期刊
NPG ASIA MATERIALS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41427-018-0066-x
关键词
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资金
- National Key Research and Development Program of China [2016YFA0201400]
- National Project for Research and Development of Major Scientific Instruments [81727803]
- National Natural Science Foundation of China [81771846, 81571810]
- Beijing Natural Science Foundation-Haidian Original Innovation Joint Fund [17L20170]
- Foundation for Innovative Research Groups of the National Natural Science Foundation of China [81421004]
- Peking University Third Hospital [BYSY2015023]
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 similar to 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 (similar to 72.4%) than CF NPs (similar to 54.1%) and liposomes loaded with CPT and FUDR (similar to 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.
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