Fabrication Of Cancer Cell Membrane Coated Nanoparticles And Their Tumor Targeting

Background:In recent years,with the rapid development of biological membrane materials,not only erythrocyte membrane,white blood cell membrane but also platelet membrane have been studied and applied in the field of drug delivery.After a complex membrane extraction step,the protein on the cell membrane remains intact.After repeated studies,it was confirmed that those membrane vehicles had the biological characteristics as their source cells.For example,the red cell membrane coated nanoparticles have accomplished the long circulation in vivo just as erythrocyte;and the white cell membrane nanoparticles still have the characteristics of driving to inflammation.Compared with the conventional liposome,those bio-membrane package has given the nano-drug delivery field with special biological activity.However,although the cell membrane carrier has achieved the corresponding biological function,but it has not shown more in the field of tumor targeted drug delivery.At the same time,the tumor cells are considered to have the characteristics of homologous adhesion due to the various adhesion molecules expressed on the membrane.It is homologous adhesion that can help tumor cells accumulate into cell aggregates,promote metastasis and resist anoikis.Most of the studies have confirmed such adhesion propertyof tumor cells in vitro.Besides,it is also found that the cancer cell membrane adhesion proteins especially E-cadherin,mediate the adhesion between adjacent cancer cells.Therefore,some researches have stripped cancer cell membrane with adhesion proteins reserved and applied as nano-drug vehicles.To their gratification,such new nano-drug delivery system has achieved selective self-target and obtained effective therapy results in vivoHowever,the adhesion proteins on tumor cell membrane are often expressed on many kinds of cancer cells,such as CEA,NCAM,E-cadherin and so on.The adhesion between different cancerous cells may takes plays.The cancer cell membrane vehicles may loss its selective homotypic targeting capacity.Moreover,it has been found that no obvious homotypic targeting property is shown on exsomes derived from homologous cancer cells.Hence,it is necessary to make studies on the targeting property of cancer cell membrane vehicles.Objective:In order to study exact homotypic targeting capacity of cancer cell membrane vehicles,and investigate the possible mechanism.Methods:In this study,we firstly designed a novel drug delivery system synthesized with a cancer cell membrane carrier and a coumarin-6 fluorescent probe loaded PLGA nanosphere core(CCNPs).Here,the membrane of MKN45 cells,AGS cells and Hela cells were used to form its corresponding CCNPs.Secondly,though strict quality control,such CCNPs were co-cultured respectively with homologous and non homologous tumor cells(including MKN45 cells,AGS cells and Hela cells),immortalized cell(including Hbe cells,Helf cells).The results were obtained by flow cytometry,confocal microscopy and fluorescence microplate in vitro.Furthermore,the self-adhesion capacity of different cancer cells was verified by 3D cell culture in vitro.Finally,Western blot analysis and immunohistochemical analysis of several adhesion proteins were used to analyze the effect of targeting.Results:Our results revealed that MKN45 cell membrane coated nanoparticles(MKN45-NPs)were more adhesive to almost all cells than AGS-or Hela-NPs,suggesting that adhesive abilities of each cancer membrane were different and heterogenous CCNPs rather than homologous CCNPs might preferentially target to some cancer cell.Moreover,a non-specific adhesion ability of those CCNPs had been found when membrane cloaking did not enable MKN45-NPs and other CCNPs to selectively target to their source cells.Then further investigations implied that adhesion abilities of CCNPs were inherited from their mother cells,and significantly affected by E-cadherin expression.And CCNPs’ uptake was also related to the surface CAMs of the recipient cells.Conclusion:Not all the cancer cell membrane coat holds homotypic targeting propety E-cadherin highly expressed cancer cell membrane carrier shows a stronger targeting,which can help target to the low-adhesive tumor cells.And,E-cadherin-present CCNP can preferentially targets to E-cadherin high-expressed tumor cells.Hence,it’s also an opportunity that membranes of some specific tumor cells can be used to deliver cargos to many other tumor cells.