Preparation Of Metal-Phenolic Networkcoated Dendrimer Nanodrugs For Antitumor Applicarions

Tumors seriously threaten human health and have become one of the main killers.Due to the high recurrence and metastasis of tumors,traditional treatments such as chemotherapy,radiotherapy and surgery have certain inherent deficiencies.In recent years,new tumor treatment strategies based on nanotechnology have continued to emerge.For example,researchers use the nanoplatforms to delivery transition metal ions Fe,Cu and Mn to react with endogenously overexpressed hydrogen peroxide（H2O2）inside cancer cells,producing harmful hydroxyl radical（·OH）.The·OH can destroy intracellular proteins,lipids and disturb DNA metabolism,therefore killing tumor cells to perform chemodynamic therapy（CDT）.And interfering the pathways related to tumor growth and metastasis（such as the endoplasmic reticulum（ER）stress pathway）by loading inhibitors in nanoplatforms has become a new target therapeutic strategy for tumor’s chemotherapy and immunotherapy.However,the desired treatment effect cannot be achieved by using single treatment,whether it is traditional or new therapautic strategy.Combination of two or more treatments can maximize the strengths and avoid weaknesses,kill cancer cells from different mechanisms,thereby enhancing the therapeutic effect.However,there are still huge challenges in constructing suitable nanoplatforms to integrate multiple therapeutic agents on the same nanoplatform.Due to the abundant terminal amino groups,easy modification and internal cavity,Poly（amidoamine）（PAMAM）dendrimers are widely used as drug,gene and contrast carriers.By functionalizing dendrimer through amino groups,the drugs,genes and contrasts are endowed with ability of targeting and responsiveness drug release.Therefore,in this study the generation 5 PAMAM（G5）dendrimer was used as nanocarrier to load toyocamycin（Toy）,an inhibitor of ER stress IRE1α-XBP1signaling pathway,through the p H-responsive borate bond and then coated with TA-Fe complex on the surface of the conjugate to prepare nanoplatform for MR imaging and chemo/chemodynamic therapy in 4T1（Mouse breast cancer cell line）tumor medols.In chapter 2,G5 PAMAM dendrimers with amine termini（G5.NH₂）were first modified with 4-carboxyl phenylboric acid（PBA）,fully acetylated to neutralize the remaining terminal amines（G5.NHAc-PBA）,and thereafter covalently conjugated with Toy via boronic ester bonding to obtain the G5.NHAc-Toy conjugates.Finally,the prepared G5NHAc-Toy,tannic acid（TA）and Fe Cl₃ solution were mixed,and resultantly the TA-Fe complex（TF）was coated on the surface of G5.NHAc-Toy by physical adsorption to form the G5.NHAc-Toy@TF nanocomplexes.We characterized the G5.NHAc-Toy@TF complexes using different techniques.The results show that the nanocomplexes have a relatively uniform size distribution with an average size of about 50.2 nm,good colloidal stability,hydroxyl radical generation ability,responsive release Toy and Fe,blood compatibility as well as excellent T₁ MR imaging relaxation performance.In Chapter 3,the therapy efficacy and MR imaging ability of G5.NHAc-Toy@TF were assessed in vitro（4T1 cells）and in vivo（xenografted 4T1 tumor model）.In vitro exprement results show that the G5.NHAc-Toy@TF complexes were able to significantly inhibit the cancer cell proliferation.After the 4T1 cells were treated with G5.NHAc-Toy@TF,the alteration of intracellular ROS,GSH,LPO and mitochondrial membrane potential indicates that the G5.NHAc-Toy@TF can be used for cancer chemodynamic therapy.Furthermore,the change in expression of ERS-related genes such as CHOP、XBP1、IRE1αsuggests that the G5.NHAc-Toy@TF has an excellent inhibitory effect on the ERS pathway IRE1α-XBP1.Finally,the in vivo results demonstrate that the G5.NHAc-Toy@TF has excellent anti-tumor and MR imaging abililty,and more importantly there was no obvious system toxicity induced by G5.NHAc-Toy@TF.In short,we prepared the nanoplatform G5.NHAc-Toy@TF,and successfully realized the combined therapy of chemotherapy and chemodynamic therapy guided by MR imaging in 4T1 tumor models.The findings of this study provide novel ideas for the development of new types of theranostic nanoplatforms.