Preparation And Primary Application Of Gold Nanoshells Modified Thermosensitive Magnetoliposomes

In order to improve tumor targeting and overcome side effects of anti-tumor chemotherapy drugs, a new type of gold nanoshell coated thermosensitive magnetoliposomes drug delivery system named DOX-TSMLs-AuNSs-PEG was developed in this study. This drug delivery system was developed based on the good biological safety of liposomes and unique characteristics of magnetic nanomaterials and gold nanomaterials. The diagnosis and treatment of this drug delivery system were investigated. The study mainly included the following parts.1. Preparation and characterization of DOX-TSMLs-AuNSs-PEG. The magnetic nanoparticles named MNPs, with small sizes and good dispersion, were synthesized by the coprecipitation method. MNPs and chemotherapy drug DOX?HCl were encapsulated into the thermosensitive magnetoliposomes to form DOX-TSMLs used the reverse-phase evaporation method, then gold nanoshells were coated on the surface of DOX-TSMLs, after the SH-PEG2000 modification, the DOX-TSMLs-AuNSs-PEG drug delivery system was finally synthesized. MNPs synthesized by the coprecipitation method showed a good water solubility, dispersity and superparamagnetism. The morphology was spherical shape and the size were in the range of 12~15 nm. Through formulation optimization, the finally developed DOX-TSMLs-AuNSs-PEG showed a uniform spherical shape and the average size was 208.3±1.3 nm. MNPs were densely packed within the DOX-TSMLs and AuNSs were reduced on the surface of it. The encapsulation efficiency was 51.4±0.6%, the concentration of Fe was 7.5 mM, showed a strong superparamagnetism. DOX-TSMLs-AuNSs-PEG also displayed a marked temperature increase under RF irradiation. According to the result of drug release, DOX-TSMLs-AuNSs-PEG were stable under the physiology condition and the DOX release rate were reached about 65% after 10 min RF irradiation indicating the RF controlled drug release. The MR and X-ray imaging results in vitro suggested that the DOX-TSMLs-AuNSs-PEG can efficiently decrease the T2-weighted MRI signal intensity and increase the CT signal intensity, revealing a great dual-mode imaging ability.2. In vitro anti-tumor activity of DOX-TSMLs-AuNSs-PEG. In this part, workes were carried out based on the human hepatoma cells HepG2. The drug delivery system showed high safety and had no obvious toxicity on HepG2 cells. The DOX-TSMLs-AuNSs-PEG can be uptaken by HepG2 cells within 2 h, and the uptaken was remarkably enhanced after magnetic treatment. When under RF irradiation, the drug can be triggered release and rapidly spread to the cell nucleus inducing cell apoptosis. The combination of magnetic tumor-targing effect, hyperthermia effect under the RF field and chemotherapy effect significantly improve the HepG2 cell inhibition.3. In vivo anti-tumor activity of DOX-TSMLs-AuNSs-PEG. The S180 tumor bearing mice were developed to detect the pharmacokinetics, tissue distribution and tumor inhibition of DOX-TSMLs-AuNSs-PEG. The pharmacokinetics results showed that after DOX were encapsulated into the liposome the mean residence time was prolonged and the clear rate was reduced, indicated a certain degree of sustained release effect. The tissue distribution declared that the DOX-TSMLs-AuNSs-PEG can effectively decrease the distribution of DOX in the heart and kidney, and increase the distribution in tumor. The amount of DOX in tumor was remarkably higher when after the magnetic treatment indicating the high magnetic tumor targeting efficiency. The tumor growth inhibition suggested that DOX-TSMLs-AuNSs-PEG showed an obvious tumor inhibition effect under the combination of magnetic tumor-targing and RF irradiation and showed no significant morphological change in normal tissues. DOX-TSMLs-AuNSs-PEG can effectively reduce the damage of DOX in heart and kidney, and improve the therapeutic index. The MR and X-ray imaging results in vivo showed that the DOX-TSMLs-AuNSs-PEG had a great MR/X-ray imaging ability, demonstrating a great potential in tumor diagnostic applications.In summary, a safe and effective drug delivery system with abilities of controled drug release, tumor targing, simultaneous diagnosis and therapy was successfully developed in this study. This study provides a reference for the exploration of new anti-tumor drug delivery system.