Cavitation-Enhanced Delivery of the Nanomaterial Graphene Oxide-Doxorubicin to Hepatic Tumors in Nude Mice Using 20 kHz Low-Frequency Ultrasound and Microbubbles

Abstract

Graphene oxide (GO) is a kind of nanomaterial. Here, we explored its application in tumor treatment. We loaded doxorubicin onto the surface of GO to form graphene oxide-doxorubicin (GO-DOX). After injection of the contrast agent SonoVue microbubbles (MBs) into the tail vein of tumor-bearing nude mice, subcutaneous hepatic carcinomas inoculated with the HepG2 cell line were irradiated with 20 kHz low-frequency ultrasound (US). Subsequently, GO-DOX was injected into the tail vein of nude mice. Transmission electron microscopy (TEM) and TUNEL assays were performed to observe the curative effects. Biocompatibility tests of GO-DOX included routine blood cell counts, blood smears, serum biochemical assays, and histological sampling of important organs. It was found that the nanomaterial GO-DOX promoted apoptosis of tumor cells in nude mice. TEM of the USMB+GO-DOX treatment showed vascular endothelial cell wall rupture, widened endothelial cell gaps, black granules in the vascular lumen, interstitial erythrocyte leakage, and apparent apoptosis of tumor cells. There were no toxic side effects of GO-DOX on the blood system and in the major organs of these mice. Ultrasound cavitation destroys tumor blood vessels and enhances the release of nanomaterials to tumor cells of nude mice.

Mutual influence of malignant cells and cellular microenvironment: prospects for manipulating tumour microenvironment with nanomaterials

“…The antitumour action of GO-PEG was to reduce the migration and invasion of subcutaneous osteosarcoma cells in mice [50]. In [51], the combined effect of low-frequency ultrasound therapy and graphene oxide-doxorubicin (GO-DOX) conjugate on local damage to endothelial cells lining the neovascular network was shown. This effect increased the penetration of the GO-DOX conjugate into the interstitial space of mouse liver carcinoma through damaged capillaries.…”

Advances in Drug Delivery Nanosystems Using Graphene-Based Materials and Carbon Nanotubes

“…Enhanced delivery of DOX loaded onto the surface of GO to hepatic tumors in nude mice could be achieved using 20 kHz low-frequency ultrasound and microbubbles. Such treatment results in vascular endothelial cell wall rupture, widened endothelial cell gaps, black granules in the vascular lumen, interstitial erythrocyte leakage, and apparent apoptosis of tumor cells, whereby ultrasound cavitation damages tumor blood vessels and increases the release of GO-DOX stimulating apoptosis of tumor cells in nude mice [ 224 ]. At administration of DOX-loaded GO to cellular models of breast cancer, this nanoformulation was found to induce an immense intracellular drug release (followed by its nuclear accumulation) upon binding to the cell plasma membrane and exhibited considerably higher anticancer effectiveness than liposomal DOX [ 225 ].…”