Abstract
The aim of the present study was to investigate whether the use of drug-loaded microbubbles combined with ultrasound promotes the apoptosis of cancer cells by regulating B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) expression. Adriamycin-loaded PLGA nanoparticles (ADM-NP) were fabricated using a modified emulsification process. Lipid microbubbles (NH2-MB) were prepared by mechanical vibration. The carboxyl groups of ADM-NP and NH2-MB underwent a condensation reaction after 48 h, and adriamycin-loaded PLGA nanoparticles microbubble complexes (ADM-NMC) were obtained. High-performance liquid chromatography demonstrated that the entrapment efficiency and drug loading of ADM-NMC were 85.32 ± 5.41% and 7.91 ± 0.27%, respectively. The VX2 liver cancer model was established in 30 New Zealand rabbits, which were subsequently divided into three groups (n=10): a control group that received 5 ml of saline, an ADM-NP group that received 5 ml of ADM-NP and an ADM-NMC group that received 5 ml of ADM-NMC. Rabbits in the ADM-NP and ADM-NMC groups underwent irradiation 120 s with low frequency ultrasound (1 MHz, 0.5 W/cm2) for 120 s following injection. The echogenicity of tumors markedly increased following ADM-NP and ADM-NMC treatment. Staining with hematoxylin and eosin demonstrated that the tumor shape became more normal in the ADM-NP and ADM-NMC groups compared with the control group. Immunohistochemical staining and Western blotting determined that the expression of Bax increased and the expression of Bcl-2 decreased following treatment with ADM-NP and ADM-NMC. Cancer cell apoptosis was detected by flow cytometry and it was determined that apoptosis significantly increased following treatment with ADM-NP and ADM-NMC (P<0.01). Therefore, the present study demonstrated that the use of drug-loaded microbubbles combined with ultrasound may enhance the efficiency of tumor inhibition. This may be due to the promotion of cancer cell apoptosis via regulation of Bax and Bcl-2 expression.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world [1]
adriamycin-loaded Polylactic-co-glycolic acid (PLGA) nanoparticles microbubble complexes (ADM-NMC) were synthesized by conjugating NH2-MB with ADM-PLGA
ADM-NMC exhibited a large number of ADM-PLGA gathered around NH2-MB in garland-like manner (Figure 1)
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world [1]. Chemotherapy remains the most common method of treating most types of advanced cancer. That impairs the efficiency of chemotherapy to tumors [4] Another obstacle to cancer therapy is the limited distribution of low molecular weight anticancer drugs within the tumor tissues [5]. Chemotherapeutic drugs must cross the cell membrane and enter the cell to become active. This presents a challenge and requires active uptake through plasma membrane transporters, which may not always be present in the target cells [6]. Adriamycin (ADM) is one important type of active chemotherapeutic agent widely used to target malignant tumors. To improve the efficiency of anticancer chemotherapeutics, the technique of microbubble-assisted ultrasound has been developed [7]. Ultrasound-targeted microbubble destruction, which is a novel, targeted drug delivery technology using ultrasonic microbubbles as a carrier, may increase the effectiveness of drug treatments in targeted regions [10]
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