Construction of nano metal organic framework materials for photodynamic therapy and low temperature photothermal therapy

Nowadays, cancer has become the number one killer threatening human health Therefore, the efficient treatment methods and appropriate biological functional materials for cancer have become the two hot spots of current research Among the bio functional materials, nano metal organic framework (nmof) has become a high-quality candidate material for the construction of bio drugs due to its adjustable chemical composition and crystal morphology, high porosity and good biological stability In recent years, many anticancer drugs, such as diclofenac sodium, cisplatin and adriamycin, have been loaded on porous nano metal organic frameworks for gene therapy and chemotherapy of tumors In addition, porous nano metal organic frameworks will also be loaded with photosensitizers for photodynamic therapy (PDT) and also be developed for photothermal therapy (PTT) Based on the existing research results, the research group of Professor Yang Zhou and Professor Dong Haifeng of Beijing University of science and technology have designed and synthesized a multifunctional nano metal organic framework connecting porphyrin ligands and zirconium metal clusters for the combined treatment of PDT and low-temperature PTT In order to increase the targeting and therapeutic properties of the metal framework, researchers loaded siRNA, an inhibitor of HSP70, on the surface of the prototype nanostructure to construct a siRNA / Zr FEP MOF therapeutic platform SiRNA/Zr-FeP MOF can realize photothermal imaging (PTI), photoacoustic imaging (PAI) and CT three modality tumor imaging Therefore, it can be used for accurate tumor diagnosis More importantly, this platform can transform H 2O 2 and O 2 into hydroxyl radicals (· oh) and singlet oxygen (1O2) for PDT At the same time, this platform has excellent PTT treatment effect Relevant achievements were published in adv funct Mater (DOI: 10.1002/adfm.201804634) Firstly, the structure of Zr fepmof and siRNA / Zr fepmof were characterized SEM and TEM images show that Zr fepmof is in the form of monodisperse shuttle, and its diameter is about 210 nm (Figure 1a and figure 1b) After that, the author confirmed that the Zr FEP MOF nanostructure was modified and constructed on the basis of mof-545 by XRD (Figure 1c) Furthermore, the FT-IR spectra of Zr FEP MOF, PEG and siRNA / Zr fepmof were compared, and it was found that siRNA / Zr FEP MOF has the characteristic peak of PEG (Figure 1D), indicating that the nano metal framework was successfully modified by PEG In order to further characterize the structure, the author conducted potential analysis From figure 1E, it can be seen that the potential of Zr FEP MOF has changed significantly after the peg with negative charge is wrapped by Zr FEP MOF; furthermore, the surface of the peg is loaded with siRNA with negative charge, and the potential of siRNA / Zr FEP MOF has changed slightly again, which proves that PEG and siRNA are successfully modified in / Zr FEP MOF Surface Finally, the author verified that siRNA / Zr fepmof has high stability (Figure 1F) and can be used in biomedical field (source: adv funct Mater.) later, in order to verify the photothermal effect of siRNA / Zr fepmof, the author carried out temperature properties and photothermal imaging experiments From figure 2a, it can be found that the temperature of siRNA / Zr FEP MOF increases with the increase of light exposure time, and the increase of temperature increases with the increase of concentration; figure 2B The photothermal image of the system shows this property more intuitively Secondly, the author explores the ability of the nano platform to generate ROS From the ESR data of figure 2c, it is found that after adding H 2O 2, siRNA / Zr fepmof has an obvious ESR signal of 1:2:2:1, indicating that siRNA / Zr fepmof can stimulate H 2O 2 degradation to form · Oh, which is verified by the UV absorption spectrum data of figure 2D In order to prove the existence of 1O2, the author selected a probe 1 with the absorbance decreasing with the increase of 1O2, 3-diphenylisobenzofuran (dpbf) It can be seen from figure 2E that under 635 nm light, the absorption intensity of dpbf is significantly reduced, which shows that 1O2 is produced The subsequent ESR experiment and single line oxygen laser scanning confocal (CLSM) imaging experiment also verify this view (source: adv funct Mater.) next, the author studied the therapeutic effect of siRNA / Zr FEP MOF in vitro and in vivo First of all, the normal cell line NHDF and tumor cell line MCF-7 were co cultured with different concentrations of siRNA / Zr FEP MOF respectively, which showed dose-dependent toxicity to MCF-7 cell line (Figure 4a), but after 635 nm light irradiation, the survival rate of tumor cells was lower than 20% (Figure 4b) The CLSM imaging of figure 4C shows that siRNA / Zr FEP MOF has a satisfactory effect on cancer treatment by comparing the staining of living / dead cells Based on the good experimental results in vitro, the author applied siRNA / Zr FEP MOF to the in vivo experiment The author injected five groups of control substances and experimental substances into the mice with tumor respectively After 15 days, the mice were killed and compared with the tumor size It was found that the tumor in the experimental group was the smallest (Figure 6a and 6b), indicating that the siRNA / Zr fepmof under light It has an excellent tumor clearance effect; by measuring the weight of mice (Figure 6c), it is found that the weight of mice does not change much, indicating that siRNA / Zr FEP MOF has a good biological safety at the same time of treatment Finally, the author further verified its excellent therapeutic effect by H & E tumor section experiment (source: Adv Funct Mater.) (source: Adv Funct Mater.) in addition to excellent therapeutic effects, another highlight of siRNA/Zr-FeP MOF is its ability to perform three mode imaging (Figure5) Figure 5A and 5b are the experimental results of photoacoustic imaging Figure 5A shows that with the increase of concentration, the imaging effect is better; from figure 5b, it can be clearly seen that siRNA / Zr FEP MOF gathers in the tumor site; figure 5C is the CT image, and the image of the tumor site after injection is clearer than that without siRNA / Zr fepmof; figure 5D The analysis of CT imaging data also proves that the higher the concentration is, the clearer the imaging is; the photo thermal imaging results of figure 5E are consistent with those of the other two imaging methods Furthermore, the author studied the biological distribution of the nanoframework, analyzed the concentration of zirconium metal clusters in the blood of mice in different time periods by ICP-AES, and drew the blood circulation curve of siRNA / Zr FEP MOF It can be seen from figure 5F that after 1.49h, the concentration of siRNA / Zr FEP MOF gradually decreased, but its time in blood circulation was longer, up to 24h, indicating that it had an excellent long-term therapeutic effect The subsequent biological distribution experiment data showed that although the nano framework had a higher aggregation in the spleen, the aggregation of siRNA / Zr FEP MOF in other main organs was smaller than that in tumors (Figure 5g), and the Zr concentration retained in the main organs of mice decreased rapidly with time, which indicated that siRNA / Zr FEP MOF was effectively removed in vivo (source: Adv Funct Mater.) Summary: Professor Yang Zhou research group of University of Science and Technology Beijing and Professor Dong Haifeng's research team have designed and synthesized a multifunctional nano metal organic framework siRNA/Zr-FeP MOF for combined therapy and three mode imaging This work is helpful for the design of nano preparations with PDT / PTT, and provides a new research idea for the development of combined therapy and multimodal imaging.