title: Modulating the therapeutic activity of nanoparticle delivered paclitaxel by manipulating the hydrophobicity of prodrug conjugates.
abstract: A series of paclitaxel prodrugs designed for formulation in lipophilic nanoparticles are described. The hydrophobicity of paclitaxel was increased by conjugating a succession of increasingly hydrophobic lipid anchors to the drug using succinate or diglycolate cross-linkers. The prodrugs were formulated in well defined block copolymer-stabilized nanoparticles. These nanoparticles were shown to have an elimination half-life of approximately 24 h in vivo. The rate at which the prodrug was released from the nanoparticles could be controlled by adjusting the hydrophobicity of the lipid anchor, resulting in release half-lives ranging from 1 to 24 h. The diglycolate and succinate cross-linked prodrugs were 1-2 orders of magnitude less potent than paclitaxel in vitro. Nanoparticle formulations of the succinate prodrugs showed no evidence of efficacy in HT29 human colorectal tumor xenograph models. Efficacy of diglycolate prodrug nanoparticles increased as the anchor hydrophobicity increased. Long circulating diglycolate prodrug nanoparticles provided significantly enhanced therapeutic activity over commercially formulated paclitaxel at the maximum tolerated dose.
authors.affiliation: Celator Pharmaceuticals Corporation, Vancouver, BC, Canada. sansell@celatorpharma.com
authors.forename: Steven M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Johnstone
authors.forename: Paul G
authors.initials: PG
authors.lastname: Tardi
authors.forename: Lily
authors.initials: L
authors.lastname: Lo
authors.forename: Sherwin
authors.initials: S
authors.lastname: Xie
authors.forename: Yu
authors.initials: Y
authors.lastname: Shu
authors.forename: Troy O
authors.initials: TO
authors.lastname: Harasym
authors.forename: Natashia L
authors.initials: NL
authors.lastname: Harasym
authors.forename: Laura
authors.initials: L
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Bermudes
authors.forename: Barry D
authors.initials: BD
authors.lastname: Liboiron
authors.forename: Walid
authors.initials: W
authors.lastname: Saad
authors.forename: Robert K
authors.initials: RK
authors.lastname: Prud'homme
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Mayer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004355:Drug Stability; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D011092:Polyethylene Glycols; D011137:Polystyrenes; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D008055:Lipids; D008823:Micelles; D011137:Polystyrenes; D011355:Prodrugs; C103390:polyethylene glycol-polystyrene; D011092:Polyethylene Glycols; D017239:Paclitaxel