Preparation Of Multifunctional Manganese Nanocomposite And Its Application In Tumor Photodynamic/Chemotherapy Combined Therapy

As a stubborn disease that is difficult to cure,the diagnosis and treatment of malignant tumor has been a major problem.Today,as more and more people pay attention to health,malignant tumor is a long-standing research hotspot in the field of medicine.How to increase the targeting of drugs so that the anti-tumor effect is enhanced and the side effects are reduced?How to integrate diagnosis and treatment to realize start treatment as early as possible and treatment was carried out simultaneously with observation?How to improve the effectiveness of treatment and reduce tumor recurrence?The emergence and development of nanotechnology offers hope for solving these seemingly impossible problems.In this project,we selected the flower-shaped manganese dioxide nanoparticles with high drug loading space as the carrier,packed the chemotherapy drug doxorubicin and the photosensitizer Ce6,and further modified by the hyaluronic acid-methotrexate complex to improve the targeting ability,and designed a nanometer platform integrating diagnosis and treatment.When the prepared nanoparticles reached the tumor site,the manganese dioxide nanoflower were decomposed and released DOX and Ce6 under the action of acidity and high concentration of glutathione and hydrogen peroxide.Under the irradiation of 630 nm laser,Ce6 can produce singlet oxygen,so as to realize the combination of chemotherapy and photodynamic therapy(PDT).In addition,manganese dioxide can react with hydrogen peroxide in acidic solution to produce oxygen,greatly reducing the hypoxia of cancer cells,thus improving the efficiency of photodynamic therapy.The hyaluronic acid-methotrexate compound can not only improve the targeting of the nanometer platform,but also enhance its biocompatibility and safety.In terms of the synthesis of nanometer platform,we found a simple method to synthesize manganous dioxide by condition optimization.It was characterized by means of Marvin laser particle size meter,scanning electron microscope(SEM),Transmission electron microscope(TEM),ultraviolet absorption,infrared spectrogram,X-ray diffraction and so on,and the success of particle synthesis was verified.The experimental results showed that the optimized synthesis method can obtain manganese dioxide nano flowers with a particle size of 154.87± 3.72 nm and a potential of-24.73±0.97 mV.We can see through transmission electron microscopy that it has a distinct flower-like structure and a large space for drug loading.The results of in vitro drug release showed that the release of doxorubicin from nanoparticles under the stimulation of the tumor microenvironment was significantly increased.In the simulated tumor microenvironment system,the drug release increased by about 40%,which means that it can greatly reduce its impact on normal organs toxic side effect.Subsequently,in vitro/vivo experiments were then carried out to see whether the nanometer platform had the desired effect.The drug release in vitro showed that the release amount of doxorubicin increased significantly under the stimulation of tumor microenvironment,which meant that the toxic and side effects on normal organs could be greatly reduced.In addition,a series of cell evaluations were conducted.The results of cell uptake experiments demonstrated that Dox/Ce6-HMMNFs nanoparticles have good folate receptor targeting ability,and the uptake increased with time.The cytotoxicity and apoptosis results showed that under laser irradiation,the cell death rate in the Dox/Ce6-HMMNFs group was greatly increased,indicating that the combined effect of nanoparticle chemotherapy and photodynamic therapy was significant.The results of animal in vivo experiments confirmed that our designed nano-platform has superior tumor targeting and can significantly inhibit tumor growth,at the same time,it proves that Dox/Ce6-HMMNFs nanoparticles have the ability of multi-modal imaging,which can realize in vivo fluorescence imaging and photoacoustic imaging.The imaging methods can complement each other to make the imaging results more reliable.And the toxicity test in animals showed that our nano-platform is safe in vivo and will not cause damage to other normal organs.The above experimental results showed that the Dox/Ce6-HMMNFs nanoparticles synthesized by us combine tumor targeting,multimodal imaging,combined therapy and other functions well,realizing the accurate delivery of anti-tumor drugs and the integration of tumor diagnosis and treatment under the premise of ensuring good in vivo safety.The results of this study can be used for reference in combination therapy and multifunctional drug delivery of tumors and have potential application value in tumor therapy.