Modulating the therapeutic activity of nanoparticle delivered paclitaxel by manipulating the hydrophobicity of prodrug conjugates.
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.
Ansell
Steven M
SM
Celator Pharmaceuticals Corporation, Vancouver, BC, Canada. sansell@celatorpharma.com
Johnstone
Sharon A
SA
Tardi
Paul G
PG
Lo
Lily
L
Xie
Sherwin
S
Shu
Yu
Y
Harasym
Troy O
TO
Harasym
Natashia L
NL
Williams
Laura
L
Bermudes
David
D
Liboiron
Barry D
BD
Saad
Walid
W
Prud'homme
Robert K
RK
Mayer
Lawrence D
LD
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
D008055:Lipids; D008823:Micelles; D011137:Polystyrenes; D011355:Prodrugs; C103390:polyethylene glycol-polystyrene; D011092:Polyethylene Glycols; D017239:Paclitaxel