Studies On The Synthesis Of Stimuli-responsive Hemoglobin-based Composite Nanoparticels And Their Applications In Tumor Theranostic

Malignant tumors(cancers)are characterized by high morbidity and mortality,and are one of the most threatening diseases to human life and health in the world.Therefore,achieving accurate diagnosis and personalized treatment of malignant tumors is still a worldwide problem that needs to be solved urgently.Malignant tumors are considered to have obvious heterogeneity and specific microenvironment.For example:(1)The higher glucose content and abnormal metabolism level of tumor tissues promote the excessive production of metabolites such as lactic acid,which leads to mildly acidic tumor microenvironment(acidosis);(2)The rapid growth of tumor cells and the distortion of blood vessels lead to the formation of a hypoxic microenvironment in solid tumors;(3)The rapid metabolism of cells in tumor tissues and insufficient blood supply lead to an increase in the concentration of hydrogen peroxide in the microenvironment.Based on the cognition of tumor microenvironment,researchers expect to improve the diagnostic accuracy and treatment efficiency on the basis of early screening,diagnosis and early warning,combined with the treatment with tumor microenvironment stimuli-responsive.This paper designs protein-based composite nanoparticles with tumor microenvironmental stimuli-responsive performance,and realizes photothermal/photoacoustic and other imaging modalities mediated synergistic therapy(involving: chemodynamic/photothermal combined therapy and starvation/chemodynamic/photothermal synergistic therapy).On the one hand,the research improved the treatment efficiency of protein-based nanoparticles through the combination of treatment modes.On the other hand,it gave the tumor microenvironment specific response function,which effectively reduced the side effects of treatment,and provided a new idea for the development of protein-based nanomedicine preparations.The main research content is briefly described as follows:(1)Hemoglobin-polydopamine(Hb-PDA)nanoparticles were designed and applied to photothermal imaging mediated chemodynamic and photothermal co-treatment of tumors.Under alkaline conditions,Hb-PDA nanoparticles were synthesized by a one-step oxidation and self-polymerization method,which has photothermal imaging and dual-modality synergistic therapeutic properties(hydrogen peroxide-responsive chemodynamic therapy and photothermal therapy).Among them,the ferrous protoporphyrin structure of hemoglobin contains ferrous ions,which can be used as the initiator of the Fenton reaction to provide a chemodynamic treatment mode for the composite system.Polydopamine formed by self-polymerization of dopamine due to its characteristic absorption in the near-infrared region which can be used as the photothermal diagnosis and treatment reagent.In this study,overexpression of hydrogen peroxide in tumor microenvironment was used to achieve specific chemical kinetic therapy.However,due to the limitation of hydrogen peroxide concentration in tumor tissue,the diagnosis and treatment effect of Hb-PDA nanoparticles is difficult to be fully exploited.In order to solve the above problems,the second subject was carried out on this basis.(2).Glucose oxidase-hemoglobin-polydopamine(GOx-Hb-PDA)composite nanoparticles was developed and applied them to photoacoustic/photothermal imaging-mediated three-modal combination therapy(starvation therapy,photothermal therapy and synergistically enhanced chemodynamic therapy).Glucose oxidase,as a kind of natural enzyme,can catalyze the production of gluconic acid and hydrogen peroxide from high-concentration glucose in tumor tissues.On the one hand,it consumes the energy source in the tumor microenvironment and achieves the purpose of starvation treatment to a certain extent.On the other hand,it provides additional hydrogen peroxide,which provides raw materials for hemoglobin-based Fenton reaction.Hemoglobin further induced cascade reaction to produce cytotoxic hydroxyl radicals,and enhanced chemodynamic was achieved under the condition of hydrogen peroxide self-supply.In addition,polydopamine is generated after polymerization of dopamine monomer,which can be used as a photothermal diagnosis and treatment agent,exerting the characteristics of photoacoustic/photothermal imaging and photothermal treatment.It is worth noting that the photothermal effect based on PDA can effectively promote the occurrence of Fenton reaction and improve the efficiency of chemodynamic treatment.Therefore,each component in the GOx-Hb-PDA composite nanoparticle plays an important diagnostic/therapeutic function and promotes each other to achieve a three-mode synergistic therapy for glucose and hydrogen peroxide response in tumor microenvironment.This work makes full use of the unique tumor microenvironment and designs a cascade reaction strategy,which provides a basis for the development of multifunctional protein-based composite nanomedicines.