Theranostics For Breast Cancer Based On Soft Mesoporous Organosilica Nanoplatforms

Objective To explore the advantages of soft mesoporous nanoplatform in processes of tumor drug delivery,including blood circulation,tumor accumulation,tumor penetration and tumor cellular uptake,and to carry out the integrated study of imaging and treatment of breast cancer based on this sort of soft nanoparticles.Methods The soft mesoporous fluorescent nanoprobe was obtained via a preferential NaOH etching approach and a modification of a near-infrared dye(Cy5.5).Comparative studies of the soft SMONs-HA-Cy5.5 and stiff ones with similar size,surface charge,and chemical composition were conducted.The uptake difference by MCF-7 cells was analyzed by confocal laser scanning microscopy(CLSM)and flow cytometry.MCF-7 cell lines were used to construct an in vitro 3D tumor cell sphere model,and the differences in penetration ability of the two types of probes in cell spheres were analyzed by CLSM observation.Circulation profiles of the two probes were obtained by measuring the Si concentration in blood samples at different time points after injection.Biodistribution differences of the two probes in MCF-7 tumorbearing mice were observed and compared using an IVIS Lumina XR system.Tumor vessels were stained with anti-CD31 antibody,and intratumoral distribution differences of the two sorts of probes were compared by confocal microscopy.Finally,the soft therapeutic nanoplatform was constructed by further modifying the photosensitizer chlorine6(Ce6)on the soft probe.The antitumor efficacies of the soft nanoplatform and its stiff counterparts were also compared at the animal and cell-based levels.Results AFM results indicate that the Young’s modulus of the soft probe is only onethird of that of its rigid counterpart(24.2 MPa vs.79.2MPa).Apart from exhibiting a twofold increase in tumor cellular uptake(40.96% vs.23.85%),the soft nanoplatform also displays a remarkable pharmacokinetic advantage,whose half-life(8.49 h)is nearly 3 times longer than that of MONs-HA-Cy5.5(3.07 h),resulting in doubleimproved tumor accumulation.Moreover,SMONs-HA-Cy5.5 exhibits a significantly higher tumor penetration and achieves 30-μm deeper tissue permeability in multicellular spheroids relative to the stiff counterparts.Results of ex vivo intratumoral distribution further reveal that the soft nanoplatform can extravasate more easily from the tumor vessels,diffuse farther in the dense extracellular matrix,and reach deeper areas in tumor tissues compared to the stiff ones.Particularly,the soft nanoplatforms generate a 16-fold improvement(43 μm vs.2.72 μm)in diffusion distance in tumor parenchyma.Based on the significantly improved blood circulation time and tumor accumulation/penetration,a soft therapeutic nanoplatform is constructed by loading photosensitizer chlorin e6 in SMONs-HA-Cy5.5.The resulting nanoplatform exhibits considerably higher therapeutic efficacy on tumors compared to the stiff ones.Conclusion Overall,the soft mesoporous organosilica nanomaterials hold demonstrate tremendous advantages over their stiff counterparts,including improved blood circulation,tumor accumulation and tumor penetration.The soft nanoplatform significantly improved the tumor therapeutic efficacy via photodynamic therapy following intravenous injection.Consequently,regulating the softness of mesoporous materials can provide a new strategy for the development of nanoplatform with long circulation and high permeability,which has great potential for further future therapeutic anticancer approaches.