Application Of Biodegradable Mesoporous Organicsilica Nanoparticle Carrier Modified With Biomacromolecules In The Treatment Of Liver Cancer

Liver cancer is one of the main killers that cause human death.The treatment methods include radiotherapy,chemotherapy and surgical resection.However,they has brought serious toxic and side effects.Meanwhile,cancer cells not only grow rapidly,but also have strong drug resistance,high metastasis rate,these factors make it extremely difficult to treat.Therefore,accurate treatment of liver cancer and reduction of damage to normal tissues have become a major challenge in the treatment.Recently,the biomedical application of nanomaterials has attracted greatly attention especially in the field of drug delivery and biological imaging.Nanocarriers are mostly inorganic materials,which can make the drugs specific to the organ or tissue and reduce the damage of drugs to normal tissues after loading the drugs.There are three core technologies of nanocarrier:1.Functionalization of nanocarrier;2.Targeted organ delivery after drug loading with nanocarriers;3.In vivo imaging.It can be said that nanocarriers have completely changed the way of drug delivery and brought new possibilities for clinical diagnosis and treatment.Recently,mesoporous silica nanoparticles(MSNs)have become a promising drug carrier due to their good biocompatibility,large specific surface area,adjustable mesoporous characteristics,low toxicity and other advantages.Many studies have proved that MSNs,as an excellent drug carrier,plays an irreplaceable role in cancer treatment.However,MSNs is almost unable to be biodegradable due to its pure inorganic framework structure,and its application is greatly limited in matrix degradation to control drug release system.For this reason,the researchers proposed that organic bridged mesoporous silica nanoparticles,in other words,functional organic silica molecules embedded in the silica framework at the molecular level,so that solved the above difficulties effectively.Researchers used organic silica molecules containing the disulfide bond to synthesized organic mesoporous silica nanoparticles(ss-MONs),disulfide bond rupture in the reducing agent,which could make the nanoparticle break up into small pieces and excrete easily,at the same time,drugs loaded into the pores are released more easily.It is well known that glutathione is higher in cancer cells than in normal cells,S-S breaks down under the glutathione,leading to the biodegradation of nanoparticles,so researchers are more willing to load drugs with this particle.Although some reports have discussed the application of ss-MONs after loading anti-cancer drugs in cancer treatment,there is no detailed report on the advantages of ss-MONs compared with MSNs in terms of biological toxicity,drug release,endocytosis and treatment effect,so this work made a detailed comparison between ss-MONs and MSNs.Our study shows that ss-MONs and MSNs have similar morphology and size,good biocompatibility,endocytosis and high drug loading capacity.More significantly,ss-MONs showed a better anti-tumor effect as they loaded adriamycin.As a result,we believe that ss-MONs could be a safer and more effective drug carrier for cancer treatment.Recently,the nanoparticles coating cell membranes have attracted much attention due to their homologous targeting and immune escape ability.The concentration of nanoparticles coating cell membrane was significantly increased at the tumor site because of avoiding clearance rapidly by the blood.In order to improve the treatment effect of ss-MONs loaded with drugs,we modified the cell membrane on the surface of nanoparticles.In this study,mesoporous organic silica nanoparticles coated HepG2 cell membrane(cm-ss-MONs)were used to load the anticancer drug berberine(cm-ss-MONs-ber)for the treatment of liver cancer.Cm-ss-MONs showed uniform morphology,good dispersion,high drug loading capacity and excellent biodegrade ability.More importantly,most Ber enter cancer cells rather than normal cells because of the homologous targeting and the selective release of drugs in the tumor microenvironment.In addition,in vitro and in vivo experiments have shown that cm-ss-MONs-ber has a highly effective chemotherapy effect and high safety.Meanwhile,we also meet a common problem of nanoparticles as carriers.They are rejected by the immune system easily,and drugs are quickly cleared by the body before they are completely released,for which we proposed a new strategy.As we all know,CD47 protein is an immunoglobulin on the cell membrane,which is a natural macromolecule.The content of this protein on the membrane of cancer cells is much higher than that of normal cells,and it binds to SIRP on the surface of immune cells,so cancer cells can escape from being engulfed.We propose to modify the particle surface with this natural polymer to achieve immune escape.In this study,ss-MONs were used to load the anti-cancer drug berberine(Ber),and then the cell membrane of HepG2 was obtained and coated on the surface of drug-loaded nanoparticles,and mesoporous silica nanoparticles(CM-ss-MONs-ber)coated the cell membrane were successfully prepared.On the one hand,it avoids the quick removal by the body because the immune escape of CD47 protein;on the other hand,the nanoparticles coated with cancer cell membrane can be used to treat homologous liver cancer tumors.Adhesion molecules on the cell membrane,such as galactoagglutinin,can target and recognize homologous tumor cells,so that nanoparticles can enter the cancer cells efficiently and achieve homologous targeting.We found that CM-ss-MONs exhibited uniform morphology,good dispersion,high drug loading capacity and biodegradability.More importantly,most Ber enter cancer cells rather than normal cells due to the homologous targeting and the selective release of drugs in the tumor microenvironment.In addition,in vitro and in vivo experiments have shown that CM-ss-MONs-ber has an effective therapeutic effect and safety.In conclusion,the natural macromolecular CD47 protein and the adhesive molecules on the cell membrane endow the nanoparticles with new properties and provide new ideas for clinical application.The main results of our work as following:1.We synthesized mesoporous inorganic silica nanoparticles(MSNs)and contains S-S mesoporous organic silica nanoparticles(ss-MONs)respectively,DOX was encapsulated in these two nanoparticles,and then compares the two kinds of nanoparticles in the morphology,size,drug delivery and release,cell toxicity and effects of cancer treatment in detail.Our study shows that ss-MONs in addition to having MSNs characteristics,has a higher drug release rate and therefore plays a more effective role in cancer treatment;2.We synthesized ss-MONs and load the anticancer drug berberine,then coated it with the cell membrane of liver cancer,finally studied its advantages in the treatment of liver cancer.The results showed that the nanoparticles coated cell membrane had better homologous targeting and immune escape,which increased the circulation time in the blood and enhanced the biocompatibility,so improving the therapeutic effect of liver cancer greatly.