Anti-tumor Activity Of Doxorubicin-conjugated Dextran-coated GoldMag Nanoparticles In Magnetically Targeted Delivery System

Malignant tumor remains one of the leading causes of death in the world. The seeking effective method of diagnosis and treatment is the common goal of the scientists. Chemotherapy kills tumor cells also damage normal cells as well as human body. The magnetically targeted drug delivery system (MT-DDS) may transport the chemotherapeutic drugs to the tumor site, then enhancing the therapeutic effect and reducing the toxic side effects on the human body. And the selection of appropriate drug-carrier is very important for MT-DDS. The GoldMag nanoparticles (GMNs) of core-shell structure have many advantages, such as large surface area, high capacity with drugs, easily functionalized surface, good magnetic response and so on. These characteristics make them ideal choices for MT-DDS drug carriers. However, the GMNs can easily cluster in the salt solution or plasma due to the great specific surface enery. The surface modification of GMNs with hydrophilic dextran may greatly improve their stability in various solutions, and make them more suitable as a drug carrier.Herein, Dextran coated GoldMag nanoparticles (DGMNs) were synthesized, characterized and demonstrated to be effective vehicles for targeted drug delivery. Characterization of DGMNs by different methods confirmed that they have uniformity sizes, good dispersibility and magnetic response. The result showed that the average hydrodynamic diameter of DGMNs was about100nm suspended in injection water, glucose injection, sodium chloride injection, PBS buffer and plasma, which showed a good stability of the colloid.In vitro drug studies showed that the cancer drug-doxorubicin (Dox) binds effectively to DGMNs and the Fourier Transform Infrared Spectroscopy (FITR) spectra was used to confirm that the Dox was successfully loaded onto the surface of DGMNs. The kinetics doxorubicin release from Dox-DGMNs in vitro showed that the drug was steadily/controllably released from the particle surface in physiological conditions.It is evident that DGMNs are not toxic to HepG2and H22cells by MTT assay in vitro, meanwhile the assessment of Dox-DGMNs showed that Dox-DGMNs killed HepG2and H22cells more effectively than Dox alone, which demonstrated that the drug was not only released from the particle surface but also probably near the cells in the culture well accounting for the increased toxicityWe did not observe any deleterious effects on animals at concentrations as high as2000mg/kg body weight (BW) in the experiments assessing the safety of DGMN particles in vivo, the results showed that DGMNs is enough safe as drug carriers. The results of animal experiments in vivo with Dox-DGMNs demonstrated that the drug may release slowly from particles surfaces and the carrier decreased toxic to animals relative to the free Dox. The LD50of Dox-DGMNs and free Dox were45.22mg/kg and15.60mg/kg, respectively. This indicated that the drug carrier may lower indeed the drug toxicity to tissues. Viscera index and pathological examination of various organs showed that the Dox from DGMNs surface concentrate on liver and spleen position and decreased the cardiotoxicity. Furthermore, Magnet localization of Dox-DGMNs in tissues showed DGMNs could be indeed localized in targeted position and ideal carrier of drugs for targeted tissues, such as treatment of liver tumor.The method to measure Dox concerntration in the plasma was successfully established by High Performance Liquid Chromatography (HPLC), which was used to study the pharmacokinetics dynamics of Dox-DGMNs in SD rats. The results showed that Dox-DGMNs and Dox-DGMNs with external magnetic field (EMF) could significantly change the pharmacokinetic characteristics of Dox, enhance the bioavailability, slow eliminate rate and reduce the toxic effects.To evaluate the therapeutic efficiency of Dox-DGMNs with EMF in vivo, the tumor-bearing mouse model was successfully established firstly. The pharmacodynamics in vivo showed Dox-DGMNs/EMF had the greatest antitumor efficacy with the different treatment protocols and significantly prolonged the life span of mice. The result illustrates that the high efficiency antitumor for Dox-DGMNs/EMF is because DGMNs enhance drug accumulation in tumor tissue.In summary, the study provides some theoretical basis for targeted delivery of drugs to treat hepatic carcinoma. Of course, the further research is needed to make DGMNs be used to transport multiple kinds of drug to their desired targets, which will make them versatile therapeutic tools. The simple nanoparticles design and the drug delivery optimization may make them ideal candidates in targeted delivery in the near future.