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

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 mu m 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.