Preparation And Studies In Vitro And Vivo Of Antitumor Drug Delivery System Based On Magnetic Titanium Dioxide Nanoparticles

Titanium dioxide（TiO₂） is a commonly used photocatalyst. For the past few years, TiO₂ has made a series of advances in photodynamic therapy as drug delivery carrier. It is a very promising photodynamic therapy material. But its use in cancer therapy still faces many challenges. On one hand, TiO₂ itself is not a tumor targeting material. It is difficult to achieve targeted drug delivery and photodynamic toxicity combinating with chemotherapy. On the other hand, its main absorption wavelength range is in the ultraviolet region, to achieve photodynamic therapy only with ultraviolet light. These drawbacks severely limit its practical application.Doxorubicin can inhibite DNA synthesis by embedding nucleotide sequence,thus kill tumor cell growth of various generation cycle. But there is strong cytotoxicity existing for normal organs. Its concentration in tumor tissues is much lower than the threshold killing cancerous cells. So the use of doxorubicin in the clinical treatment has been limited.This topic is to design the TiO₂ and Fe₃O₄ nanocomposite. Tumer magnetic targeting can be achieved under external magnetic field. It can deliver the magnetic fluid loading drug to the targeted tumor site, to increase drug enrichment in tumor.So that we can reduce toxic side effects on human body. Doxorubicin is anthracenedione. Its unique meta-hydroxylated quinone of anthraquinone ring structure can complex with Fe2+. At the same time, after modified by PEI, the surface of TiO₂-Fe₃O₄ contains more amino groups, which can also complex with Fe2+.Thereby we produce TiO₂-Fe₃O₄-PEI-DOX drug delivery system, based on complexing bond. This system has good pH sensitivity. In an acidic environment,DOX release quickly from the drug delivery system, while in a neutral environment,the complex bond firmly. The experimental results showed that, DOX released from TiO₂-Fe₃O₄-PEI-DOX faster in slightly acidic environment（pH =4.0）, over 90% in48 h, while in neutral environment（pH = 7.4） it released slowly, less than 15% in48 h.We select human hepatoma cell line（SMMC-7721） to study anti-tumor effect of TiO₂-Fe₃O₄-PEI-DOX in vitro, combining with phototherapy. The results showed that TiO₂-Fe₃O₄-PEI-DOX could fully enter cells within 1h, faster and more than DOX coutrol group. The inhibitory effect of TiO₂-Fe₃O₄-PEI-DOX on SMMC-7721 cells was better than the DOX control group. There is a significant difference. The inhibitory effect combing with 808 nm laser phototherapy was best among all groups.The cell cycle results showed that, SMMC-7721 cells in TiO₂-Fe₃O₄-PEI-DOX group were arrested in S phase, and this phenomenon in 808 nm laser group wasmore obvious, the amount of phase cells reached 91.56%. In apoptosis experiments,the total number of necrosis and apoptosis cells in TiO₂-Fe₃O₄-PEI-DOX group was15.7%, while the total number of necrotic and apoptotic cells in TiO₂-Fe₃O₄-PEI-DOX / laser group was 33.6%. Thus laser group could better induct apoptosis. And the proportion of early apoptotic and late apoptotic was equle.We use rats as an model animal to study the in vivo pharmacokinetic differences between TiO₂-Fe₃O₄-PEI-DOX and DOX groups. Besides, we study tissue distribution characteristics and pharmacodynamic properties of TiO₂-Fe₃O₄-PEI-DOX using mice. The results of TiO₂-Fe₃O₄-PEI-DOX group showed a slower metabolism, significantly reduced clearance rate, longer residence time and significant increased AUC in rats. These results illustrated TiO₂-Fe₃O₄-PEI-DOX increased bioavailability compared with DOX, which can significantly improve the pharmacokinetic properties of doxorubicin. In addition, the results of tissue distribution showed that in heart and kidney, the AUC of DOX in TiO₂-Fe₃O₄-PEI-DOX group significantly less than that in the control group. This suggests that TiO₂-Fe₃O₄-PEI-DOX can effectively reduce cardiac and renal toxicity in the clinical application caused by DOX. On the contrary, the index of TI in the liver, lung and tumors were 150.70,106.86 and 320.76, respectively, AUC of TiO₂-Fe₃O₄-PEI-DOX group was significantly higher than DOX group, indicating TiO₂-Fe₃O₄-PEI-DOX had obvious liver, lung and tumor targeting ability.Pharmacodynamic results indicated that compared with the NS group, tumor volume in DOX, TiO₂-Fe₃O₄-PEI-DOX and TiO₂-Fe₃O₄-PEI-DOX / laser groups were all showed a clear downward trend after administration for one week. And TiO₂-Fe₃O₄-PEI-DOX / laser group declined more obviously. There were 2 mice died in DOX group, while no mice deaths occurred in other groups. This suggested that TiO₂-Fe₃O₄-PEI-DOX was less toxic than DOX group. For the results of tissue distribution, we could draw inferences. Due to magnetic targeting,TiO₂-Fe₃O₄-PEI-DOX could deliver more drug to the tumor site than the DOX group,so that TiO₂-Fe₃O₄-PEI-DOX group is more effective than DOX group. After laser irradiation, TiO₂-Fe₃O₄-PEI-DOX suppressed the S180 sarcoma better. This showed that combing with phototherapy could significantly increase the therapeutic effect.