Preserving the Integrity of Surfactant-Stabilized Microbubble Membranes for Localized Oxygen Delivery

Abstract

Ultrasound contrast agents consist of stabilized microbubbles. We are developing a surfactantstabilized microbubble platform with a shell composed of Span 60 (Sorbitan monostearate) and an emulsifying agent, water-soluble vitamin E (α-tocopheryl poly(ethylene glycol) succinate, abbreviated as TPGS), named SE61. The microbubbles act both as an imaging agent and a vehicle for delivering oxygen to hypoxic areas in tumors. For clinical use, it is important that a platform be stable under storage at room temperature. To accomplish this, a majority of biologicals are prepared as freeze-dried powders, which also eliminates the necessity of a cold chain. The interfaces among the surfactants, gas, and liquids are subject to disruption in both the freezing and drying phases. Using thermocouples to monitor temperature profiles, differential scanning calorimetry to determine the phase transitions, and acoustic properties to gauge the degree of microbubble disruption, the effects of the freezing rate and the addition of different concentrations of lyoprotectants were determined. Slower cooling rates achieved by freezing the samples in a −20 °C bath were found to be reproducible and produce contrast agents with acceptable acoustical properties. The ionic strength of the solutions and the concentration of the lyoprotectant determined the glass-transition temperature (T g ′) of the frozen sample, which determines at what temperature samples can be dried without collapse. Crucially, we found that the shelf stability of surfactant-shelled oxygen microbubbles can be enhanced by increasing the lyoprotectant (glucose) concentration from 1.8 to 5.0% (w/v), which prevents the melt temperature (T m) of the TPGS phase from rising above room temperature. The increase in glucose concentration results in a lowering of T m of the emulsifying agent, preventing a phase change in the liquid-crystalline phase and allowing for more stable bubbles. We believe that preventing this phase change is necessary to producing stabilized freeze-dried microbubbles.

Investigating the Role of Lipid Transfer in Microbubble-Mediated Drug Delivery

“…While sonication has several shortcomings as a fabrication process in terms of the polydispersity of the microbubbles, it does meet the above requirements. Moreover, it is still widely used in the manufacture of commercial agents and in the research literature 25,26 and thus enables comparison of microbubble characteristics with those reported in other studies. Briefly, the relevant lipids (Avanti Polar Lipids Inc.) and polyoxyethylene (40) stearate (PEG40S, Sigma-Aldrich, U.K.) were dissolved in chloroform (Sigma-Aldrich, U.K.) and mixed in a glass vial at the molar ratios given in Table 1 (total weight of constituents = 20 mg).…”

Preparation of multifunctional nanobubbles and their application in bimodal imaging and targeted combination therapy of early pancreatic cancer

“…However, MBs cannot pass through the tumor vascular endothelial gap (380–780 nm) and arrive at the target on tumor cells because of their large size (> 1 μm) 10 . Even then, the short lifespan of MBs in vivo is also an obstacle to their therapeutic effects in tumors 11 . To achieve real molecular imaging and effective treatment of tumors, stable nanosized ultrasound contrast agents are necessary.…”

Engineering the Acoustic Response and Drug Loading Capacity of PBCA-Based Polymeric Microbubbles with Surfactants

“…Surfactants are chemicals used in the synthesis of polymeric MB as they reduce the gas–liquid interfacial tension, stabilizing the formation of bubbles and acting as templates for shell polymerization. − Surfactants can be classified according to the nature of their hydrophilic groups ( i.e. , nonionic, cationic, anionic surfactants). , Nonionic surfactants are among the most common reagents for MB synthesis (particularly Tween and Triton X surfactants) because of their commercial availability and long track record of use in the pharmaceutical industry. ,− In addition to the chemical structure, the colloidal behavior of surfactants strongly depends on their molecular weight (MW) and hydrophilic–lipophilic balance (HLB) value. For instance, the increased MW for a set of reagents of the same family can lead to an increase in the gas–liquid interfacial tension of the resulting solutions with surfactants. − Regarding the HLB of surfactants, it acts as an indicator of their hydrophilic (HLB > 10) or lipophilic nature (HLB < 10).…”