Development of highly efficacious hydrophobic paclitaxel prodrugs delivered in nanoparticles for fixed-ratio drug combination applications
Authors: Steven Ansell, Sharon Johnstone, Paul Tardi, Lily Lo, Sherwin Xie, Yu Shu, Troy Harasym, Natashia Harasym, Laura Williams, David Bermudes, Barry Liboiron, Walid Saad, Robert Prud'homme, Lawrence Mayer
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

5734 

In vitro evidence has revealed that many drug combinations can act either synergistically or antagonistically, depending on the exposed drug ratio. Since the pharmacokinetic behavior of the individual drugs cannot be controlled when administered in a conventional aqueous based cocktail, drug delivery systems must be utilized to maintain optimal drug ratios. We report here the development of nanoparticle delivery systems for hydrophobic drugs where plasma drug levels can be controlled in a manner that can be readily adapted to deliver drug combinations. Paclitaxel is a hydrophobic chemotherapeutic drug that is typically used in combination with other agents to treat breast, lung and ovarian cancer. Poor drug solubility necessitates its formulation into a mixture of Cremophor and ethanol. Toxicity associated with the use of Cremophor has resulted in formulation efforts using polymer micelles or nanoparticles with hydrophobic cores to serve as a drug reservoir. While paclitaxel can be efficiently solubilized in these delivery systems, the drug is rapidly cleared from circulation following injection. We have generated a series of hydrophobic paclitaxel prodrugs with the objective of enhancing and controlling drug circulation lifetime through changes in the hydrophobic lipid anchor composition. Paclitaxel prodrugs were stably incorporated into amphiphilic block copolymer nanoparticles and administered intravenously into mice. The 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 rates ranging from 1h to 24 h. The nanoparticle formulations could be stored stably at 4°C for several months. To evaluate the therapeutic activity of the various paclitaxel prodrugs, nanoparticle formulations were administered intravenously into mice bearing HT29 human colon xenograph tumors. As the plasma half-life and area under the curve of the prodrug increased, activity against HT29 tumors also increased. Paclitaxel prodrug nanoparticles more than doubled the time for HT29 tumors to reach 400 mg relative to commercial paclitaxel in Cremophor, when both treatments were administered at MTD using optimal treatment regimens. The paclitaxel prodrugs could be co-formulated with hydrophobic prodrug analogues of water-soluble agents such as doxorubicin and dual-drug nanoparticles maintained the two agents at the injected drug:drug ratio in the plasma for extended times after injection. Formulating hydrophobic prodrugs in nanoparticles provides a novel approach to co-deliver anticancer drug combinations with widely differing physicochemical properties and maintain optimal drug:drug ratios in vivo .