Ultrasound contrast agent microbubbles with ultrahigh loading capacity of camptothecin and floxuridine for enhancing tumor accumulation and combined chemotherapeutic efficacy

In addition to the well-known use of microbubbles (MBs) as powerful contrast agents for general tissue delineation and perfusion in ultrasound (US) imaging, US-targeted MB destruction (UTMD) has been demonstrated to be an emerging technique for noninvasive drug delivery to tumor sites. However, the very limited drug-loading capacity of conventional MBs remains a great obstacle to their application as an efficacious cancer therapy. In this study, an amphiphilic Janus camptothecin-floxuridine (CF) conjugate was synthesized to engineer CF MBs with ultrahigh drug-loading contents (up to 56.7 ± 2.3%). CF MBs were proven to be an excellent contrast agent to enhance US imaging for identifying the location and size of tumors. Upon local US exposure to burst CF MBs under the guidance of contrast-enhanced US imaging, successful conversion of CF MBs into CF NPs in situ resulted in ~14 times higher drug accumulation of the CF conjugate via the sonoporation effect than that of CF NPs and CF MBs without US. After CF was internalized by tumor cells and its ester bond was hydrolyzed, camptothecin (CPT) and floxuridine (FUDR) were released at an exact 1:1 ratio to achieve coordinated pharmacokinetics, leading to significantly higher tumor growth inhibition in murine tumor models of CF MBs combined with US (~72.4%) than CF NPs (~54.1%) and liposomes loaded with CPT and FUDR (~21.6%). Overall, these results demonstrate that the combination of CF MBs with US is a powerful strategy for remarkably enhancing the combined chemotherapeutic efficacy and greatly reducing the undesirable side effects. Tiny gas-filled bubbles that help microscopes spot tumors can also deliver drug nanoparticles to tumor cells. Microbubbles have resonant properties that enhance the quality of ultrasonic images, and are safe to introduce into the bloodstream. Zhifei Dai from Peking University in Beijing, China, and co-workers have now developed a synthetic procedure that combines two promising anticancer drugs in a complex that spontaneously forms microbubbles following mechanical agitation with a fluorinated gas. Ultrasound imaging demonstrated that these microbubbles could be tracked as they circulated to tumor sites in mice. Then, using minute-long ultrasound applications, the team burst the bubbles and created drug nanoparticles. Therapeutic studies revealed that the ultrasound waves facilitated drug movement across tumor cell membranes, leading to lower rates of tumor growth compared to intravenous injections of the nanoparticles. Amphiphilic Janus camptothecin-floxuridine (CF) conjugate was synthesized for engineering CF microbubbles (CF MBs) with ultrahigh drug-loading contents. CF MBs exhibited excellent capability to enhance ultrasound (US) imaging for identifying the location and size of the tumors, while it can be efficiently converted into CF NPs upon sonication, conducing to remarkably high drug tumor accumulation via sonoporation effect. Both camptothecin (CPT) and floxuridine (FUDR) could be released at an exact 1:1 ratio in the tumor microenvironment, achieving significantly improved therapeutic efficacy. Overall, the CF MBs combining with US technique will provide a step toward the application of targeted theranostics.