Anti-CD19 MAb Modified Mesoporous Titanium Dioxide As Targeting Vector For B-lymphoblastic Leukemia Therapy

Research Background:B-acute lymphocytic leukemia(B-ALL)is a clonal hematopoietic stem cell tumor derived from B-cell progenitor cells.It mainly occurs in children and adolescents,and is one of the main causes of cancer death in this population.Although the new CAR-T(Chimeric Antigen Receptor T Cell)therapy has a better therapeutic effect on B-ALL,there are toxic side effects such as cytokine release syndrome that restrict its application.Therefore,further exploration of effective treatment methods for the treatment of B-ALL,including the discovery of more effective molecular targets and carriers,has become an important scientific issue in current B-ALL research.Research objective:CD19 is specifically expressed on the membrane of most malignant B cells,which is widely used as a marker of B-ALL antigen-specific immunotherapy.This study explored the synthesis method of mesoporous titanium dioxide nanoparticles(MTNs)-based antibody drug delivery system(CD19-PEG-MTN/DOX)and detected the recognition,uptake,cytotoxicity and mechanism of the nano-drug system in vitro to provides new ideas for B-ALL treatment.Research content and results:MTN nanoparticles were prepared by hydrothermal synthesis,and then modified with polyethylene glycol and anti-CD19 antibody,then the model drug doxorubicin(DOX)was loaded.In this study,transmission electron microscope(TEM),scanning electron microscope(SEM),Malvern particle size analyzer,IR and EDS were used to characterize the morphology,size,groups and characteristic elements of nanoparticles respectively.The results show that the CD19-PEG-MTN/DOX nanoparticles have a regular spherical mesoporous structure with a size of 200nm.The recognition,targeting and effect of CD19-PEG-MTN/DOX nanoparticles were evaluated by flow cytometry and laser confocal microscopy.The results showed that the CD19-PEG-MTN/DOX nanoparticle could recognize CD19~+B-ALL cell lines(KOPN 8 and NALM-6)and induced them apoptosis.By contrast,CD19-PEG-MTN/DOX didn’t play a part on CD19~-AML cell line U937.Meanwhile,the expression of apoptosis related proteins was detected by Western blot to explore the mechanism of CD19-PEG-MTN/DOX nanoparticles.After treated with CD19-PEG-MTN/DOX nanoparticle,pro apoptotic proteins Bax and Caspase-3 in KOPN 8 and NALM-6 cells were significantly up-regulated,but anti apoptotic proteins Bcl2,MCL-1,HSP 70,and BAG 3 were down-regulated.Conclusion:In this study,a MTN nanoplatform with CD19 coupled and loaded with DOX was designed.The nano-platform has the advantages of strong specificity,good biocompatibility,and remarkable effects.Therefore,our data shed light on the development of CD19-PEG-MTN/DOX as a novel class of antitumor agents,which,if further validated,may help target molecular therapy of B-ALL.