Journal
ONCOLOGY RESEARCH
Volume 17, Issue 7, Pages 283-299Publisher
COGNIZANT COMMUNICATION CORP
DOI: 10.3727/096504009787721212
Keywords
Doxorubicin; Pluronics; Formaldehyde; AN-9; Ultrasound
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The chemotherapeutic agent doxorubicin forms drug-DNA adducts that are enhanced by formaldehyde-releasing prodrugs such as AN-9. One of the major limitations of doxorubicin is dose-limiting cardiotoxicity therefore, the use of a targeting strategy that enables drug delivery and release at tumor sites is of great interest. The major aim of this study was to use the Pluronic-ultrasound delivery system to encapsulate doxorubicin and formaldehyde-releasing prodrugs within Pluronic micelles, and then use ultrasound to trigger controlled drug release from micelles. Pluronic micelles themselves were not stable upon dilution and required the use of a stabilizing agent DSPE-PEG2000 to form stable mixed micelles. Following the separation of free doxorubicin, approximately 60% of doxorubicin remained encapsulated within mixed micelles with a retention half-life of approximately 12 h. The formaldehyde-releasing prodrugs, however, were not retained within mixed micelles, but could potentially be administered separately to doxorubicin-loaded micelles to achieve tumor-localized formation of doxorubicin-DNA adducts. The use of low-frequency, high-power ultrasound (20 kHz, 100 W/cm(2)) released 7-10% of doxorubicin from mixed micelles. Collectively, these results indicate that the Pluronic-ultrasound system could be used to deliver and release doxorubicin with the potential of forming cytotoxic DNA adducts at tumor sites with coadministrated formaldehyde-releasing prodrugs.
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