Development of pluronic micelle-encapsulated doxorubicin and formaldehyde-releasing prodrugs for localized anticancer chemotherapy.
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/cm2) 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.
Ugarenko
Michal
M
Department of Biochemistry, La Trobe University, Victoria, 3086, Australia.
Chan
Chee-Kai
CK
Nudelman
Abraham
A
Rephaeli
Ada
A
Cutts
Suzanne M
SM
Phillips
Don R
DR
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods*; D005557:Formaldehyde / Q000737:chemistry; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D008823:Micelles; D011355:Prodrugs / Q000008:administration & dosage*; D014465:Ultrasonics
D000903:Antibiotics, Antineoplastic; D008823:Micelles; D011355:Prodrugs; D005557:Formaldehyde; D004317:Doxorubicin