Plasma sterilization of poly lactic acid ultrasound contrast agents: surface modification and implications for drug delivery.

Poly lactic acid (PLA) ultrasound contrast agents (CA) have been developed previously in our laboratory for ultrasound (US) imaging, as well as surface coated with doxorubicin to create a potential targeted platform of chemotherapeutic delivery using focused US. However, we have previously found it impossible to sterilize these agents while at the same time maintaining their acoustic properties, a task that would probably require fabrication within a clean facility. The purpose of this paper is to investigate the feasibility of using plasma to sterilize these CA while maintaining maximum echogenicity, a step that would greatly facilitate in vivo investigations. Effects of plasma exposure time (1, 3 and 6 min) and intensity (low-10 mA, 6.8 W; medium-15 mA, 10.5 W; and high-25 mA, 18 W) on the CAs' acoustic properties, surface morphology, zeta potential, capacity to carry chemotherapeutics and overall sterility are described. Both increases in plasma intensity and exposure time increased CA zeta potential and also significantly increased drug payload. High-intensity plasma exposure for 3 min was found to be an optimal sterilization protocol for maximal (100%) preservation of CA echogenicity. Plasma exposure resulted in sterile samples and maintained original CA enhancement of 20 dB and acoustic half-life over 75 min, while increasing CA zeta potential by 11 mV and doxorubicin loading efficiency by 10%. This study not only shows how a highly temperature- and pressure-sensitive agent can be sterilized using plasma, but also that surface modification can be used to increase surface binding of the drug.