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.

除了众所周知的使用微泡（MBs）作为超声（US）成像中常规组织描绘和灌注的强力造影剂外，美国靶向的MB破坏（UTMD）已被证明是一种新兴的无创给药技术到肿瘤部位。然而，常规MB的非常有限的载药能力仍然是其作为有效的癌症治疗应用的巨大障碍。在这项研究中，合成了两亲性Janus喜树碱-氟尿苷（CF）共轭物，以工程化具有超高载药量（高达56.7±2.3％）的CF MB。事实证明，CF MBs是一种出色的造影剂，可增强US成像以确定肿瘤的位置和大小。在美国当地在增强对比的美国成像的指导下暴露于破裂的CF MB的情况下，将CF MBs成功地原位转化为CF NPs，通过声波穿孔作用产生的CF共轭物的药物蓄积比没有US的CF NPs和CF MBs高约14倍。在CF被肿瘤细胞内化并水解其酯键后，喜树碱（CPT）和氟尿苷（FUDR）以精确的1：1比例释放，以实现协调的药代动力学，从而导致CF的鼠肿瘤模型对肿瘤生长的抑制作用显着提高与CF NP（〜54.1％）和载有CPT和FUDR的脂质体（〜21.6％）相比，MB与US（〜72.4％）相结合。总体而言，这些结果表明，将CF MB与US结合使用是一种强有力的策略，可显着提高联合化疗的疗效并大大降低不良副作用。