The Construction And Evaluation Of A Tumor-targeting Controlled Drug Delivery System Based On PEG Modified GO@Au Nanoparticles

Currently, chemotherapy is still an important means of cancer treatment indispensable, however, its poor specificity, toxicity and low drug bioavailability, severely limit its application. Controlled release drug delivery system can purposefully regulate the release of drugs to increase their selectivity to the target tissue and reduce the toxicity of chemotherapy drugs, improving the antitumor activity of the drugs. Despite advances in controlled drug delivery, drug delivery systems with activatable, high spatial/temperal resolution control of drug release are still needed. While photothermal therapy has become more and more concerned in recent years, due to its unique advantage,such as minimally invasive, controllable and efficient.PEGyalation has been extensively employed to increase the circulation time of controlled drug delivery systems, however, PEG is unfavorable for the uptake by tumor cells because of its steric hindrance. In this study, we took the advantage of the high photo-thermal sensitivity of GO and AuNPs as the NIR stimulus antenna for photothermal therapy (PTT) and NIR-triggered drug delivery system (DDS), furthermore, a tumoral acid-specific cleavable PEGyalation was introduced to the DDS, thus the hindrance effect of PEG on DDS uptake can be avoided without sacrifice of long circulating properties. Firstly, Au nanoparticles (10-20nm) were chemically deposited onto the surface of GO to get GO@Au nanocomposites through hydrothermal coprecipitation, which were then functionalized with PEG2000 via pH-sensitive, using the dispersing effect of DSPE extremity to improve the water-soluble and to increase the circulation time of controlled drug delivery systems. Ultimately, the first-line anticancer drugs doxorubicin (DOX) was loaded onto the GO@Au-PEG through π-π stacking interactions, resulting in a tumor-specific cleavable PEG-modified drug delivery system (GO@Au-PEG/DOX). The synthetic process was characterized by transmission electron microscopy (TEM), ultraviolet full wavelength scanning (UV), fourier transmission infrared spectroscopy (FT-IR), inductively coupled plasma (ICP) and laser nano particle size analyzer (DLS). Meanwhile, we also investigated its aqueous solubility and stability. The results showed that the carrier system was successfully constructed, had good stability, high aqueous solubility, particle size and potential distribution.We also studied the thermal effect of GO@Au-PEG under 808nm laser and the release of PEG from GO@Au-PEG Results indicated that the temperature of GO@Au-PEG solution (20ug/ml) was higher than GO solution (20ug/ml) about 10℃ after irradiated 5min under 2W/cm2 808nm laser. Besids, PEG showed no significant changes after incubating in acetate buffer (pH 7.4) at room temperature for 4 h. howere, only 2.2% of PEG was left after incubating in acetate buffer (pH 5.5) at room temperature for 4 h, and this result clearly showed the pH sensitivity of GO@Au-PEGIn vitro experiments, we chose breast cancer cells MCF-7 as the experimental subject to inspect the antitumor activity of the GO@Au-PEG-DOX under 808nm laser. It turned out that the toxicity of GO@Au-PEG are very low without the irradiation of 808nm laser, however, the toxicity of them increased significantly due to the effect of photothermal therapy of the GO and Au nanoparticles. Compared with DOX, the inhibition to MCF-7 cells of GO@Au-PEG/DOX by 808nm laser was greatly enhanced. In the uptake experiments, the results indicated that the acidic environment could enhance the cell internalization of GO@Au-PEG/DOX and DOX release could be remote-controlled by 808nm laser stimulation in cellular system.In vivo, the S180 tumor-bearing mice were chosen as the model to examine the tissue distribution and the antitumor effect of GO@Au-PEG/DOX. Meanwhile, we also investigated the thermal effect of GO@Au-PEG/DOX in vivo. The results showed that the distribution of GO@Au-PEG can be concentrated in tumor and the tumoral acid environment resulted in the PEG dissociating. The results of thermal effect experiments in vivo show that the temperature in tumor site of GO@Au-PEG+NIR group significantly increased 14.1℃, explaining the efficacy of PTT in vivo. The antitumor effect experiments show that GO@Au-PEG/DOX has better therapeutical effect and less toxicity compared with DOX.To sum up, the drug delivery system GO@Au-PEG/DOX is pH sensitive to cleave PEG and NIR sensitive to release DOX in vitro and in vivo. Besides, it also have good light hyperthermia, can be used in future cancer treatment.