Research On Functional Nano-modulators Disrupting The Homeostasis Of Gas Signaling Molecules In Cancer Cell

Since cancer was discovered,it has seriously threatened people’s life and health due to its extremely high mortality and low cure rate.With the development of medicine and technology,the treatment methods for cancer are also constantly developing.In addition to traditional treatment methods:surgery,radiotherapy,and chemotherapy,new methods such as photodynamic therapy,photothermal therapy,targeted therapy,immunotherapy,and gene therapy have also emerged in recent years.These methods have their own advantages and disadvantages.For example,small molecule chemotherapy drugs have severe systemic toxicity and are difficult to diffuse into the tumor stroma because of the poor diffusivity,and;the hypoxic environment in the tumor region also makes it resistant to various treatment methods,etc.Many studies have shown that gas therapy,as a"green"cancer treatment method,has the characteristics of on-demand release,precise treatment,low side effects and can synergistically enhance the effect of other therapies to inhibit tumor growth.The important endogenous gases nitric oxide（NO）,hydrogen sulfide（H₂S）and carbon monoxide（CO）in the organism have dual effects on cancer,that is,promoting tumor growth at low concentrations and anti-tumor effects at high concentrations.Gas therapy increases the intracellular gas concentration through exogenous introduction,which can not only reverse its cancer-promoting effect,but also enhance other therapeutic methods for synergistic treatment through the sensitization of cancer cells to X-ray or reactive oxygen species,etc.Therefore,combining existing cancer treatments with gas therapy can greatly improve treatment efficiency.Researchers achieved precise and controlled release therapeutic gases by stimulating their donors at the tumor site by exogenous X-rays,ultrasound,and light,as well as hydrogen peroxide,glutathione,and acidic tumor microenvironment.The introduction of exogenous gas for treatment has achieved certain results,but the complex intracellular regulation tends to stabilize the exogenous gas at a concentration suitable for tumor growth,which cannot achieve in reaching high-concentration threshold for homeostasis disruption and further apoptosis.Therefore,there is an urgent need to develop new materials that can realize the destruction of intracellular homeostasis while increasing the gas concentration,and synergistically achieve efficient cancer gas therapy.Based on this,the research progress that has been made in this paper is as follows:（1）As a multifunctional gas molecule with free radical properties,NO can promote tumor progression by inducing tumor cell invasion and the expression of angiogenic factors.High concentrations of NO gas are highly cytotoxic and can directly damage organelles through nitrosation of mitochondria and DNA.However,due to the complex feedback regulation mechanism in cells,it is difficult to keep NO at a lethal concentration for hemostasis disruption through exogenous introduction without endogenous intervention.In view of this,the nano-regulator CLSGM was developed,which can achieve in the intracellular reciprocal disruption of calcium ion and NO dual homeostasis for therapeutic purposes.In this nano-regulator,L-arginine（L-Arg）-doped calcium carbonate（Ca CO₃）nanoparticles were synthesized for the first time and coated with silica shell to form a core-shell structure.After modification of glucose oxidase（GOx）,the surface was coated with cancer cell membrane fragments for the purpose of homologous targeting and immune escape.When the nano-regulators enter cancer cells and localize in acidic lysosomes,the Ca CO₃/L-Arg core will dissociate to release Ca²⁺and L-Arg.The modified GOx can catalyze the conversion of glucose into gluconic acid and H₂O₂and the former will accelerate the decomposition process and the latter can react with L-Arg to generate NO.At the same time,the released Ca²⁺activates nitric oxide synthase（NOS）to generate endogenous NO,and the generated H₂O₂ and NO can further damage the calcium buffering function of organelles and desensitize Ca²⁺-related channels through oxidative stress to inhibit Ca²⁺efflux.In addition,the depletion of glucose and the inhibitory effect of NO on cellular respiration severely inhibited the intracellular energy supply and weakened the ability of intracellular regulation.Therefore,CLSGM is able to achieve reciprocally-enhancing disruption of Ca²⁺and NO homeostasis,inducing irreversible apoptosis.（2）Hydrogen sulfide（H₂S）is not only highly toxic because of its strong inhibitory effect on key enzymes in the human body,but also an important central nervous system regulator,which can be used in muscle relaxation,neuro-protection and inflammation treatment.As for cancer cells,H₂S has both pharmacological and pathology effects.At high concentrations,H₂S can inhibit cancer cell proliferation by inducing uncontrolled intracellular acidification and cell cycle arrest to induce apoptosis.Now high-concentration H₂S has been used in cancer treatment research,but the exogenous introduction of H₂S at this stage mainly relies on organic donors and metal sulfides,etc.These H₂S donors have low biocompatibility and H₂S gas treatment is mostly as adjuvant therapy.In this work,dendritic mesoporous organosilicon（DMOS）was combined with GOx.In the tumor microenvironment（TME）,DMOS nanoparticles with disulfide bonds were not only efficient nanocarriers,but also react with reduced glutathione（GSH）for both GSH comsuption and H₂S generation.As a high-content reducing substance in cancer cells,GSH plays an important role in resisting oxidative stress and protecting cancer cells.The reduction of GSH can enhance the killing effect of hydrogen peroxide（H₂O₂）produced by the reaction of GOx with intracellular glucose on tumor cells,which will enhance the inhibitory effect of high concentrations of H₂S on tumors for cancer treatment.