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Antitumor Effects of Intra-Arterial Delivery of Albumin-Doxorubicin Nanoparticle Conjugated Microbubbles Combined with Ultrasound-Targeted Microbubble Activation on VX2 Rabbit Liver Tumors

1
Department of Radiology, Seoul National University Bundang Hospital, 82 Gumi-ro 173, Bundang-gu, Seongnam 13620, Korea
2
Department of Chemical & Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Korea
3
Department of Radiology, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea
4
Department of Radiology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul 03080, Korea
5
IMGT Co., Ltd., 172 Dolma-ro, Bundang-gu, Seongnam 13605, Korea
6
Institute of Radiation Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul 03080, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(4), 581; https://doi.org/10.3390/cancers11040581
Received: 4 March 2019 / Revised: 20 April 2019 / Accepted: 22 April 2019 / Published: 24 April 2019
(This article belongs to the Special Issue Cancer Nanomedicine)
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Abstract

Image-guided intra-arterial therapies play a key role in the management of hepatic malignancies. However, limited clinical outcomes suggest the need for new multifunctional drug delivery systems to enhance local drug concentration while reducing systemic adverse reactions. Therefore, we developed the albumin-doxorubicin nanoparticle conjugated microbubble (ADMB) to enhance therapeutic efficiency by sonoporation under exposure to ultrasound. ADMB demonstrated a size distribution of 2.33 ± 1.34 µm and a doxorubicin loading efficiency of 82.7%. The echogenicity of ADMBs was sufficiently generated in the 2–9 MHz frequency range and cavitation depended on the strength of the irradiating ultrasound. In the VX2 rabbit tumor model, ADMB enhanced the therapeutic efficiency under ultrasound exposure, compared to free doxorubicin. The intra-arterial administration of ADMBs sufficiently reduced tumor growth by five times, compared to the control group. Changes in the ADC values and viable tumor fraction supported the fact that the antitumor effect of ADMBs were enhanced by evidence of necrosis ratio (over 70%) and survival tumor cell fraction (20%). Liver toxicity was comparable to that of conventional therapies. In conclusion, this study shows that tumor suppression can be sufficiently maximized by combining ultrasound exposure with intra-arterial ADMB administration. View Full-Text
Keywords: albumin nanoparticles; microbubble; ultrasound; theranostics; hepatocellular carcinoma; VX2 tumor; intra-arterial chemotherapy albumin nanoparticles; microbubble; ultrasound; theranostics; hepatocellular carcinoma; VX2 tumor; intra-arterial chemotherapy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Lee, J.H.; Moon, H.; Han, H.; Lee, I.J.; Kim, D.; Lee, H.J.; Ha, S.-W.; Kim, H.; Chung, J.W. Antitumor Effects of Intra-Arterial Delivery of Albumin-Doxorubicin Nanoparticle Conjugated Microbubbles Combined with Ultrasound-Targeted Microbubble Activation on VX2 Rabbit Liver Tumors. Cancers 2019, 11, 581.

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