Preparation And Preliminary Investigation Of Drug Delivery System Based On Titanium Dioxide/Multi-wall Carbon Nanotubes For Cancer Phototherapy

With the deep understanding of cancer,tumor target and combination therapy have become the focus on cancer research.As a new type of treatment methods,phototherapy with tumor-specific and low toxicity has been widely concerned.Phototherapy,including photothermal treatment?PTT?and photodynamic treatment?PDT?,is a photo-initiated,noninvasive and efficient cancer treatment model.The accumulation of photosensitizer in the tumor site and the light utilization efficiency are the main factors that determine phototherapy effect.Titanium dioxide?TiO₂?is a commonly used photocatalyst,with high catalytic activity,good chemical and light stability,non-toxicity and easy availability.Under light irradiation,TiO₂ has a certain therapeutic effect on various tumors,as a kind of promising PDT materials.But it only can be excited by ultraviolet light because of its wide band-gap.Furthermore,as drug carriers,the drug loading efficiency of TiO₂ nanoparticles is very low,due to its smooth surface and poor adsorption performance.These drawbacks greatly limit its further application in the medical field.In this paper,titanium dioxide-multi-walled carbon nanotubes composite nanomaterials?TiO₂@MWCNTs?were synthesized.TiO₂@MWCNTs can not only expand the spectral absorption range of TiO₂,but also maintain the light and heat conversion capacity and efficient drug loading capability of MWCNTs.Then hyaluronic acid?HA?was grafted on TiO₂@MWCNTs to improve its water dispersibility and tumor selectivity.Finally,the photosensitizer hematoporphyrin monomethyl ether?HMME?was loaded onto HA-TiO₂@MWCNTs by the way of physical adsorption to prepare a novel tumor targeting phototherapy system?HA-TiO₂@MWCNTs/HMME?.The Human breast cancer MCF-7 cell lines were chosen as tumor cells model to study the in vitro anti-tumor effects of HA-TiO₂@MWCNTs/HMME.The results showed that the composite nanocarriers had no obvious toxicity to MCF-7 cells.After 808 nm laser irradiation,the cell viability decreased from 95.6% to 81.4%.After 532 nm laser irradiation,the cell viability was significantly reduced to 73.3%,showing significant phototoxicity.Combined with 532 nm and 808 nm laser,the cytotoxicity of HA-TiO₂@MWCNTs was further enhanced,with cell viability of 59.4%.Compared with HMME,HA-TiO₂@MWCNTs/HMME demonstrated stronger toxicity with 532 nm laser.After combination of 532 nm and 808 nm lasers,the phototherapy toxicity of HA-TiO₂@MWCNTs/HMME significantly enhanced,with cell viability of 16.6%,the results indicating that combined with 532 nm and 808 nm lasers,HA-TiO₂@MWCNTs/HMME can significantly enhance the anti-tumor effect.Cell uptake experiments showed that more than 90% HA-TiO₂@MWCNTs could be taken by MCF-7 cells within 4h,while there was only 40.7% of TiO₂@MWCNTs being uptaken.It indicated HA-TiO₂@MWCNTs has rapid and efficient internalization ability with the help of HA.The results of reactive oxygen species?ROS?showed that HA-TiO₂@MWCNTs/HMME can efficiently induce ROS under 532 nm laser irradiation.Cell cycle results showed that MCF-7 cells in HA-TiO₂@MWCNTs/HMME group were arrested in S phase?43.53%?,and this phenomenon in 532 nm laser group was more obvious?56.36%?.Single cell gel electrophoresis results indicated that the DNA damage caused by single PTT?20.9%?or PDT?29.1%?was significantly lower than the combination of PTT and PDT?65.4%?.S180 bearing mice were chosen as the model animals to study in vivo anti-tumor activity of HA-TiO₂@MWCNTs/HMME.We qualitatively examined the tissue distribution and pharmacodynamics properties of HA-TiO₂@MWCNTs/HMME.The results showed that HA-TiO₂@MWCNTs had no obvious toxicity and did not affect the tumor growth.When combined with 532 nm or 808 nm laser irradiation,the tumor had a slight inhibitory effect,and tumor inhibition rates were 28% and 34.6% respectively.The anti-tumor effect of lasers combination was the most?49.6%?.HA-TiO₂@MWCNTs/HMME/PTT group?39.3%?and HA-TiO₂@MWCNTs/HMME/PDT?49.8%?group showed more tumor suppressing effect when two kinds of lasers were used respectively.And HA-TiO₂@MWCNTs/HMME/PTT/PDT group had the most tumor suppression effect than other groups?70.8%?.The tumors were almost completely inhibited.The in vivo imaging results confirmed that HA-TiO₂@MWCNTs had a good tumor targeting effect,so it could enhance the accumulation of PS in tumor tissues.In summary,in this study we successfully established a drug delivery system HA-TiO₂@MWCNTs/HMME.Those results in vitro and in vivo showed that the anti-tumor effect of this system-mediated PTT/PDT were significantly more than those of single treatment manner.In addition,this drug delivery system could realize high ratio of drug loading,sustained drug release and active targeted accumulation in tumor.These results suggest that HA-TiO₂@MWCNTs/HMME has high potential for tumor synergistic phototherapy as a precise drug delivery nanoplatform.