucia
authors.initials: L
authors.lastname: Grumetto
authors.forename: Francesco
authors.initials: F
authors.lastname: Barbato
mesh_terms: D000473:Alkanes / Q000138:chemical synthesis*; D000478:Alkylation; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D007202:Indicators and Reagents; D008823:Micelles; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000138:chemical synthesis* / Q000627:therapeutic use; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000473:Alkanes; D000900:Anti-Bacterial Agents; D007202:Indicators and Reagents; D008823:Micelles; D008911:Minocycline