Further investigation of the mechanism of Doxorubicin release from P105 micelles using kinetic models

Abstract

The kinetics of the release of Doxorubicin from Pluronic P105 micelles during ultrasonication and its subsequent re-encapsulation upon cessation of insonation were investigated. Four mechanisms are proposed to explain the acoustically-triggered Doxorubicin (Dox) release and re-encapsulation from Pluronic P105 micelles. The four mechanisms are: micelle destruction; destruction of cavitating nuclei; reassembly of micelles, and the re-encapsulation of Dox. The first mechanism, the destruction of micelles during insonation, causes the release of Dox into solution. The micelles are destroyed because of cavitation events produced by collapsing nuclei, or bubbles in the insonated solution. The second mechanism, the slow destruction of cavitating nuclei, results in a slow partial recovery phase, when a small amount of Dox is re-encapsulated. The third and fourth mechanisms, the reassembly of micelles and the re-encapsulatin of Dox, are independent of ultrasound. These two mechanism are responsible for maintaining the drug release at a partial level, and for recovery after insonation ceases. A normal distribution was used to describe micellar size. Parameters for the model were determined based upon the best observed fit to experimental data. The resulting model provides a good approximation to experimental data for the release of Dox from Pluronic P105 micelles.

Fig. 1

(a) First 10 s of data from five separate runs immediately after insonation begins. Light gray markers indicate the raw data, and the dark gray markers indicate the average of the five runs. (b) Sixty seconds of data from five separate runs immediately after insonation begins. Light gray markers indicate the raw data, and the dark gray markers indicate the average of the five runs. Only one run extended beyond 55 s.

Fig. 2

Data from five separate runs, immediately after insonation ceases.

Fig. 3

(a) Results from the simulation compared to experimental data for five runs, the first 10 s after insonation begins. The solid black line is the model output. Light gray markers indicate the raw data, and the dark gray markers indicate the average of the five runs. (b) Results from the simulation compared to experimental data for five runs, the first 60 s after insonation begins. The solid black line is the model output. Light gray markers indicate the raw data, and the dark gray markers indicate the average of the five runs. Only one run extended beyond 55 s.

Fig. 4

Normalized number of micelles over time for each micellar group during insonation. Results from the simulation.

Fig. 5

(a) Fraction of Dox which is encapsulated in each micellar group during first 10 s of insonation. Results from the simulation. (b) Fraction of Dox which is encapsulated in each micellar group during 60 s of insonation. Results from the simulation.

Fig. 6

Fraction of Dox which is encapsulated over time, during the post-insonation period. Results from the simulation compared to data from five separate runs.

Fig. 7

Fraction of Dox which is encapsulated over time during pulsed insonation. The insonation period was 2.0 s. The post-insonation period was 1.6 s. Results from the simulation (black line) compared to data from 10 cycles (gray symbols).

Fig. 8

Fraction of Dox which is encapsulated over time during pulsed insonation. The insonation period was 0.4 s. The post-insonation period was 2.0 s. Results from the simulation (black line) compared to data from 10 cycles (gray symbols).

Fig. 9

Fraction of Dox which is encapsulated over time during an experimental run consisting of several pulsed cycles. The insonation period was 2.0 s. The post-insonation period was 1.6 s. The maximum release of Dox (corresponding to the minimum of encapsulated Dox) increases slightly over the first few cycles.