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

摘要

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 56.7uu2.3%). 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.