Degradation kinetics of stabilized Pluronic micelles under the action of ultrasound

Abstract

The majority of research in the area of acoustically-activated drug delivery from stabilized micelles has been focused on the rapid release of chemotherapy drugs from the core of such nano-carriers. Previous publications have shown that low-frequency ultrasound is able to release approximately 2% of Doxorubicin (Dox) from the core of Pluronic P105 micelles stabilized using a cross-linked network of N,N-diethylacrylamide (NanoDeliv) within 2 s of applying 70-kHz ultrasound. Here we use a custom-made ultrasound exposure chamber with fluorescence detection to measure the long-term fluorescence emissions of Dox from the NanoDeliv after 2 h of exposure to two ultrasound frequencies, 70 and 476 kHz, at a mechanical index of 0.9. Fluorescence measurements are then used to deduce the degradation kinetics of stabilized Pluronic micelles during 24 h following exposure to ultrasound. Results show that ultrasound does disrupt the covalent network of the stabilized micelles, but the time constant of network degradation is very long compared to the time constant pertaining to drug release from micelles. Experiments also show no significant difference in degradation rates when employing the two frequencies in question at the same mechanical index.

Figure 1

Typical normalized fluorescence degradation curve. A NanoDeliv™ solution, loaded with 10 μg/ml Doxorubicin, was subjected to ultrasound for two hours at 70 kHz immediately prior to this measurement. Note the inconsistent behavior during the first 10 hours.

Figure 2

Normalized fluorescence beginning 10 hours after ultrasonicating NanoDeliv™ solutions, loaded with 10 μg/ml Doxorubicin, using a 70-kHz bath. The data display three superimposed experiments, each indicated by a different gray-scale and are scaled to start at 1 (or 100% encapsulation of Dox inside these miscelles).

Figure 3

Normalized fluorescence beginning 10 hours after ultrasonicating NanoDeliv™ solutions, loaded with 10 μg/ml Doxorubicin, using a 476-kHz transducer. The data displays three superimposed experiments, each indicated by a different gray-scale and are scaled to start at 1 (or 100% encapsulation of Dox inside these micelles).

Figure 4

Normalized Fluorescence behavior after incubating the Dox-micellar solution (NanoDeliv™ solutions, loaded with 10 μg/ml Doxorubicin) for ten hours. No prior insonation was used in these experiments. The data displays three superimposed experiments, each indicated by a different gray-scale.