Journal
ACS NANO
Volume 12, Issue 7, Pages 7312-7326Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.8b03674
Keywords
photodynamic therapy; chemotherapy; microbubble; drug resistance; colorectal cancer
Categories
Funding
- National Key Research and Development Program of China [2016YFA0201400]
- Beijing Natural Science Foundation-Haidian original innovation joint fund [17L20170]
- National project for research and development of major scientific instruments [81727803]
- Foundation for Innovative Research Groups of the National Natural Science Foundation of China [81421004]
- National Natural Science Foundation of China [81771846, 81571810]
- Peking University Third Hospital [BYSY2015023]
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Multidrug resistance remains one of the main obstacles to efficient chemotherapy of colorectal cancer. Herein, an efficient combination therapeutic strategy is proposed based on porphyrin/camptothecin-floxuridine triad microbubbles (PCF-MBs) with high drug loading contents, which own highly stable co-delivery drug combinations and no premature release. The triad PCF-MBs can act not only as a contrast agent for ultrasound (US)/fluorescence bimodal imaging but also a multimodal therapeutic agent for synergistic chemo-photodynamic combination therapy. Upon local ultrasound exposure under the guidance of ultrasound imaging, in situ conversion of PCF-MBs into porphyrin/camptothecin-floxuridine nanoparticles (PCF-NPs) leads to high accumulation of chemo-drugs and photosensitizer in tumors due to the induced high permeability of the capillary wall and cell membrane temporarily via sonoporation effect, greatly reducing the risk of systemic exposure. Most importantly, it was found that the PCF-MB-mediated photodynamic therapy could significantly reduce the expression of adenosine-triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG(2)), which is responsible for the drug resistance in chemotherapy, resulting in a prominent intracellular camptothecin increase. In vivo experiments revealed that the PCF-MBs in combination with ultrasound and laser irradiation could achieve a 90% tumor inhibition rate of HT-29 cancer with no recurrence. Therefore, such triad PCF-MB-based combination therapeutic strategy shows great promise for overcoming drug resistance of colorectal cancer and other cancers.
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