| Cancer remains one of the leading causes of death in most parts of the world and chemotherapy is the common treatment. The main reason for failure of chemotherapy is the poor accessibility of antineoplastic agents to the tumor, requiring higher doses, and the nonselective nature of these agents causes severe toxicity. The magnetically targeted-drug delivery system (MT-DDS) involves binding anticancer drug to biocompatible magnetic particles, injecting into the blood stream and using an external magnetic field to pull them out of suspension in the target region. The drug can be enriched and released at the specific region and enriched at the specific region, reducing their systemic distribution as well as the possibility of administering lower but more accurately targeted doses of the drug in the treatments. This local therapy could improve the efficiency of the treatment, reducing systemic toxicity. In this project, the kinetics of doxorubicin(DOX) adsorption on GoldMag nanoparticles surface and drug release were investigated firstly. The cytotoxicity assay of GoldMag nanoparticles and GoldMag nanoparticles loaded with doxorubicin combined with the permanent magnetic fields to the human hepatocellular liver carcinoma cell line (HepG2) in vitro were also tested. Then we modified GoldMag (Fe3O4/Au) nanoparticles with PEG5000-thiol (PEG-SH)(PGMNs) and investigated the kinetics of absorption and release of DOX of PGMNs in vitro. The biodistribution of DOX-loaded PGMNs combined with external magnetic field were also investigated in vivo. Additionally the therapeutic efficiency of DOX-loaded PGMNs combined with external magnetic field of DOX-loaded PGMNs was investigated. The results showed that:1. The content of drug adsorbed on the GoldMag nanoparticle surface increased rapidly within 30 min and the maximum drug loading rate is about 10.2%.The cell viability remained more than 92% by using of GoldMag nanoparticles at the concentration as high of 2.0 mg/ml, suggesting the good biocompatibility of the nanoparticles. IC50 (0.731μg/ml) of the Dox-GoldMag group were higher than those (0.522μg/ml) of the Dox group (P<0. 05). However, the Dox-GoldMag group combined with the magnetic fields had obviously increased the inhibition rate for HepG2 cell line and IC50 was lower than Dox group (0.421μg/ml).2. The PEG modified GoldMag nanoparticles (PGMNs) have saturated magnetization of 34 emu/g with a size range of 50 nm. The maximum quantity of doxorubicin (DOX) loaded on the particles is about 107.78mg/g (10.8%). The PGMNs loaded with DOX (DOX-loaded PGMNs) exhibited a controlled drug release within 4 h and then the drug slowly, sustained release to 96 h. The cell viability remained more than 92% incubated in cell culture medium RPMI-1640 contained PGMNs at the concentration as high as 2.0 mg/ml, suggesting the biocompatibility of the nanoparticles.3. The results of the biodistribution of DOX-loaded PGMNs applied permanent magnetic in vivo indicated that the concentration of DOX in the liver exposed to magnetic field group (60.7±8.14,53.6±4.89,44.8±6.41 and 38.4±2.58 ng/g) were much higher than those of no magnetic field applied group (40.8±9.96,31.9±7.01,28±6.11 and 20.7±5.78 ng/g) at 0.5,1,2 and 4 h (P<0.05), respectively. Histological studies suggested a larger particle concentration in the targeted area of liver in comparison to the no exposed to magnetic field and control.4. The results of therapeutic efficiency of DOX-loaded PGMNs combined with external magnetic field showed that DOX-PGMNs and DOX-PGMNs-M groups (M represent magnetic field) displayed more tumor suppression than DOX group. The relative tumor volumes of DOX-PGMNs-M, DOX-PGMNs, DOX and Control were 5.46,9.21,14.8 and 24.3 respectively in H22 cell-bearing mice on the 33rd day. The life span of H22 cell-bearing mice treated with DOX-PGMNs-M, DOX-PGMNs, DOX and control were 74.8±9.95,66.1±13.5, and 31.3±3.31 and 25.8±10.1 days, respectively. Histological studies suggested a larger amount necrotic cells in the targeted area of liver in comparison to the no exposed to magnetic field and control.Summary, GoldMag nanoparticles, as a new targeting drug delivery carrier, were capable of carrying drug for targeting therapeutic purposes due to its novel property. DOX-loaded PGMNs combined with external magnetic can significantly increase the level of drug concentration in specific site and reducing their systemic distribution as well as the possibility of administering lower but more accurately targeted doses of the drug in the treatments. This local therapy system could improve the therapeutic efficiency, reducing systemic toxicity. Our study will provide basis for GoldMag nanoparticles used to drug targeting delivery carrier.
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