A Novel Redox-sensitive System Based On Single-walled Carbon Nanotubes For Chemo-photothermal Therapy And Magnetic Resonance Imaging

Theranostics is a newly emerging concept which involves simultaneous execution of therapeutic and diagnostic approaches for personalized medicine. It allows real-time evaluation of therapeutic effects in vivo, which is critical for medical intervention through noninvasive methods. In this respect, nanocarriers which can simultaneously perform multiple functions, such as tumor targeting, imaging ultrasensitivity and drug delivery, have become more and more popular in the domain of cancer therapy.Nanomaterials with multiple functions, such as drug carrier, MRI and optical imaging, photothermal therapy etc, have become more and more popular in cancer research. Single-walled carbon nanotubes（SWCNTs） have unique size and structure, special optical properties, large surface area and transmembrane ability. Gd³⁺-based carbon nanotubes with unique nanoscalar properties and superior performance as MRI CAs show promise for molecular imaging and other advanced applications. While this compound has some defects we might not ignore, such as highly hydrophobic surface, poor biocompatibility, etc. The study found that hyaluronic acid（HA） is a natural linear polysaccharides which carries negative charge. HA modified SWCNTs could improve its biocompatibility and biodegradability. And as a target, HA could mediate nanocarriers into cell through HA specific receptor（CD44）.In this work, a novel redox-sensitive system constructed from hyaluronic acid, SWCNTs, doxorubicin（DOX） and gadolinium（Gd） were successfully developed through a series of characterization, such as ultraviolet spectrum, infrared spectrum, unclear magnetic resonance hydrogen spectrum, transmission electron microscopy（TEM） and hyperspectral microscopy. Herein, HA-modified SWCNTs（HA-SWCNTs） was firstly synthesized, and then DOX was conjugated with HA by disulfide bond（SWCNTs-HA-ss-DOX）. Through the preparation prescription screening, the optimal prescription determined to be pure soybean lectithin as surfactant, loading proportion of SWCNTs-HA-ss-DOX: Gd was 1:7, probe ultrasonic time was 30 min. Then the size distribution was measured as 180 nm and zeta potential of nanoparticles as-25 mV. Finally, MRI contrast agents, Gd³⁺-ion loading occurred through the side wall defects of SWCNTs, whose cytotoxicity could be sequestered within the SWCNTs. In vitro release of DOX, about 57.7% of DOX was released in 4 h and almost 80.2% was released in 24 h, showed that this system accomplished much faster drug release under reducing condition.Florecence microscopy and confocal microscopy analysis confirmed that Gd/SWCNTs-HA-ss-DOX were capable of simultaneously delivering DOX and SWCNTs into MCF-7 cells via HA-receptor mediated endocytosis followed by rapid transport of cargoes into the cytosol. But, only with the GSH sensitive disulfide bond could drugs rupture release from the vector to make the DOX into the nucleus further play a role of killing cancer cells. Enhanced cytotoxicity of Gd/SWCNTs-HA-ss-DOX further proved that the sensitive system were more potent for intracellular drug delivery as compared to the insensitive control. Gd/SWCNTs-HA-ss-DOX had low IC50 values of 1.0 μg DOX equiv./ml at 48 h. Meanwhile, tumor cell killing potency was improved when Gd/SWCNTs-HA-ss-DOX were combined with NIR irradiation, with IC50 of 0.61 μg/ml at 48 h.Pharmacodynamics in vivo results was preparation can effectively inhibit tumor growth. Especially after 808 nm laser irradiation, the tumor volume of treatment groups was much smaller than the control groups without laser irradiation, showing that combining chemotherapy and thermotherapy can enhance the efficacy of treatment. In vivo imaging experiments including MR imaging and in vivo imaing analysis showed that Gd/SWCNTs-HA-ss-DOX could effectively accumulate in tumor sites and possessed the greatest synergistic antitumor efficacy, especially under the 808 nm laser irradiation,it has significantly antitumor efficacy. More importantly, this system could be used as a contrast agent for MRI to identify the location, extent and oberseving the development of tumor tissues, Gd/SWCNTs-HA-ss-DOX showed the T1-weighted positive contrast-enhanced MR imaging capability for the tumor tissues after intravenous administration. These results suggested that Gd/SWCNTs-HA-ss-DOX might be a promising system for targeting chemo-photothermal therapy and MRI diagnosis in future clinical anticancer applications.