The molecularly targeted drugs often have mild toxicities because of their selective interfere with certain hallmarks of cancer. However, these agents commonly have unfavorable distribution to the tumor tissue. In addition, serious toxicities may be associated with the organic solvents/surfactants that are used to dissolve the highly lipophilic drug molecules. The long-term goal of our research program is to devise novel micellar nanocarriers with broad applicability for tumor- targeted drug delivery. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a potent heat shock protein 90 (Hsp90) inhibitor that is currently undergoing Phases I and II clinical trials in patients with advanced cancers. The therapeutic outcomes of 17-AAG have been hampered owing to its severe hepatotoxicity as well as the large amount of toxic organic excipients used in the current intravenous formulations. Our preliminary studies have demonstrated that 17-AAG is efficiently loaded and retained within polyethylene glycol 2000-distearoylphosphatidylethanolamine (PEG2000-DSPE)/- tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles without the inclusion of any organic solvents. We propose to functionalize these mixed micelles with folic acid or hyaluronic acid (HA), to target FR-- or CD44-overexpressing tumor cells, respectively. The central hypothesis of this proposal is that folate- or HA-conjugated PEG2000-DSPE/TPGS micelles will increase 17-AAG levels in the tumor tissue while reducing the drug distribution to the healthy organs, and enhance the anticancer efficacy of 17-AAG.
The specific aims of the proposal are: (1) To generate the functionalized PEG2000-DSPE/TPGS micellar nanocarriers for the targeted delivery of 17-AAG;(2) To characterize the physicochemical properties of 17-AAG-incorporating functionalized PEG2000- DSPE/TPGS micellar nanocarriers;(3) To examine the uptake and anticancer activity of 17-AAG- incorporating functionalized PEG2000-DSPE/TPGS mixed micelles in tumor cells;and (4) To evaluate the pharmacokinetics, pharmacodynamics and anticancer efficacy of 17-AAG-incorporating functionalized PEG2000-DSPE/TPGS mixed micelles in mice bearing human tumor xenografts.
The successful completion of this project will identify highly effective and safe nanocarriers for tumor-targeted delivery of 17-AAG, significantly enhancing the antitumor efficacy and reducing the toxicities of the drug. Without the inclusion of any organic solvents, the proposed nanocarriers will provide a robust nanomedicine platform for delivering poorly water-soluble anticancer drugs to many common cancer types. Importantly, the proposed nanocarriers are also engineered to delivery anticancer drugs into cancer stem cells, a rare population of cancer cells in the tumor which are known to be resistant to drug therapy and cause tumor recurrence.
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