Fabrication And Properties Of Carbon Nanotubes Thermo-seed Composite For Tumor Hyperthermia

One of the major problems of tumor hyperthermia is how to make the temperature in tumor increase to 43℃and therefore to kill the tumor cells,without damaging the normal tissue nearby in recent years.A novel thermo-seed material with high thermal efficiency and good biocompatibility can carry out tumor targeted therapy in microwave hyperthermia.It will be a newly and highly effective way for the tumor hyperthermia. CNTs is a typical representative of nanomaterial.Due to outstanding microwave absorbing and thermal properties,carbon nanotubes could be used as thermo-seed material for microwave tumor targeted therapy.In this paper,the biological effects,the surface modification,microwave absorbing properties and the thermal effects of MWNTs were researched.Following are the main contents:1,We exposed different sizes mutil-wall carbon nanotubes(MWNTs)into Wistar rats in intratracheal instillation and intravenous injection two different administration modes.At the same time,we used silica(SiO₂)and acetylene carbon black(Cb),as positive and negative control.The results showed that:In intratracheal instillation experiments,the nanoparticles caused different levels of lung damage.The order of lung injury degree is:Cb＞10nm MWNTs＞40-60nm MWNTs＞SiO₂.In addition,MWNTs showed dose-dependent relationship on the extent of lung injury.In the low-dose(1mg/kg),40-60 nm MWNTs only caused minor damage to lung inflammation,there were no difference with the control group almost.As the dose increased,the lung injury degree became more and more severely.When carbon nanotubes was exposed into rats by the method of intravenous injection the structure of lung tissue can produce obvious histopathologic changes but other tissues are almost in order.When the same dose carbon nanotubes was poured into the rats by intravenous injection and intratracheal instillation respectively,the inflammation reflection is mild that arose by the former than the latter. Under the conditions of this test,pulmonary exposure to MWNTs in rats by intratracheal instillation produced a series of multiple lesion in a dose-dependent and time-dependent manner,evidence of a foreign tissue body reaction.Although there are anormous differences in lung between rodent animals and human beings,the results could call attention to the human beings at potential risk for exposure to MWNTs.2,In this paper,the suface of CNTs were modified by hydroxyapatite(HAp),iron oxide(Fe₃O₄)and chitosan(CS)which are currently recognized to be biocompatible in order to attain a kind of multi-wall nanotubes composites combining the biocompatibility and the unique properties of pristine multi-wall carbon nanotubes.This will enlarge the potential application of CNTs in tumor hyperthermia.HAp nanoparticles were decorated on CNTs successfully by a simple and effective coprecipitation and hydrothermal treatment method.When CNTs content was 10%, after hydrothermal treatment,a certain high degree of crystallinity,pure component single HAp layer were obtained on the surface of CNTs.Fe₃O₄ nanoparticles were densely decorated on CNTs successfully prepared by a simple and effective coprecipitation and hydrothermal treatment method.Fe₃O₄ nanoparticles in the surface of carbon nanotubes were uniform and universal;The hysteresis loops of the decorated MWNTs were measured by vibrating sample magnetometer(VSM),and the results showed that the composite was ferromagnetism with the saturated magnetization of 64.53 emu/g,and the coercive of 14.03 Oe.This results showed that CNTs/Fe₃O₄ composite had superparamagnetic character so that it could be easily magnetized in a applied magnetic field and could be used as a new tumor-tageted material in hyperthermia.We have successfully decorated the CNTs with chitosan by a controlled surface deposition and crosslinking process.The results of XRD and IR all expressed that the surface of CNTs were fully coverd with chitosan.This condition resulted in the external diameter of CNTs became thicker from 40-60nm to about 100nm which was very clear in TEM micrograph.We expect that the decoration can improve the biocompatibility of carbon nanotubes and the wettability of CNTs surface.3,The complex permeability and permittivity of the carbon nanotube composite were measured.Based on the theoretical calculation of reflection loss,the microwave absorption property of carbon nanotube composite has been measured in the frequency range from 0.5-5.0 GHz.The results showed that: CNTs/HAp composite had better absorbing properties in the 0.5-5.0 GHz range. With increasing of carbon nanotubes content,the microwave absorbing capacity of CNTs/HAp composite has been gradually strengthened,the absorption peak towards high frequency,the bandwidth was increased.When CNTs content was 8%,a maximum reflection loss value of-26 dB had been obtained at 3.0 GHz.The results indicated that this composite had significant potential for electromagnetic wave absorption application in tumor hyperthermia.CNTs/Fe₃O₄ composite also had better absorbing properties in the 0-5 GHz range. when CNTs content was 4%,the reflection loss value of -19dB and the bandwidth of 1G had been obtained at 2.2GHz.The results indicated that this composite had significant potential for electromagnetic wave absorption application in tumor hyperthermia.4,The thermal effect of thermo-seed material were described by heating experiment in the microwave field.The results showed that:With the increasing of CNTs content,the thermal effect was more obvious.But when CNTs content exceeded 8%,the thermal effect was gradually stabilized.CNTs played a dominant role in the thermal effect of CNTs/HAp composite powders.The thermal effects of CNTs/Fe₃O₄ composite was evident in the microwave field.When CNTs content exceeded 8%,the thermal effects of CNTs/Fe₃O₄ composite was comparative with pure CNTs.5,Carbon nanotubes composite-chitosan thermosensitive gels were prepared, which were characterized by Scanning Electronic Microscope(SEM)and Fourier Transform Infrared Spectrometer(FTIR).In this system chitosan thermosensitive gels were used as the carrier with CNTs composite dispersed in it.IR and SEM images indicated that CNTs composite were dispersed homogeneously in the carrier,and there were no chemical reactions between CNTs composite and gels components.The initial gelation temperature rised because the network structure of gel were damaged by adding nano thermal-seed material,Meanwhile,they still had thermo-sensitive properties.The viscoelastic properties of thermo-sensitive gel for hyperthermia,as investigated rheologically,indicated that if the region was below 37℃, where G′was lower than G″,showed the common viscoelastic behavior of a liquid;in the second region,G′and G″increased with the increasing of temperature and G′was higher than G″,indicated that an elastic gel network had been formed.Nano thermal-seed materials had a good heat production capacity in the microwave field,and were distributed uniform in the gel system.Under this condition(the power, 25w;irradiated temperature,10 minutes),when the content of CNTs was 6 mg/ml,the temperature of the system could increased by 34.6℃.when the content of CNTs/Fe₃O₄ was 20 mg/ml,the temperature of the system could increased by 34.6℃,when the content of CNTs/HAp was 20 mg/ml,the temperature could increased by 35℃.6,Cytotoxicity evaluation using L-929 cells as model system showed that the CNTs-CS thermo-sensitive gels,CNTs-Fe₃O₄-CS thermo-sensitive gels and CNTs-HAp- CS thermo-sensitive gels were nontoxic in proper composition.Option and SEM micrographs showed good morphology of L-929 cells in these hydrogels.MTT assay confirmed that there were no signicant difference between the hydrogels and control in cell avtivity,the toxicity level were 0-1 level.The results would be useful for the further research of developing these thermo-sensitive gels for tumor hyperthermia.This paper was supported by the Natural Science Foundation of the People's Republic of China(Grant No.30540061 and 50672051)...