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

Lee Lee,Kim Kim,Han Han,Moon Moon,Chung Chung,Ha Ha

doi:10.3390/cancers11040581

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.

Highlights

Image-guided intra-arterial (IA) therapies, such as hepatic arterial infusion chemotherapy (HAIC)or trans-arterial chemoembolization (TACE) are frequently used for the treatment of primary or secondary liver cancers [1,2,3,4,5,6]
Albumin-doxorubicin nanoparticles were fabricated by the dropwise addition of ethanol to albumin
The doxorubicin was released in a sustained manner from the albumin-doxorubicin nanoparticles at an in vitro release rate of 24.2% for 50 h with the initial burst

Summary

Introduction

Image-guided intra-arterial (IA) therapies, such as hepatic arterial infusion chemotherapy (HAIC)or trans-arterial chemoembolization (TACE) are frequently used for the treatment of primary or secondary liver cancers [1,2,3,4,5,6]. HAIC involves the local and targeted delivery of high concentrations of chemotherapeutic drugs directly to the tumor, whereas TACE, with or without drug-eluting beads, combines local and targeted drug delivery with concurrent tumor-feeding artery embolization. The theory behind this treatment recommends delivering the maximal dose of the chemotherapeutic agent to the target tissue while minimizing systemic toxicity. Local tumor recurrences at the periphery of the treated area are common and are often a cause for treatment failures [12] Another limitation in clinical field is side effects

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