| Background:Gastric Cancer is one of the most common malignant tumors and the second malignant tumors of the digestive tract in China.The most common age is over 50years old[1].As a malignant disease that seriously threatens public health,the 5-year survival rate of gastric cancer patients is only 10%[2].Although early gastric cancer is expected to be completely cured by surgical treatment,most patients have often progressed to middle and advanced stages due to the hidden onset of the disease,and the probability of being cured by radical surgery without chemotherapy is not high.However,traditional chemotherapy is still the main method for postoperative treatment of gastric cancer.5-fluorouracil（5-Fu）and its derivatives are the basis of standard chemotherapy regimen for gastric cancer[3].Since most chemotherapy drugs are metabolized in the liver,hepatotoxicity and myelosuppression are the main limitations of chemotherapy.Nausea and vomiting caused by chemotherapy are also common adverse reactions during medical treatment.In recent years,the continuous emergence of new chemotherapy regimens does not seem to significantly improve the side effects caused by chemotherapy,one of the important reasons is the existence of multidrug resistance and the lack of efficacy caused by the traditional route of administration.Therefore,it is urgent to develop new routes of administration and agent types to improve the toxic and side effects of traditional chemotherapy drugs.With the vigorous development of nanomedicine,nanoparticles can be used as a new tool to replace traditional cancer treatment and diagnosis,and are known as the most promising drug delivery route.Nanoparticles are considered to be ideal carriers for targeting tumor tissues due to their good biodistribution,bioavailability,and the ability to reduce the inherent toxicity of drugs.As a biocompatible copolymer,poly（lactic-co-glycolic acid）（PLGA）is a nanodrug with adjustable degradation time and can be hydrolyzed in vivo.It produces lactic acid and glycolic acid as biodegradable monomers,which can be effectively treated in vivo and exhibit minimal systemic toxicity.In addition,PLGA is also favored for its unique physical and chemical properties such as moderate tensile strength,solubility in most organic solvents,and controlled hydrophility in medical applications.Curcumin（Cur）is a natural polyphenolic pigment extracted from the root of Curcuma longa.As a recognized safe compound approved by the US Food and Drug Administration（FDA）,it has great potential value in food and health products due to its high safety and biological activity.In recent years,curcumin has attracted more and more attention from the medical community due to its anti-cancer properties.Several studies have shown that curcumin inhibits the initiation and progression of various malignancies including colon and prostate cancers[4].However,the disadvantages of curcumin,such as poor water solubility,fast liver metabolism,limited systemic circulation,and low bioavailability,have become great obstacles to its development[5].If PLGA-loaded curcumin is used to treat gastric malignant tumors,on the one hand,it can not only improve the anti-tumor effect of curcumin,but also prolong the drug action time.On the other hand,it can overcome the toxic side effects of traditional nanoparticles and further reduce the damage of drug delivery system to the body.However,the morphology of synthetic nanocarrier is similar to that of pathogen,and it has the problem of being cleared by immune system,and often cannot be retained in the body’s circulation system for a long time.A versatile nanomaterial based on the biomimetic properties of cell membranes and their functionality has emerged as an attractive therapeutic delivery system.Mesenchymal stem cells（MSCs）are stem cells derived from umbilical cord,which have the advantages of wide sources,easy sampling and autologous transplantation[6].Since stem cells always maintain the potential of self-replication and multi-directional differentiation during long-term in vitro culture,their immunogenicity is weak,and they can produce positive effects whether they are transplanted locally or by intravenous route.The use of umbilical cord-derived stromal/Stem cells is a promising strategy to promote angiogenesis in regenerative medicine.In the absence of inducing factors,stem cell membranes（SCM）are targeted to tumor cells by chemotaxis and cell-cell surface contact.We can take advantage of the low immunogenicity and tumor targeting properties of stem cell membrane to prolong the half-life of drugs,improve the maintenance time in the circulation system,and improve the specific targeting of drugs to improve the efficacy of drugs.Objective:To construct a stem-cell membrane-disguised polylactic acid-co-glycolic acid（PLGA）-loaded curcumin nano-drug delivery system,and to study the sustained release ability of the drug delivery system and the growth inhibition effect on gastric cancer cells,so as to provide a theoretical basis for improving the anti-tumor effect of curcumin and possibly improving the adverse reactions of traditional drugs.Methods:In this study,we designed PLGA nanoparticles as nanocapsules to load the hydrophobic anticancer drug curcumin,wrapped the mesenchymal stem cell membrane on its surface by ultrasonic extrusion method,and detected the particle size of the synthesized PLGA-Cur@SCM NPs.The PLGA-Cur@SCM NPs were characterized and verified by transmission electron microscopy,infrared spectroscopy,and UV-visible absorption spectroscopy.The mode of drug release was detected in vitro experiments,and the anti-tumor ability of PBS group,free Cur group,PLGA-Cur NPs group,and PLGA-Cur@SCM NPs group on gastric cancer cells was detected.The effects of each group on the invasion and migration of gastric cancer cells were detected by cell scratch and trans well assay,and the killing effect of the drug-loaded system on tumor cells was detected by plate cloning assay and Calcein-AM/PI live/dead cell double staining assay.In addition,the total amount of RNA extracted by PCR and the expression of related proteins detected by western blot were used to explore the effect of PLGA-Cur@SCM NPs on apoptosis signal and EMT related pathways in gastric cancer cells.Results:The 249±29nm PLGA-Cur@SCM NPs nanoparticles were formed by covering the mesenchymal stem cell membrane with curcumin.The results of UV-vis absorption spectrum and infrared spectrum confirmed that curcumin was effectively loaded on PLGA.In addition,wound healing assay,Transwell assay,plate clone formation assay,Calcein-AM/PI live/dead cell double staining assay and CCK8 assay all showed that curcumin-loaded gastric cancer cells had good therapeutic effects,while the stem cells coated with curcumin-loaded membrane showed better tumor cell killing ability.The results of cell scratch and Transwell experiments confirmed that PLGA-Cur@SCM NPs had better tumor cell migration and invasion inhibition ability than each group.Plate cloning assay,Calcein-AM/PI live/dead cell double staining assay,colony formation assay and CCK8 assay also confirmed that the drug-loaded system had a significant inhibitory effect on the growth of tumor cells.The results of PCR and Western Blot confirmed that PLGA-Cur@SCM NPs could effectively inhibit the expression of BCL-2 and promote the expression of E-cadherin,thereby inhibiting the apoptosis and EMT of gastric cancer cells.Conclusion:1.The PLGA-Cur@SCM NPs nanodrug delivery platform loaded with Curcumin was successfully constructed;2.The drug release of the novel drug delivery system occurs in a biphasic manner,with a burst release phase followed by a sustained release phase;3.The novel drug delivery system can significantly increase biocompatibility of curcumin;4.The novel drug delivery system can significantly improve the water solubility of curcumin and enhance the anti-tumor effect of curcumin. |
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