Shaping the synthesis of surfactant-stabilized oxygen microbubbles to accommodate encapsulated drug

We have developed oxygen filled microbubbles, SE61_O2, for localized, ultrasound-triggered oxygen delivery to hypoxic tumors prior to radiation therapy. Microbubbles, created by sonication, have a shell composed of D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) and sorbitan monostearate. Preliminary studies in mice with breast tumor xenographs showed that increases in oxygen partial pressure levels lasted less than 3 min, which is insufficient for most clinical applications. Hence, we investigated the potential of incorporating a hydrophobic antiglycolytic drug, modeled with Nile red. A new fabrication method was developed by first creating drug-loaded TPGS micelles. The resulting microbubbles had similar shell compositions, physical size, morphology, and acoustic properties as the original method. However, microbubble yield was more than doubled, resulting in twice the encapsulation efficiency. For the TPGS micelle method these include similar shell compositions (94.4 ± 0.6 % Montane 60), physical size post freeze-drying and reconstitution (1.57 ± 0.42 μm), morphology (spherical), and acoustic properties (maximum enhancement 19.92 ± 0.55 dB). However, microbubble yield was more than doubled, resulting in twice the encapsulation efficiency (up to 10.49 %). We propose that a nonideal mixture is formed when the surfactants are combined by the standard method, resulting in the formation of mixed micelles that are more stable, making microbubble creation more difficult during the sonication step.