Construction Of Nanoparticles For Imaging And Treatment For Atherosclerosis

The incidence of cardiovascular and cerebrovascular disease rate has been high,which serious harms to the human’s health. As an important pathological basis of cardiovascular disease induced by atherosclerosis, there is still a lot of space for research. Although the diagnosis and treatment of atherosclerosis means of this disease have been formed, but the current diagnostic methods are lagging behind. If we can find patients and treat them early in the disease, we will greatly reduce the risk of the disease. Therefore, we have designed and synthesized a series of multifunctional nanoparticle systems, which can be used to load the imaging agents or drugs.In order to prepare the multi functional nanoparticle carrier, we synthesized the star PAMAM dendrimers by the method of divergence. By using ethylenediamine as the core, different generations of PAMAM dendrimers were synthesized through the reaction of repetitive Michael addition and ester amide stepwise. The dendrimers were characterized by NMR, FT-IR, MS and so on. After the synthesis of the modified dendritic molecules, the different algebraic PAMAM ligands were obtained. Then, the QDs of the amine ligand was coated with different PAMAM ligands. The results showed that the PAMAM and PEG-PAMAM could be used to exchange the ligand with QDs through the interaction between ions. After the exchange reaction, QDs can be dissolved in water, ethanol and other most solvents, and optical properties have been retained together with a smaller particle size. By using the same experimental method, the coating of IONPs was realized. The results showed that the solubility of IONPs were changed after coating. The TEM and DLS results show that the exchangeed IONPs still maintained a good dispersion and uniform particle size. TGA results show that the coating efficiency of IONPs by PAMAM is 87%. The successfully modify of the two kinds of contrast agent provides a basis for the follow-up of more functional modification.After that, we use the synthesis of the third generation of PAMAM as the carrier,T1/T2 co-imaging contrast agent with targeting effect 5-HT-PEG-G3.0-DTPA--Gd@IONPs was successfully synthesized by stepwise modification method. The each products in the synthesis process were characterized by NMR, FT-IR to prove the success of the synthesis. DLS results show that the hydraulic diameter of the final product is 25.8nm. The size of the particle make it easy to get through the blood vessel endothelial cells. VSM analysis showed that after the ligand exchange, IONPs still retains super paramagnetic although the saturation magnetization decreased. The results provide a theoretical basis for magnetic resonance imaging. The study of proton relaxation rate of contrast system shows that the contrast agent can be T1 and T2 weighted imaging and the imaging effect is higher than the current clinical application of products. In addition, we tested the cytotoxicity of the product. At each concentration of the test, the RAW264.7 of mouse macrophages reached a high survival rate(more than 80%). The results meet the requirements of the biological safety of the imaging system, and it shows that the T1/T2 imaging contrast agent can be used as the diagnostic system of atherosclerosis.According to the pathological features of atherosclerosis, we select the light sensitive switch to release the drug. We designed and synthesized a drug delivery system by using G3.0PAMAM as the carrier, fluvastatin as drugs and nitro benzyl as the photosensitive group. In addition, we have synthesized a new kind of target molecule ISO-1 and connected it to the PAMAM. Finally, a targeted drug delivery system PAMAM-g-ISO-1-g-FS was synthesized. Mass spectrometry and nuclear magnetic characterization demonstrated the success of the synthesis. In the light of broken bond test, prodrugs and PAMAM-g-ISO-1-g-FS showed similar results of drug release. The results showed that the cumulative drug release rate was 25% within 3hours under 312 nm light irradiation. However, in the control experiment, the drug release was not shown under the natural light. The conclusion above shows that PAMAM-g-ISO-1-g-FS has high drug release rate and provides theoretical basis for the later biological experiments.To sum up, we take PAMAM as the foundation to prepare various polymeric delivery system aiming at atherosclerosis. These polymer transmission systems have their own function modules and application prospects, and provide more ideas for the diagnosis and treatment of this disease.