Preparation Of Polymer-based Composite Nanoshuttles And Their Application In Tumor Diagnosis And Treatment

In the research of tumor diagnosis and treatment,polymer nanoparticles have been widely concerned by researchers because of their high biocompatibility,low biotoxicity,high colloidal stability and structural stability.At the same time,the abundant functional groups in the polymer nanoparticles can provide the possibility for the loading,doping or modification of more multifunctional elements.It is conducive to the construction of multifunctional nanocomposites,which is the development direction of polymer-based theranostic reagents.To improve the diagnosis and treatment performance of nanomaterials,the first is to improve the accumulation of nanoparticles in the tumor;the second is to enhance the retention and cell internalization of nanoparticles in the tumor;the third is to make full use of the characteristics of the tumor,utilizing the special effects or changes of nanoparticles under some special physical and chemical properties to improve the diagnosis and treatment effect.In this dissertation,we constructed polyaniline composite nanoshuttles and polyamino acid composite nanoshuttles,and improved the accumulation of nanomaterials in tumor sites by taking advantage of the one-dimensional spindle-like morphology.On this basis,we made full use of various characteristics of tumor tissue and tumor microenvironment through rational design,and achieved better tumor diagnosis and treatment performance.In the second chapter,we utilized the enhancement of surface negative charge caused by the overexpression of sialic acid on the cell membrane after drug resistance of tumor cells to achieve a better diagnosis and treatment effect for drug resistant tumors.We prepared PEG coated,VCR-loaded,Cu²⁺-Fe³⁺co-doped polyaniline composite nanoparticle(PEG-VCR-CuFePani NSs)with MRI,chemotherapy and photothermal therapy functions.In the dual tumor model of KB and KBV,PEG-VCR-CuFePani NSs showed better stealth-like effect due to PEG modification,which was characterized by prolonged blood circulation half-life and increased tumor retention.Because the surface negative charge of KBV cells is stronger,the enrichment of PEG-VCR-CuFePani NSs with positive surface charge in KBV tumors is significantly higher than that in KB tumors under electrostatic attraction.Therefore,under MRI,the signal of KBV tumor is stronger,the imaging resolution is higher,and the tumor boundary is more obvious.Also,due to the higher PEG-VCR-CuFePani NSs content in KBV tumors,the photothermal therapy requires shorter illumination time and lower laser power,which is of great significance to improve the safety of the treatment.In the third chapter,we built a hierarchical targeted diagnosis and treatment platform based on the responsive transformation of the surface charge of nanomaterials in the pH of the tumor microenvironment,and realized tumor localization and thermo-chemotherapy elimination.We prepared citrate modified,VCR loaded,Cu²⁺-Fe³⁺co-doped polyaniline composite nanoshuttles(SC-VCR-CuFePani NSs)with tumor microenvironment responsiveness,which has the functions of MRI,chemotherapy and photothermal therapy.In KB tumor model,the surface of SC-VCR-CuFePani NSs was negatively charged due to the modification of citrate,showing a better stealth-like effect,which was characterized by prolonged blood circulation half-life and increased tumor retention rate.In acidic tumor microenvironment,citrate was protonated and detached,and the SC-VCR-CuFePani NSs recovered the positive surface,and the ability of cell internalization was significantly enhanced.Compared with before citrate modification,hierarchical targeting significantly increased the amount of SC-VCR-CuFePani NSs in tumor sites and their bioavailability was improved.Therefore,the signal of the tumor under MRI is stronger,the boundary is more obvious,the temperature rises faster during photothermal therapy,and the therapeutic effect is better.Moreover,the release of thermally stimulated chemotherapeutic drugs can play the role of postoperative chemotherapy.With the synergistic effects of photothermal therapy and chemotherapy,the tumor was completely eliminated without recurrence.In the fourth chapter,we used the chemical reaction between metal ions released by the disintegration of nanomaterials under the stimulation of tumor microenvironment and components in tumor microenvironment to realize tumor localization and treatment.We selected two substances that are very safe for organisms,Fe³⁺and tyrosine,and successfully prepared polytyrosine composite nanoshuttles with very low toxicity and conducive to cell uptake through pH-regulated one-dimensional assembly.Its positive surface charge and one-dimensional spindle morphology make it easier to be uptaked by tumor cells.At the same time,the coordination of Fe³⁺and polytyrosine allows the composite nanoshuttles to be used as a T1-weighted MRI contrast agent,and the presence of?-FeOOH allows the composite nanoshuttles to be used as a T2-weighted MRI contrast agent.In addition,under the action of GSH overexpressed in the tumor microenvironment,the composite nanoshuttles disintegrated and released Fe³⁺.Fe³⁺can clear GSH,reduce the activity of glutathione peroxidase 4,and cause the accumulation of lipid peroxides.Fe²⁺formed by the reaction can also produce a large number of reactive oxygen species through Fenton reaction,they all can lead to ferroptosis.Therefore,the composite nanoshuttles prepared by us have good MRI function and the effect of ferroptosis,which can localize bladder tumors and realize the treatment of bladder tumors.