Abstract
We demonstrate the megavoltage (MV) radiosensitization of a human liver cancer line by combining gold-nanoparticle-encapsulated microbubbles (AuMBs) with ultrasound. Microbubbles-mediated sonoporation was administered for 5 min, at 2 h prior to applying radiotherapy. The intracellular concentration of gold nanoparticles (AuNPs) increased with the inertial cavitation of AuMBs in a dose-dependent manner. A higher inertial cavitation dose was also associated with more DNA damage, higher levels of apoptosis markers, and inferior cell surviving fractions after MV X-ray irradiation. The dose-modifying ratio in a clonogenic assay was 1.56 ± 0.45 for a 10% surviving fraction. In a xenograft mouse model, combining vascular endothelial growth factor receptor 2 (VEGFR2)-targeted AuMBs with sonoporation significantly delayed tumor regrowth. A strategy involving the spatially and temporally controlled release of AuNPs followed by clinically utilized MV irradiation shows promising results that make it worthy of further translational investigations.
Highlights
Radiotherapy (RT), as a powerful anticancer modality, is applied to 40% of patients who are eventually cured [1]
Radiosensitization is a process to increase the efficacy of RT by introducing radiosensitizers, which are molecules/materials with the ability to enhance the radiosensitivity of tumor cells [2,3]
We hypothesize that the augmented delivery of AuNPs through sonoporation with AuMBs to human hepatocellular carcinomas promotes the subsequent radiosensitization when applying MV X-rays
Summary
Radiotherapy (RT), as a powerful anticancer modality, is applied to 40% of patients who are eventually cured [1]. The leaky vasculature with compromising lymphatic drainage, referred to as the enhanced permeability and retention (EPR) effect, allows AuNPs (typically sized 1–100 nm) into the tumor tissue [8,12] These advantages make AuNPs a radiosensitizer that is superior to conventional macro-sensitizers [10]. There have been encouraging demonstrations of AuNP-mediated radiosensitization when applying clinically suitable MV energies Those promising results rely on high systemic concentrations of AuNPs [13,14,15], or the further modification of AuNPs with targeting moieties such as thioglucose [16,17], HER-2 (human epidermal growth factor receptor-2) [18], or goserelin [19] depending on specific tumor types. We hypothesize that the augmented delivery of AuNPs through sonoporation with AuMBs to human hepatocellular carcinomas promotes the subsequent radiosensitization when applying MV X-rays
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