The incidence and mortality of malignant tumors remain high. According to statistics,2018The number of new malignant tumors in the world was as high as1 810Million cases, and the number of cancer deaths reached960Ten thousand cases[1], which has caused a huge burden on patients' families and national medical expenditure. Modern medical research has found that tumors are closely related to the immune function of the body, and immune escape is an important mechanism of tumorigenesis[2]Under normal circumstances, the body can recognize, monitor and remove malignant cells that have lost normal regulatory ability, but some cells can escape the clearance of the immune system, and shape with the immune system to enter a "balance period" without clinical symptoms. Once this balance state is broken, tumor cells will have immune escape and further develop metastasis[3]Therefore, reactivating the body's own immune system to fight against tumors is a key measure for the current treatment of malignant tumors.
Ginseng is a plant of Panax ginseng in AraliaceaePanax ginseng C. A. MeyerThe dry root of "it is mainly used to nourish the five internal organs, calm the spirit and calm the soul, eliminate evil spirits, brighten your eyes, be happy, benefit your intelligence, take long clothes, lighten your body and prolong your life "[4]In recent years, it has been found that ginsenosides in its chemical constituentsRg3（ginsenoside Rg3，G-Rg3）With significant antitumor effect[5]。G-Rg3It is a tetracyclic triterpene saponin with the chemical formula ofC42H72O13，The relative molecular mass is784.30, yes20 (s) - Ginsenoside Rg3and20 (R) - Ginsenoside Rg3. according toC20Differences in spatial location can be divided into20(R)、20(S) 2. In addition to inhibiting tumor cell proliferation, promoting apoptosis, reducing tumor angiogenesis, and controlling tumor cell proliferationCell invasion, metastasis and other pathways play an anti-tumor role[5]，G-Rg3It can also activate the body's anti-tumor immune response and control tumor development[6]。This article fromG-Rg3Discussion on up regulating the antigenicity and immunogenicity of tumor cells, enhancing the function of immune effector cells and immune active molecules, and regulating the local immune microenvironmentG-Rg3The research progress of immunomodulatory effect on tumor and its nano drug delivery systemG-Rg3.
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1 Regulating tumor cell autoantigenicity and immunogenicity
TCell activation is the key link of the body's immune system to exert anti-tumor effects, which usually requires the stimulation of dual signal pathways and antigen presentationAntigenic peptides on cells-Major histocompatibility complex（MHC）Molecular complexes withTCellular receptors（TCR）1Signaling pathways; Costimulatory molecules on antigen presenting cellsB7（CD80、CD86）WithTCell expressedCD28Combination is the first2Signaling pathways[7]。Tumor cells can usually be activated by downregulation ofMHC IClass molecules, which weaken their antigenicity to evade immune recognition or overexpress inhibitory costimulatory factor receptor programmed death receptor1（PD-L1）, cytotoxicityTLymphocyte associated protein4（CTLA-4）, human apoptosis related factor ligand（FasL）Equal toTCell, natural killer（NK）Cells combine to reduce immunogenicity and inhibit the anti-tumor immune response of the body. ,GinsenosidesRg3Can be achieved by inhibiting nuclear transcription factors-κBp65（NF-κBp65）And protein kinasesB（Akt）, decreasedPD-L1Expression, recoveryTCytotoxicity of cells to tumors[8], prolonging the survival time of patients[9],GinsenosidesRg3It can induce the expression of calreticulin and heat shock protein on the surface of tumor cells and the transcription of related genes to enhance the immunogenicity of tumor cells and promote dendritic cells（DC）Maturation and uptake and presentation of tumor antigens[10]。
2 Regulation of immune effector cell function
Immune effector cells are the main members of the immune system, which play a role in clearing foreign body antigens and performing effector functions in the anti-tumor immune response of the body. Improving the activity of immune effector cells is the key to activating human anti-tumor immunity.
2.1 Innate immune related cells
Innate immunity is the first line of defense of the body's immune system, which can recognize pathogens and activate adaptive immune responses. Among them, phagocytes can distinguish between "self" and "non self" components and kill tumor cells through phagocytosis.Shinetc.[11]Found in murine macrophagesRAW264.7Medium, regulated by extracellular signal kinases（ERK）/c-JunPathway regulation,GinsenosidesRg3Can promoteRAW264.7Cell activation.DCIt is the most powerful antigen-presenting cell in vivo found so far. DCHigh expression of costimulatory and adhesion factors can activate the initialTcell[12]。GinsenosidesRg3ProcessedDCCells versus those withoutGinsenosidesRg3Compared with the control group, the formerCD83、CD80、CD86The expression increased significantly, while the cytotoxic lymphocyte stimulating factor interleukin12（IL-12）The increased secretion ofTCell proliferation and activation enhance the anti-tumor immune ability of the body[13]. in addition, Wang Ying et al[14]Research findingsG-Rg3It can be enhanced enoughNKCell activity, improvingNKThe binding rate of cells and cancer cells, play a more powerful anti-tumor efficacy.
2.2 Adaptive immune related cells
Lymphocytes are key components in the adaptive immune response[15], which can directly destroy target cells or release lymphokines in combination with target cells, expand and enhance immune effects and participate in the immune response of the body. Research findings[16], tumor patients are often in a state of immune imbalance, and the bodyCD4+TCell reduction,CD4+T/CD8+TDecline, cellular immune function disorder.GinsenosidesRg3Can stimulate lymphocyte expressionCD4, improveCD4+TLymphocyte activity, promotingγ-（IFN-γ）, tumor necrosis factor-β（TNF-β）、IL-2Secretion of other antitumor cytokines, upregulationCD4+T/CD8+TRatio, enhance immune function[17]. can further promoteCD4+TCells differentiate intoTh1Cells, regulatoryTh1/Th2, inducing it to drift towards immune enhancement[18]. this regulatory effect can be achieved not only by inhibitingDCproduceIL-12To achieve, but also directly affectTIn cellsTh1Cell differentiation program to mediate[19]. in addition,G-Rg3Can regulate the bodyBNumber and activity of lymphocytes, upregulation of immunoglobulinsG（IgG）、IgMThe expression of antibodies enhances the humoral immune response against tumors[20]. Combined Acupuncture[21]Or chemotherapy[22]Can enhanceRg3Improve the immune function.
3 Regulatory immunoactive molecules
Immunoactive molecules are small molecular proteins secreted by immune cells or non immune cells, which can be divided intoIL、IFN, growth factors, etc., are important components of the human immune system.TNFIt is a cytokine with clear antitumor activity in vivo.Kimetc.[23]Confirmed by experimentsGinsenosidesRg3Can increase tumor necrosis factor in the peripheral blood of melanoma bearing miceTNF-α、IL-2Levels, increased the weight of immune organs in mice, and was associated withRh2The effect of combined use is better.IFNIt can induce tumor cells to express specific antigens, which is convenient for immune recognition and clearance; Enhancing tumor specificityCD8+TThe role of cells to promote memoryTThe production of cells induces the secretion of specific antibodies.G-Rg3Can increaseIFN-γTo enhance cellular immunity in mice, and20 (R) - Ginsenoside Rg3Better than20(S)-GinsenosidesRg3[24]. by upregulatingTANKBinding kinase1（TBK1）/NF-κBInhibitory kinase（IKK）epsilonPathways andDDX3Expression,GinsenosidesRg3Can improveIFN-βExpression, enhancing innate immunity[25]. transforming growth factor-β1（TGF-β1）-Mesenchymal transformation（EMT）Promote the migration, invasion and anti anoikis of cancer cells.20(R)-GinsenosidesRg3Able to inhibitA549In lung cancer cellsTGF-β1Secretion to achieve the purpose of anti-tumor[26]。
4 Local regulation of tumor immune microenvironment
At present, more and more researchers recognize that tumor as a whole is not only the product of gene mutation of tumor cells, but also the adaptation of mutant cells to the microenvironment. [27]。
4.1 PH
Energy production through high-speed aerobic glycolysis is a metabolic hallmark of cancer cells, known asWarburgEffect. The massive accumulation of metabolite lactate eventually forms an acidic tumor immune microenvironment, leading to vascular endothelial growth factor（VEGF）Upregulation of gene expression, acceleration of extracellular matrix degradation, suppression of immune cell function, induction ofEMT, plusRapid tumor progression.20(S)-GinsenosidesRg3Ability to influenceLncRNARegulatory networks and in cellsSTAT3/HK2Signaling pathways[28], inhibiting theWarburgeffect[29], controlling tumor development.Lietc.[30]findG-Rg3Can downregulate epidermal growth factor（EGF）-Epidermal growth factor receptor（EGFR）-ERK1/2-Hypoxia inducible factor1α（HIF-1α）signaling pathway， reduceIThe expression of β - type sodium hydrogen exchanger protein makes hydrogen ions unable to be pumped externally, thereby reducing the intracellularpHValue, changing the acidic microenvironment of tumor, inhibiting the invasion and metastasis of hepatocellular carcinoma.
4.2 oxygen content
The hypoxic microenvironment of tumor is caused by the rapid growth of tumor and abnormal internal vascular structure. Studies have found that the degree of hypoxia in tumors is positively correlated with the progression of tumors, and inhibition ofHIF-1Is an effective strategy to treat tumors[31-32]In ovarian cancer, glioma and other tumor groupsWeaving,20(S)-Rg3Can be activated by ubiquitin-Proteasome pathway promotionHIF-1αDegradation, inhibiting the development and metastasis of malignant tumors[33-35]。G-Rg3It can significantly enhance the inhibitory effect of chemotherapy on esophageal squamous cell carcinoma in mice, probably through down-regulationHIF-1αandVEGFHorizontal realization[36-37]。Gemcitabine（GEM）It is a commonly used drug for the treatment of non-small cell lung cancer, butGEM（ROS）Production, up regulationAkt、ERK, promotingNF-κBandHIF-1αOf nuclear accumulation, leading to drug resistance of tumors, whileG-Rg3Can reverse this process[38]。
5 Nano drug delivery system
G-Rg3. The emergence and development of nanotechnology has become the key to solve this problem. Using nanoscale polymer materials as carriers and insolubleG-Rg3The nano drug delivery system formed by the combination can effectively improve its water solubility. （EPR）[39], enabling the nanodrug loaded system to passively target tumor tissuesOn this basis, targeting ligand pairs that can specifically recognize tumor tissue were introduced to loadG-Rg3The modification of drug delivery system can further endow it with active targeting. Among them, the liposome drug delivery system that has been studied more is encapsulated by lipid materials such as phosphatidylcholine and cholesterol with good biocompatibilityG-Rg3It has the effect of inhibiting the progression of liver cancer, gastric cancer and other solid tumors, and is not easy to cause the body's immune response. Nanomicelles rely on the self-assembly of hydrophilic and hydrophobic copolymers to form "cores"-Envelope load of "shell" structureG-Rg3, greatly improvedG-Rg3. In recent years, combined with physicochemical oriented targeting technology, a variety of nanoparticles prepared by using the magnetic, thermal, pH sensitive and other characteristics of the carrier can change when the external environment changes, slowly release drugs, and improve theG-Rg3The solubility further enhances the killing effect on tumor cells, improves the targeting accuracy, and reduces the impact on normal tissues and organs. G-Rg3Of nanodrug delivery systems usually haveSmaller diameter, higher surface reaction activity, stronger adsorption capacity, higher catalytic efficiency, and more active centers can greatly increase drug stability bioavailability、 [40], inG-Rg3The application of is of great significance. 10Annual relevant loadG-Rg3The research progress of nano drug delivery system is shown in table1。
6 Problems and Prospects
G-Rg3It can regulate the immunity of the body from many aspects and exert the anti-tumor effect. The emergence of nano drug loading system solved theG-Rg3Poor water solubility and low bioavailability. However, at present, forG-Rg3However, there are still many gaps in the study of（1）Most of theG-Rg3The research of nano drug delivery system mostly focuses on the direct killing effect of tumor cells, and lacks the explanation of tumor immune regulation and mechanism. The（2）An evaluation system for the quality standards of nanomedicines has not yet been formed,G-Rg3The study of nano drug delivery system is still in the experimental stage, and the interaction with cells and biomacromolecules in human body has not yet been revealed. The long-term adverse reactions of nanomedicines and their degradation products in human body are unknown, and the safety of clinical application needs further evaluation. The（3）Most nanocarriers have poor specific drug release performance, and the drug is suddenly released, resulting in high local concentration and greater toxicity[55]How to improve the slow and controlled release performance of drugs, avoid frequent dosing, and maintain appropriateG-Rg3Blood concentration, increasing the stability of treatment is. The（4）The problems of low drug loading, few types of pharmaceutical carriers, and high production costs also limitG-Rg3The industrial production of nano drug delivery system has hindered the clinical use and promotion. The（5）At the same time, the damage of nanocarriers to the natural environment and ecosystem is also a problem that needs to be considered in the development of nanomedicines.
References (omitted)
Come Source:Wang Man, Huang Nian, lingchangquan Research Progress on the immunomodulatory effect of Ginsenoside Rg3 on tumor and its nano drug delivery system [j]. Chinese herbal medicine, 2019, 50 (15): 3729-3734