Development of novel PLGA contrast agents for use as ultrasound targeted drug delivery vehicles

Ultrasound is limited in its ability to distinguish between diseased and normal tissue. This limitation has led to the development of contrast agents. We have produced novel air-filled microcapsules of poly (lactic-co-glycolic) acid (PLGA/PLA) that work well as ultrasound contrast agents. The agent demonstrated acoustic enhancements up to 24 dB in vitro and in vivo. Furthermore, in vivo Doppler enhancements of a rabbit kidney were reported with injections of a 0.1mL/kg dose. The rabbits did not show any side effects from multiple injections (24) of the agent.; The contrast agent was fabricated by modifying a double emulsion method to encapsulate sublimable materials in the oil and aqueous phases. The encapsulated materials were then sublimed, leaving a void in their place.; The degradation of contrast agents was found to be closely related to both capsule morphology and insonation frequency at which they were exposed. Agent degradation was monitored by high performance liquid chromatography (HPLC). Amounts of lactic and glycolic acids produced were quantified. Glycolic acid repeat units showed a greater degradation rate than lactic acid units.; Additional in vitro studies were carried out to further optimize and characterize the agent. The surfactant solution temperature was found to play an important role in agent morphology and acoustic response. An attenuation study indicated that their resonance frequency was ∼2 MHz. Furthermore, in vivo and in vitro studies concluded that the 50:50 PLGA agent is temperature sensitive, lasting up to 20 min at 25°C (minimal loss of signal (4 dB), while at 37°C the signal drops close to baseline with in the first 5 minutes. It was concluded that fabrication of the contrast agent with a more hydrophobic polymer extends its acoustic time response.; Preliminary drug delivery and targeting studies were also investigated. The reported results are promising and lay the foundation for future work.; This research has led to the development of novel PLGA/PLA contrast agents that have shown potential use for targeted drug delivery vehicles.