Dosimetric assessment of antitumor treatment by enhanced bleomycin delivery via electroporation and sonoporation

Abstract

Targeted and controlled techniques of intratumoral delivery of chemotherapeutic agents are under extensive development, since they diminish detrimental side-effects of conventional anticancer drugs. We investigated the effectiveness of chemotherapy using bleomycin (1 mg/ml) and Sonovue microbubbles combined with: electroporation (EP), mainly designed for subcutaneous tumor therapy, and sonoporation (SP) - for deeper localized tumors. Research was performed on hepatoma MH-22A tumors in murine models, exposed to EP or SP and combined (EP + SP) treatment. Animal survival time and the rate/ speed of tumor growth reduction were examined. Study demonstrated that both EP or SP and their combination (EP + SP) were able to induce the reduction of tumor volume from the 3rd day after treatment. The employment of EP before SP allowed to significantly reduce the values of inertial cavitation dose (ICD), necessary to induce complete tumor reduction and prolong animal survival. The analysis of ultrasound (US) side-scattered signals and B-scan imaging indicated the occurrence of inertial cavitation at our experimental conditions. Strong (R² = 0.88; p < 0.0001) correlation of ICD with the survival time of corresponding unrecovered mice indicates the option for the dosimetric control and standardization of cavitation activities for in vivo practice.

Keywords: Antitumor therapy; Bleomycin; Dosimetry; Drug delivery; Electroporation; Microbubbles; Sonoporation.