The Rational Design, Anti-cancer Activity And Photothermal Therapy Of Targeted Carbon Nanotubes-based Drug Delivery Systems

Due to the special structural features, carbon nanotubes have been widely used to study the electrochemical, mechanical properties, biomedical and so on. Because of a high specific surface area, it can adsorb and covalent bonding most molecules in a degree. While physical properties such as strong absorption in the near infrared region(NIR), it can be used for photothermal therapy. Based on these characteristics, carbon nanotubes were modified with various polymers, target ligands and loaded different anticancer drugs. Chemotherapy and photothermal therapy co-treatment or not were studied for the anti-tumor activity and action mechanism. The main contents are as follows: 1. The Mechanism of suppressing glioma C6 cell proliferation by Biotin@MWCNTs/Oxa. MWCNTs were modified with target ligand biotin, which can recognize tumor cells specifically. It can effectively inhibit the proliferation of C6 cells by MTT assay. In addition, it can significantly increase the amount of drug accumulation in tumor cells via biotin specifically recognizing biotin receptors in tumor cell membrane. Meanwhile, Biotin@MWCNTs/Oxa can enter into cells by receptor-mediated and muscle protein, clathrin, a lipid raft-mediated endocytosis and release in lysosomes, causing overproduction of ROS and DNA damage, thereby inhibiting the proliferation of C6 cells. 2. Comparison of Targeted SWCNTs and MWCNTs systems doxorubicin-loaded in anti-tumor activity and mechanism. SWCNTs and MWCNTs were modified by RGD-c and loaded doxorubicin. Comparing two systems in many ways such as chemical characterization, antitumor activity and action mechanism. SWCNTs system has a comparative advantage in the drug enfficiency, drug release rate and selectively cell uptake, which possibly due to its higher specific surface area. In terms of antitumor activity, compare the safety index towards different normal cells; SWCNTs system and MWCNTs system have their own advantages. Flow cytometry analysis indicated that DOX@SWCNTs-F127-RGD and DOX@MWCNTs-F127-RGD caused MCF-7 cell death via apoptosis and G0/G1 phase arrest. 3. The mechanism of functionalized carbon nanotubes drug delivery systems in photothermal therapy co-treatment with chemotherapy. In this chapter, we designed and prepared pH responsive triblock polymers and targeting polypeptide AE105 to double modify the carbon nanotube system, while poorly water-soluble PSeD was loaded as antitumor drugs. Take advantages of carbon nanotubes possessing strong NIR absorption and high surface area, PSeD were loaded to antagonize cell proliferation and metastasis of breast cancer MDA-MB-231 cells and deeply molecular mechanism was studied. Functionalized modified CNT-based system accumulated in tumor microenvironment, thereby increasing the amount into the tumor cells. Meanwhile, AE105 could selectively bind to uPAR on tumor cell membrane, which overexpressed in cancer cells. When PSeD@MPPTA-AE105 entered tumor cells, CNT-based system heated up under 808 nm laser and PSeD detached from the CNT due to violently inter molecular movement. When the temperature rose to 42 ℃ or above, it could cause fatal damage of intracellular components and leading to cell death. In the area without irradiation, PSeD exhibited the subsequent anti-tumor effect. PSeD@MPPTA-AE105 under 808 nm laser irradiation could significantly increase ROS levels. Western Blotting analysis show that overproduction of intracellular ROS by PSeD@MPPTA-AE105+Laser could upregulate DNA damage associated proteins including ATM, P-His, P-Chk1, P-Chk2 and BRCA1, which activated the p53 pathway and MAPKs signal pathway, further activation of Caspases family, and finally to promote apoptosis; Meanwhile, PSeD@MPPTA-AE105+Laser inhibited the expression of FAK and FAK phosphorylation at different sites, which stimulated the activation of MMPs and uPA protein. The expression level of uPA, uPAR and MMP-2/-9 was suppressed, while raising the TIMP-1(metalloproteinase inhibitors) expression levels so that invasion and metastasis of MDA-MB-231 cells is suppressed. PSeD@MPPTA-AE105 achieved effective results in photothermal therapy and chemotherapy co-treatment and further explore of its anti-tumor effects in vivo was necessary.