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 formula...

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Veröffentlicht in:Journal of medicinal chemistry 2008-06, Vol.51 (11), p.3288-3296
Hauptverfasser: Ansell, Steven M, Johnstone, Sharon A, Tardi, Paul G, Lo, Lily, Xie, Sherwin, Shu, Yu, Harasym, Troy O, Harasym, Natashia L, Williams, Laura, Bermudes, David, Liboiron, Barry D, Saad, Walid, Prud’homme, Robert K, Mayer, Lawrence D
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container_end_page 3296
container_issue 11
container_start_page 3288
container_title Journal of medicinal chemistry
container_volume 51
creator Ansell, Steven M
Johnstone, Sharon A
Tardi, Paul G
Lo, Lily
Xie, Sherwin
Shu, Yu
Harasym, Troy O
Harasym, Natashia L
Williams, Laura
Bermudes, David
Liboiron, Barry D
Saad, Walid
Prud’homme, Robert K
Mayer, Lawrence D
description 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.
doi_str_mv 10.1021/jm800002y
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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. 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Med. Chem</addtitle><description>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. 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subjects Analysis
Animals
Antineoplastic agents
Biological and medical sciences
Cell Line, Tumor
Drug Stability
General aspects
General pharmacology
Humans
Hydrophobic and Hydrophilic Interactions
Lipids - chemistry
Medical sciences
Mice
Mice, Nude
Micelles
Nanoparticles
Neoplasm Transplantation
Paclitaxel - administration & dosage
Paclitaxel - chemistry
Paclitaxel - pharmacology
Pharmacology. Drug treatments
Polyethylene Glycols
Polystyrenes
Prodrugs - administration & dosage
Prodrugs - chemistry
Prodrugs - pharmacology
Transplantation, Heterologous
title Modulating the Therapeutic Activity of Nanoparticle Delivered Paclitaxel by Manipulating the Hydrophobicity of Prodrug Conjugates
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