The Study Of Carbon Nanotubes Based Brain Glioma Targeting Drug Delivery And Tumor Hyperthermia

Carbon nanotubes (CNTs) are made from rolled up graphene with a cylindrical nanostructure, which are extremely promising for biological and biomedical applications due to their unique intrinsic properties and good biocompatibility. CNTs after pretreatment and surface modification have been proved to be a versatile carrier for a wide variety of biomolecules, including drugs, proteins, peptides, and especially anti-tumor drugs. And the intrinsic near infrared (NIR) light absorption property of CNTs has also been used to destruct cancer cells in vitro and tumor photothermal therapy in vivo. Considering CNTs can not only accumulate in tumors but also distribute in brains, we developed a novel dual-targeting drug delivery system based on PEGylated multi-walled carbon nanotubes (MWNTs) modified with angiopep-2(MWNTs-PEG-ANG) for treatment of brain glioma in the first part. In the second part, we developed an Fe3O4NPs-decorated MWNTs with strong magnetic properties, and applied it to in vivo photothermal treatment of tumor as effective thermal ablation agents.In the first part, we sucessfully prepared PEGylated oxidized multi-walled carbon nanotubes (O-MWNTs-PEG), and modified with angiopep-2on the end of PEG (O-MWNTs-PEG-ANG), which had average particle size of150nm and Zeta potential lower than-20mV. Fluorescent molecule FITC labeled and NIR fluorescent molecule DiR labeled O-MWNTs-PEG-ANG were successfully prepared, which could be used to evaluate the targeting ability in vitro and in vivo and investigate the biodistribution of O-MWNTs-PEG-ANG. The results showed that the two MWNTs complexes established in this paper could be targeting delivered to brain and glioma, and O-MWNTs-PEG-ANG improved targeting effects compared with O-MWNTs-PEG without permanent brain accumulation. Due to the ultrahigh surface area of CNTs, DOX-loaded O-MWNTs-PEG (DOX-O-MWNTs-PEG) and O-MWNTs-PEG-ANG (DOX-O-MWNTs-PEG-ANG) were sucessfully prepared with remarkably high loading efficiency. The accumulative release curves of DOX-O-MWNTs-PEG-ANG showed that the drug release was pH-dependent and there was a faster release in pH5.5than in pH7.4. DOX-O-MWNTs-PEG-ANG exhibited a higher cytotoxicity compared to DOX and DOX-O-MWNTs-PEG, and in vivo anti-glioma effect of DOX-O-MWNTs-PEG-ANG was assessed by median survival time of glioma bearing mice, which showed a better anti-glioma effect than DOX. Cytotoxicities of O-MWNTs-PEG and O-MWNTs-PEG-ANG were investigated, and CD68immunohistochemical analysis after repeated injection of complexes was evaluated, which proved O-MWNTs-PEG-ANG was good biocompatibility and low toxicity. Histopathological analysis after repeated injection of DOX-O-MWNTs-PEG-ANG was evaluated, which suggested a lower cardiac toxicity than DOX. In conclusion, O-MWNTs-PEG-ANG is a promising glioma targeting carrier to deliver DOX for the treatment of brain tumor and has good biological safety without permanent brain accumulation.In the second part of the paper, we developed a facile and novel synthesis approach via a solvothermal method to prepare orderly distributed Fe3O4 NPs-decorated on the surface of MWNTs (MWNTs-Fe3O4). It showed that the MWNTs have a mean diameter of60nm with the length of about200-800nm, and Fe3O4NPs have a narrow size distribution with average diameters of ca.40nm. The magnetic characterization showed that the MWNTs-Fe3O4nanomaterials had superparamagnetic property and high magnetization with saturation value of41.7emu·g-1. An aqueous biocompatible MWNTs-Fe3O4solution was firstly prepared by noncovalently modified with PEG (PL-MWNTs-Fe3O4). PL-MWNTs-Fe3O4could absorb NIR owing to the MWNTs ingredients, and absorbed NIR promotes molecular oscillation leading to efficient heating of the surrounding environment. The feasibility of using PL-MWNTs-Fe3O4as novel thermal ablation agents for thermal destruction of cancer was investigated in vitro and in vivo. In vitro researches included the cytotoxicities of PL-MWNTs-Fe3O4, cancer cell destruction by PL-MWNTs-Fe3O4in combination with808nm NIR laser, and cell uptake of PL-MWNTs-Fe3O4. In vivo researches included anti-tumor effect evaluation of PL-MWNTs-Fe3O4in combination with808nm NIR, biological safety evaluation by prussian blue staining and histopathological analysis. In summary, we presented a novel and facile synthesis approach to prepare MWNTs-Fe3O4nanomaterials for biomedical applications. Our results suggested that the combination of PL-MWNTs-Fe3O4and NIR irradiation may be a promising approach for tumor therapy.On the whole, MWNTs were modified by two different methods in this paper, one of which was modified by Angiopep as targeting ligand, the other was by Fe3O4nanoparticles. The two MWNTs complexes could be used in anti-tumor drug targeting delivery and photothermal treatment of tumor respectively, and also showed good biological safety.