Delivery Of MiR-375 And Doxorubicin By Lipid-Coated Hollow Mesoporous Silica Nanoparticles For The Treatment Of Liver Cancer

Purpose: Among the chemotherapeutic agents available for clinical cancer treatment,doxorubicin(DOX)is most widely used while DOX-based chemotherapeutic options for cancers are often ineffective due to multidrug resistance(MDR).Nanotechnology based on mesoporous silicon nanoparticles become a promising strategy that can be effectively overcome MDR.Herein,we prepared a lipid-coated HMSN(LH)formulation containing DOX and mi R-375(LHD/mi R-375)and explored its efficiency to deliver mi R-375 and DOX into MDR HCC cells.On the one hand,the nanoparticle itself can bypass P-gp pump.On the other hand,mi R-375 can repress the expression of P-gp protein on molecular level so as to combat MDR synergeticly.Methods: 1.First,synthesis of HMSN on the basis of St? ber method.Then lipid coated HMSN were prepared with liposome fusion method.Morphology,particle size,surface potential,drug loading,in vitro release of nanoparticles were characterized by transmission electron microscopy(TEM),dynamic light scattering or ultraviolet spectrophotometer.2.We evaluated the cellular uptake efficiency and the proliferation suppression of LHD/mi R-375 in Hep G2/ADR cells.The endocytic mechanism and intracellular fate of LHD/mi R-375 in Hep G2/ADR cells were evaluated by confocal microscope and flow cytometry so as to further explanin the mechanism of anti-drug resistance.The results showed that LHD/mi R-375 can exert synergetic anti-tumor effect.3.We use both Hep G2/ADR xenograft tumor mouse model and primary HCC tumor mouse model to detect the anti-tumor effect of LHD/mi R-375.Results: 1.We successfully synthezed soluble HMSN and the lipid-coated nano system that can co-deliver DOX and mi R-375.2.LHD/mi R-375 can effectively bypass P-gp pump and mainly release from late-endosome in cell,which increased the DOX accumulation and anti-tumor effect.3.LHD injections led to higher DOX accumulation in the mouse livers and tumors than the free DOX injection did and greatly decreased the accumulation in heart.As a result,the side effects of DOX in the normal organs,especially injury to the heart,may be reduced.Conclusion: In general,we prepared lipid-coated HMSN for co-delivery of DOX and mi R-375.LHD/mi R-375 could exert dual effects to overcome DOX resistance in vitro and in vivo.