Ultrasound Mediated Drug-Loaded Nanoparticles Crossing Cell Membranes as a New Strategy to Reverse Multidrug Resistance In Human Leukemia Cell Line K562/A02
Authors: Chen Bao-An , Zhang Hai-jun , Wang Xue-mei , Jiang Hui , Gao Chong , Gao Feng , Ding Jia-hua , Cheng Jian , Sun Yun-yu , Wang Jun , Song Hui-hui , Bao Wen 
Published: October 2019

Abstract
Abstract 3969

Objective:
Although many strategies have been explored to overcome the multidrug resistance (MDR) in leukemia which has rendered many currently available chemotherapeutic drugs ineffective, the results have been disappointing to the obstacle. The aim of this study was to investigate whether the new strategy of combining drug-loaded nanoparticles (Nps) and ultrasound (US) would show useful effects on the reversal of MDR in human leukemia cell line K562/A02.

Methods:
In this study, daunorubicin (DNR), a frequently chemotherapeutic agent known to cause DNA damage and induce apoptosis and cell death, was loaded on the TiO2 Nps which is chemically stable, environmental friendly, and shows weak or non cytotoxic to apply as the nano-drug carrier. The MDR leukemia K562/A02 cells were treated with the DNR-loaded TiO2 Nps drug carrier and US exposure. Then, we examined the effectiveness of delivering DNR into the MDR leukemia K562/A02 cells with the electrochemical studies, observed the bio-effects on the cell viability by MTT assays, investigated the induced apoptosis, and assessed the reversal ability and the mechanism of MDR by combining the drug-loaded Nps and US.

Results:
We observed good biocompatibility of the therapeutic approach. When the K562/A02 cells were incubated with DNR only, the cathodic current decreased by only 10% normalized to the DNR (10 μg/mL) standard, indicating less DNR was absorbed by the MDR cells. The cathodic current decreased by 39% and 63% in the presence of US or DNR-loaded TiO2 Nps, respectively. In comparison, when the cells were treated by the novel strategy of US mediated drug-loaded Nps crossing cell membranes, the cathodic current of DNR in the supernatant decreased greatly by 82% and became the minimal, which suggesting the least amount of DNR remained outside the MDR cells in this case and the largest uptake into the cells by this new strategy. These observations demonstrated that the remarkable synergistic effect of the novel strategy facilitated the accumulation of DNR in the MDR K562/A02 cells. In addition, our MTT assay illustrated comparative sensitization of the MDR K562/A02 cells under the treatment of US or drug-loaded Nps, but especially enhanced effect by combining drug-loaded Nps and US. The resisting fold of the MDR leukemia K562/A02 became obviously lower, decreasing from 58.71 to 16.69. The fresh evidence from caspase-3 immunocytochemistry demonstrated that the strategy could induce the apoptosis in the cells as well.

Conclusion:
It was therefore concluded that the strategy could have good reversal ability of MDR in tumor. These findings reveal that the reversal of MDR in tumor by US mediated drug-loaded Nps crossing cell membranes could represent promising approach in cancer therapy.

Disclosures:
No relevant conflicts of interest to declare.