<p>Enhancement of Radiosensitization by Silver Nanoparticles Functionalized with Polyethylene Glycol and Aptamer As1411 for Glioma Irradiation Therapy</p>

Abstract

BackgroundThe efficacy of radiotherapy for glioma is often limited by the radioresistance of glioma cells. The radiosensitizing effects of silver nanoparticles (AgNPs) on glioma were found in the previous studies of our group. In order to enhance the radiosensitivity of tumor cells and selectively kill them while reducing the side effects of irradiation therapy, targeted modification of AgNPs is urgently needed.Materials and methodsIn the present study, AgNPs functionalized with polyethylene glycol (PEG) and aptamer As1411 (AsNPs) were synthesized and subsequently characterized by transmission electron microscopy, ultraviolet-visible spectroscopy and Fourier transform infrared spectroscopy. Then the targeting property of AsNPs was evaluated by dark-field imaging, confocal microscopy and in vivo imaging. Both colony formation assay and glioma-bearing mouse model were employed to study the radiosensitizing effect of AsNPs.ResultsThe characterization results revealed a spherical shape of AgNPs with an average diameter of 18 nm and the successful construction of AsNPs. AsNPs were confirmed to specifically target C6 glioma cells, but not normal human microvascular endothelial cells. Moreover, AsNPs could not only internalize into tumor cells, but also penetrate into the core of tumor spheroids. In vitro experiments showed that AsNPs exhibited a better radiosensitizing effect than AgNPs and PEGylated AgNPs (PNPs), inducing a higher rate of apoptotic cell death. In vivo imaging demonstrated that Cy5-AsNPs preferentially accumulated at the tumor site, and the ratio of fluorescence intensity of Cy5-AsNPs to that of Cy5-PNPs reached the maximum at 6 h post-systemic administration. Furthermore, the combination of AsNPs with irradiation significantly prolonged the median survival time of C6 glioma-bearing mice.ConclusionOur results indicated that AsNPs could be an effective nano-radiosensitizer for glioma targeting treatment.

Aptamer-Based In Vivo Therapeutic Targeting of Glioblastoma

“…With the nanotechnology improvements, different metal nanomaterials have been also developed to enhance the antitumor efficacy of radiotherapy. In particular, silver nanoparticles (AgNPs) showed excellent radiosensitizing properties that have been confirmed on glioma cells in vitro and in vivo [ 46 , 111 , 112 , 113 , 114 ]. Thus, in order to enhance the radiosensitivity of tumor cells, Zhao and co-authors [ 46 ] conjugated NPs with polyethylene glycol (PEG) and the AS1411 aptamer (AsNPs), and demonstrated that conjugated AsNPs led to a lower cytotoxicity and enhanced the AgNP endocytosis into C6 GBM cells.…”

“…In addition, only the PEG–AS1411 conjugated nanoparticles reached the spheroid core, suggesting an improved penetration ability. Since previous studies indicated the apoptosis induction as a potential mechanism of radiosensitization, the authors demonstrated that AsNPs carried out their radiosensitizing function triggering the apoptotic response [ 46 ]. For the in vivo radiosensitization experiments, AsNPs were conjugated with the Cy5 fluorophore and systematically administrated to nude mice bearing intracranial glioma.…”

“…Cy5–AsNPs were able to accumulate into the tumor and, most importantly, the median survival time of mice, treated with AsNPs plus irradiations, was significantly elongated. Notably, systemic toxicity was not observed in injected mice [ 46 ].…”

“…Aptamers have been largely tested in vitro, showing multiple anticancer properties in GBM cell lines [ 10 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. However, only some of the GBM aptamers, able to reach the tumor site in vivo, are capable of efficiently treating this cancer [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

Aptamers: a novel targeted theranostic platform for pancreatic ductal adenocarcinoma

“…Analogously, the combination of silver nanoparticles with polyethylene glycol (PEG)-functionalized AS1411 aptamer improved the outcome of radiation therapy in preclinical glioma models. Significantly prolonged median survival times were shown in animals undergoing the combined aptamer radiotherapy protocol vs. aptamer treatment alone [76]. Apart from metal formulations, the anti-MUC1 aptamer was conjugated to the radiosensitizer 1,10 phenanthroline for in-vitro radiosensitization of breast cancer cells, although the actual radiosensitizing potential of this complex has not yet been fully proven [77].…”