Development And Biomedical Application Of Free Radical Metabolism-Targeted Functional Nanosystems

Free radicals are ubiquitous in living organisms and play an essential role in regulating biological functions,including the maintenance of cell metabolic homeostasis,and the regulation of cell behaviors and functions.Normally,the level of free radicals is tightly controlled by the antioxidant defense system.Once free radical metabolism disorder occurs,it will cause oxidative damage,leading to a series of pathological events.Accumulated evidence has demonstrated the correlation of abnormal free radical metabolism with the initial and progress of diseases,including cancer,bacterial infections,and cardiovascular and cerebrovascular diseases.Therefore,free radical-based therapy has been widely investigated in oxidative stress-related diseases.Thus far,several small-molecule drugs have been approved by FDA for the treatment of free radical metabolism-related diseases.However,several intrinsic limitations hinder their further therapeutic effects,such as rapid renal clearance and nonspecific distribution.Thanks to the remarkable advances in nanomedicine,the development of nanomaterial-based free radical catalysts lead to a significant advance in free radical-related therapy,due to their advantageous pharmacokinetics,stable catalytic activities,and tolerance to harsh environments.It is worth noting that,while free radical-catalysis has shown great potential in animal studies,this field is still in its infancy.Several issues need to be solved,including limited design of catalysts,ambiguous catalytic mechanisms,poor biocompatibility,short retention rate in pathological tissues,and unsatisfied therapeutic efficiency.To solve these issues,this thesis focuses on how to rationally design free radical catalysts and optimize catalytical activities,to improve the efficiency of traditional therapy and provide potential paradigms for enhanced catalysis therapy.The specific contents are as follows:（1）Pathological condition is highly implicated in diseases from the initiation to progression.Therefore,regulating the pathological environment is emerging as a powerful means for improving therapeutic effects.In cancer therapy,hypoxia tumor microenvironment plays a critical role in preventing effective cancer treatments,such as radiotherapy and chemotherapy.Given the H₂O₂-rich cancer microenvironment,a biocompatible Mn Fe₂O₄catalyst is developed to remodel the tumor hypoxia microenvironment by converting H₂O₂into O₂via the Fenton catalysis mechanism.The catalytic performance of Mn Fe₂O₄has been investigated in a hypoxic cellular model.Systematic studies reveal that Mn Fe₂O₄can efficiently catalyze H₂O₂into O₂,thus alleviating hypoxia in tumor cells.This work provides a new strategy for radiosensitization therapy.（2）Although free radical-based nanomedicine has made great advances,some important issues should be addressed,such as poor biocompatibility,unwanted nonspecific organ distribution,long-time retention in vivo,which potentially lead to acute and long-term chronic toxicity.Herein,inspired by the protective effect of melanin in human body,ultrasmall melanin nanoparticles are synthesized for the regulation of a series of free radicals.Notably,melanin contains multiple functional groups,such as catechins,quinones and amino groups,as well as the stable unpaired electrons at the center of the stacked units,contributing to its efficient scavenging performance against multiple oxygen-containing and nitrogen-containing free radicals.After cellular uptake,the ultrasmall melanin can effectively scavenge excessive free radicals in damaged renal tubule cells.Meanwhile,free radical scavenging by melanin can suppress the activation of inflammatory cells for reduced inflammatory response towards tissues.More impressively,the ultrasmall particle size enables the clearance of melanin through the renal elimination pathway,minimizing the interference on free radical metabolism in normal tissues associated with long-term retention of catalysts.（3）Up to now,most of free radical catalysts are explored derived from energy catalytic systems and naturally occurring materials,including enzymes and biopolymers,and are generally synthesized via a trial-and-error strategy.However,research on the detailed catalytic mechanisms is still lacking.Since a rational design of free radical catalysts could lead to on-demand catalytical activities and better understanding of biocatalysis processes,it is necessary to design free radical catalysts from the electronic point of view,along with detailed catalytic kinetics and mechanism.Herein,based on that oxygen vacancies can offer efficient electronic orbitals to bind with O-containing small molecules and exhibit tailored catalytic kinetics,oxygen vacancy-rich Bi O_2-XNSs are constructed by defect engineering.Bi O_2-XNSs allow environment-adaptive free radical catalysis.Different from traditional chemodynamic therapeutic agents,Bi O_2-XNSs catalyze production of highly toxic O₂^·-and^·OH in cancer cells via logic enzymatic reactions to induce cell apoptosis,without disturbing the redox balance in normal cells.On the basis of their multienzyme properties and on-demand catalytic kinetics,the design of Bi O_2-XNSs shew a great potential in cancer therapy,and might provide theoretical guidance for the development of novel free radical catalysts.（4）To date,ever-growing free radical-regulating efforts have been devoted to developing physical/chemical dynamic strategies capable of amplifying the generation of toxic free radicals to aggravate oxidative damage to cancer cells,but largely ignoring the fact that highly toxic free radicals in the tumor microenvironment may induce side effects in immune cells,triggering the formation of immunosuppressive tumor microenvironment and subsequently impeding host immune responses and further therapeutic treatments.In this chapter,based on the aforementioned environment-adaptive Bi O_2-XNSs free radical catalyst,we presente an oxygen vacancy-driven reversible free radical catalysis strategy for enhanced chemodynamic therapy.Bi O_2-XNSs present remarkable“dual modality”in regulating free radicals adaptable to microenvironment changes.Namely,Bi O_2-XNSs function as free radical boosters,resulting in additional oxidative assault and apoptosis of cancer cells,yet scavenge the accumulated free radicals and immunosuppressive mediators in TME-associated noncancerous cells.In a tumor xenograft model,Bi O_2-xNSs efficiently accumulate in tumor,elicit tumor cell apoptosis,and improve T-cell infiltration,contributing to effective antitumor effects.This work may offer the way to actuate a minimized tradeoff between therapeutic benefits and risks towards free radical regulation to improve cancer dynamic treatment.