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Cancers 2018, 10(9), 311; https://doi.org/10.3390/cancers10090311

Insonation of Systemically Delivered Cisplatin-Loaded Microbubbles Significantly Attenuates Nephrotoxicity of Chemotherapy in Experimental Models of Head and Neck Cancer

1
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
2
Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
3
Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 10607, Taiwan
4
Department of Pathology, Taoyuan Armed Forces General Hospital, Taoyuan 32551, Taiwan
5
Department of Biomedical Engineering, Ming Chuan University, Taoyuan 33348, Taiwan
6
Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 11490, Taiwan
7
Laboratory Animal Center, National Defense Medical Center, Taipei 11490, Taiwan
8
Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan
9
Taichung Armed Forces General Hospital, Taichung 41168, Taiwan
*
Authors to whom correspondence should be addressed.
Received: 15 July 2018 / Revised: 30 August 2018 / Accepted: 3 September 2018 / Published: 5 September 2018
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Abstract

The use of cisplatin (CDDP), the most common chemotherapy drug for head and neck cancer, is limited by its undesirable side effects, especially nephrotoxicity. We investigated ultrasound microbubbles (USMB) as a tool to increase the local intra-tumoral CDDP level while decreasing systemic CDDP cytotoxicity. We allowed CDDP to interact with human serum albumin and then sonicated the resulting CDDP‒albumin complex to generate CDDP-loaded MBs (CDDP-MBs). We then established a head-and-neck tumor-bearing mouse model by implanting FaDu-fLuc/GFP cells into severe combined immunodeficiency mice and used IVIS® bioluminescence imaging to determine the tumor xenograft formation and size. Twice weekly (until Day 33), we administered CDDP only, CDDP + MBs + US, CDDP-MBs, or CDDP-MBs + US intravenously by tail-vein injection. The US treatment was administered at the tumor site immediately after injection. The in vivo systemic distribution of CDDP indicated that the kidney was the most vulnerable organ, followed by the liver, and then the inner ear. However, CDDP uptake into the kidney and liver was significantly decreased in both the CDDP-MBs and CDDP-MBs + US groups, suggesting that MB binding significantly reduced the systemic toxicity of CDDP. The CDDP-MBs + US treatment reduced the tumor size as effectively as conventional CDDP-only chemotherapy. Therefore, the combination of CDDP-MBs with ultrasound is effective and significantly attenuates CDDP-associated nephrotoxicity, indicating a promising clinical potential for this approach. View Full-Text
Keywords: ultrasound; microbubble; cisplatin; nephrotoxicity; head and neck cancer; chemotherapy ultrasound; microbubble; cisplatin; nephrotoxicity; head and neck cancer; chemotherapy
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Chen, H.-K.; Zhang, S.-M.; Chang, J.-L.; Chen, H.-C.; Lin, Y.-C.; Shih, C.-P.; Sytwu, H.-K.; Fang, M.-C.; Lin, Y.-Y.; Kuo, C.-Y.; Liao, A.-H.; Chu, Y.-H.; Wang, C.-H. Insonation of Systemically Delivered Cisplatin-Loaded Microbubbles Significantly Attenuates Nephrotoxicity of Chemotherapy in Experimental Models of Head and Neck Cancer. Cancers 2018, 10, 311.

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