Ultrasound sonication with microbubbles disrupts blood vessels and enhances tumor treatments of anticancer nanodrug

Chung-Yin Lin¹*, Hsiao-Ching Tseng¹*, Heng-Ruei Shiu¹, Ming-Fang Wu², Cheng-Ying Chou³, Win-Li Lin^1,4
1Institute of Biomedical Engineering, ²Laboratory Animal Center, ³Department of Bio-Industrial Mechatronics Engineering, National Taiwan University, Taipei, Taiwan; ⁴Division of Medical Engineering Research, National Health Research Institutes, Miaoli, Taiwan

*These authors contributed equally to this work

Abstract: Ultrasound (US) sonication with microbubbles (MBs) has the potential to disrupt blood vessels and enhance the delivery of drugs into the sonicated tissues. In this study, mouse ear tumors were employed to investigate the therapeutic effects of US, MBs, and pegylated liposomal doxorubicin (PLD) on tumors. Tumors started to receive treatments when they grew up to about 15 mm³ (early stage) with injection of PLD 10 mg/kg, or up to 50 mm³ (medium stage) with PLD 6 (or 4) mg/kg. Experiments included the control, PLD alone, PLD + MBs + US, US alone, and MBs + US groups. The procedure for the PLD + MBs + US group was that PLD was injected first, MB (SonoVue) injection followed, and then US was immediately sonicated on the tumor. The results showed that: (1) US sonication with MBs was always able to produce a further hindrance to tumor growth for both early and medium-stage tumors; (2) for the medium-stage tumors, 6 mg/kg PLD alone was able to inhibit their growth, while it did not work for 4 mg/kg PLD alone; (3) with the application of MBs + US, 4 mg/kg PLD was able to inhibit the growth of medium-stage tumors; (4) for early stage tumors after the first treatment with a high dose of PLD alone (10 mg/kg), the tumor size still increased for several days and then decreased (a biphasic pattern); (5) MBs + US alone was able to hinder the growth of early stage tumors, but unable to hinder that of medium stage tumors. The results of histological examinations and blood perfusion measurements indicated that the application of MBs + US disrupts the tumor blood vessels and enhances the delivery of PLD into tumors to significantly inhibit tumor growth.

Keywords: ultrasound, microbubbles, nanodrug, mouse tumor, vascular disruption, tumor growth response

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