The Construction And Bio-application Of Tumor Microenvironment-responsive Nano-assemblies

Malignant tumor is a serious threat to human life and health,and i s a major problem that needs to be solved by modern life medicine.Traditional clinical treatment modes(radiotherapy,chemotherapy,etc.)do not have tumor-specific killing ability and cannot circumvent the damage to normal tissues.Unlike normal cells,t umor cells are located in an extremely complex microenvironment,such as acidic environment,lack of oxygen,redox imbalance,uneven vascular distribution,abnormal metabolism and immune escape,which provide conditions for tumor proliferation and metastas is.In recent years,with the rapid development of nanoscience,conditionally activated nanoparticles can be used for the regulation or improvement of tumor physiological environment to achieve effective tumor therapy.Therefore,the design of efficient an d highly specific nano-agents based on tumor microenvironment response strategies is of great significance to promote clinical research on targeted tumor therapy.This thesis addresses many unresolved problems and needs in tumor therapy,and uses modern nanotechnology as a support to design and construct advanced intelligent responsive nano-assemblies for tumor microenvironment and introduce therapeutic strategies such as chemokinetic therapy,immunotherapy,and starvation therapy,etc.It provides innovative ideas and technical support for targeted tumor therapy by deeply investigating the important effects and relationships of nano-assemblies in body physiological functions and tumor therapy.This dissertation focuses on the functionalized controlled design of nanoassemblies and biomedical applications as follows.In chapter 2,the high proliferation,redox imbalance and nucleic acid mutations of tumor cells severely limit the efficacy of tumor therapy,agents with highly efficacious tumor nucleic acid damage properties are expected to overcome these barriers.In this chapter,inspired by biomineralization,a symbiotic nanoenzyme@bioenzyme Cu@GOD was designed,with continuously glucose/GSH consuming and ROS generation ability through a cyclic cascade cataly tic reaction.The metabolic perturbation,nutrient depletion,selective disruption of redox homeostasis with a sustained ROS production ability ensured that Cu@GOD possessed multi-pathway nucleic acid damage to tumors.This nanoenzyme@bioenzyme strategy with persistent and multi-pathway tumor intracellular nucleic acid damage properties would be the preferred pathway to break tumor proliferation barriers and provide a new conceptual idea to inhibit tumor proliferation.In chapter 3,how to coordinate the balanced occurrence between immunogenic death(ICD)of tumor cells and activation of M1 polarization of tumor-associated macrophages is a consistent difficulty in tumor immunotherapy.In this chapter,Zn O₂-ATM,an endogenous/exogenous simultaneous H₂O₂-producing nanomaterial was designed and synthesized,which could be used as an adjuvant for both ICD and M1 polarization drugs.The balanced action of ICD and M1 polarization exhibited better synergistic immune effects,by effectively inhibit the growth of primary/distal metastases.This endogenous/exogenous balancing strategy helps to deepen our understanding of the effects of the inherent concept of nanomaterial immunotherapy.In chapter 4,the abnormal metabolism and imbalance of blood supply to tumor cells result the malignant proliferative features to tumor cells.By regulating tumor cell metabolism and modulating progressive tumor vascular embolization,the tumor proliferation would be inhibited.In this chapter,a tumor microenvironment acid-responsive Fe-GA@Ca CO₃ nanoparticles was designed and synthesized,which could transform into biocompatible Ca²⁺and Fe(III)within the tumor microenvironment.In situ progressive oxygen depletion generates precipitated Fe(III)could embolize tumor blood vessels and isolate O₂/nutrients by blocking blood supply.Meanwhile,free Ca²⁺acted on tumor cells to induce mitochondrial dysfunction through calcium overload,contributing to irreversible tumor cell damage.Both pathways acted synergistically and provided precise functional inhibition to tumor vessels and cells,provided innovative solutions for antitumor interventions.In chapter 5,the tumor regional calcification is considered to be a predictor of good prognosis.Inducing tumor cell calcification by exogenous induction is an innovative idea for tumor therapy.In this chapter,a tumor a cidic environment-responsive Ca HPO₄ covalently doped L-ascorbic acid nanoparticles(Ca P-AA)was designed and synthesized.Ca HPO₄ could release Ca²⁺and PO₄^3-within the tumor,Ca²⁺then trigger calcium overload in tumor cells,which could prompt mitochondrial dysfunction and causing ROS surge.In addition to acting as a n exogenous antioxidant,the L-ascorbic acid could also promote collagen deposition,which could work together with Ca²⁺and PO₄^3-in the interstitial space of tumor cells to produce Ca₃(PO₄)₂ precipitation attach to collagen fibers,both Ca HPO₄and L-ascorbic acid promote the occurrence of calcification and form stable calcification foci.In conclusion,the introduction of exogenous responsive Ca sources as a therapeutic strategy for calcium overload and tumor calcification would be an effective therapeutic agent for cancer treatment.