Active targeted delivery of small molecule drugs is becoming increasingly important in personalized therapies, especially in cancer, brain disorders, and a wide variety of other diseases. However, effective means of spatial targeting and delivering high drug payloads in vivo are still lacking. Focused ultrasound combined with superheated phase-shift nanodroplets, which vaporize into microbubbles using heat and sound, are rapidly becoming a popular strategy for targeted drug delivery. Focused ultrasound can target deep tissue with excellent spatial precision and without using ionizing energy, thus can activate nanodroplets in circulation. One of the main limitations of this technology has been poor drug loading in the droplet core or the shell material. To address this need, we have developed a strategy to combine low-boiling point decafluorabutane and octafluoropropane (DFB and OFP) nanodroplets with drug-loaded liposomes, creating phase-changeable droplet-liposome clusters (PDLCs). We demonstrate a facile method of assembling submicron PDLCs with high drug-loading capacity on the droplet surface. Furthermore, we demonstrate that chemical tethering of liposomes in PDLCs enables a rapid release of their encapsulated cargo upon acoustic activation (>60% using OFP-based PDLCs). Rapid uncaging of small molecule drugs would make them immediately bioavailable in target tissue or promote better penetration in local tissue following intravascular release. PDLCs developed in this study can be used to deliver a wide variety of liposome-encapsulated therapeutics or imaging agents for multi-modal imaging applications. We also outline a strategy to deliver a surrogate encapsulated drug, fluorescein, to tumors in vivo using focused ultrasound energy and PDLCs.
Phase-change contrast agents (PCCAs) are liquid nanodroplets (ND) that transition into gas microbubbles (MB) when exposed to pulsed ultrasound (US) . The purpose of this study was to investigate the activation threshold of size-isolated PCCAs under physiologically relevant hydrostatic pressures. Size-isolated PFB NDs were prepared using an extrusion method and filter sizes of 100 or 400 nm. Using a programmable US scanner and linear array transducer, a custom scan sequence was implemented that interleaved pulsed US transmissions for both PCCA activation and MB detection. An automated US pressure sweep was performed (3 to 6 MPa, N = 200 discrete intervals), and grayscale US images were acquired at each increment. PCCAs were circulated through a flow phantom at 37 deg. Hydrostatic pressures applied to the PCCAs was controlled by constriction of flow phantom tubing. Reference measures were recorded by a calibrated pressure catheter. Activation thresholds were quantified using custom MATLAB software. The US-detected PCCA activation threshold increased with increased hydrostatic pressure in the range of 0 to 75 mmHg. The 100 nm size-isolated PCCAs activated at a higher US pressure as compared to 400 nm agents (4.3 ± 0.2 mmHg versus 3.7 ± 0.2 mmHg, p < 0.001). A positive correlation was found between the PCCA activation threshold and applied hydrostatic pressure for both 100 and 400 nm PCCAs (R 2 > 0.95, p < 0.001). This strong linear relationship could be exploited for noninvasive pressure estimation using US and PCCAs.
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