The Construction And Primary Application Of Remote-control Drug Release From A Mesoporous Titanium Drug Delivery System

Despite advances in drug delivery systems(DDSs), the stimuli-responsive controlled release DDSs with high spatial/ temporal resolution are still the best choice, especially in enhancing antitumor efficiency, reducing side effect, and so on. Mesoporous nanoparticles with low toxicity, stable mesostructure, large surface areas, and tailorable pore size, which are suitable for basis material of stimuli-responsive controlled DDS. The mesoporous titanium nanovehicle(MTN) is one kind of Mesoporous nanoparticles, could strongly absorb untrasound(US), and generate a lot of reactive oxygen species(ROS, such as hydrogen peroxide, hydroxyl radicals, super oxides and Singlet oxygen). In the study, MTN with low toxicity, large surface areas, and tailorable pore size, that was used for basis material. After drugs(Docetaxel, DTX) were loaded in the pores of MTN efficiently, β-CD was attached to the outer surface of MTN via a ROS-sensitive bond as a gatekeeper to block the pores. As a result, an ideal stimuli-responsive controlled DDS was developed. A large number of ROS were generated by the DDS under US radiation, leading to the cleavage of the ROS-sensitive linker, thus, DTX could be released rapidly since the gatekeepers(β-CD) were detached. Besides, the generation of ROS could also be used for tumor-specific sonodynamic therapy(SDT), integrated sonodynamic therapy(SDT) and chemotherapy in a DDS, and inhibited tumor through multiple mechanisms. The DDS entraped the DTX in the pores and would not generate ROS during the normal physiological environment. Thus, the DDS significantly decreased the side effects of DTX by avoiding the toxicity to the normal tissue.Herein, the MTN were synthesized via a sol-gel route using F68 as the structure-directing agent and Titanium tetraisopropanolate(TIP) as the TiO2 source. DTX was loaded into a large number of pores in the MTN with a high drug loading efficiency(120%). The β-cyclodextrin(β-CD, a bulky gatekeeper) was attached to the outer surface of MTN via a ROS sensitive linker to block the pores(MTN@DTX-CD). As a result, a controlled-release DDS with well dispersibility was developed. In the study, we made a single design to optimize prescription process. MTN@DTX-CD was characterized by Fourier Transform Infrared Spectroscopy(FT-IR), Thermal Gravimetric Analysis(TGA), Transmission Electron Microscopy(TEM), Dynamic Laser light Scattering(DLS), Pore Size Analyzer(V-sorb 2800P). The drug releasing from the prescription and the stability of the preparation in the commonly used biological medium were studied. In the study, MTN@DTX-CD could entrap the DTX in the pores without a focused ultrasound(US) and allow the rapid release until a US emerged. A large number of ROS were generated by MTN under US radiation, leading to the cleavage of the ROS-sensitive linker; thus, DTX could be released rapidly since the gatekeepers(β-CD) were detached(96.8% of drug released until 24 h). The studies have shown the feasibility of MTN@DTX-CD for US-triggered DTX release and sonodynamic-chemotherapy.The vitro antitumor studies: the SRB experiments were performed to research antitumor efficacy of MTN@DTX-CD on MCF-7 cells. Without a focused ultrasound(US), the DTX could be entraped in the pores of MTN@DTX-CD. Therefore, the inhibition efficiency of MCF-7 cells was very low(survival%: 80.9%). A large number of ROS were generated by MTN under US radiation(US, 30 s, 1 W/cm2), so that DTX could be released rapidly. Besides, the generation of ROS could also be used for tumor-specific sonodynamic therapy(SDT), as it could damage the DNA and mitochondria. The SDT and chemotherapy could be integrated into a system, inhibiting the proliferation of cells. Therefore, about 8.8% of the cells survived after cultured by MTN@DTX-CD(US, 30 s, 1 W/cm2) for 48 h.The vivo antitumor studies: the biodistribution of DTX and inhibition ratio of tumor in S180 tumor-bearing mice were evaluated. The result suggests the in vivo tumor-targeting by EPR effect, the long circulating abilities of the nanoparticle group and the integrating SDT and chemotherapy into a DDS. The MTN@DTX-CD showed excellent antitumor efficacy. More importantly, the DDS entraped the DTX in the pores and would not generate ROS during the normal physiological environment, significantly decreased the side effects of DTX by avoiding the spleen toxicity.