Intercellular Adhesion Molecule 1 Antibody-mediated Mesoporous Drug Delivery System For Targeted Treatment Of Triple-Negative Breast Cancer

Objective At present,the research on effective targeted therapy for triple-negative breast cancer?TNBC?is still facing great challenges.Here,we successfully constructed an ICAM-1 antibody mediated drug delivery system for TNBC targeted therapy.Methods The PMOs were synthesized via a CTAB-directed sol-gel process and were modified with Cy5.5 and ICAM-1 antibody molecules by a click reaction between the thiol and maleimide groups.To construct the targeting drug delivery system DOX@PMO-Cy5.5-ICAM,DOX was then loaded into the PMO mesochannels.The PMO was characterized by Transmission electron microscopy?TEM?and Dynamic light scattering?DLS?.The mesoporous size of PMO was verified by nitrogen adsorption and desorption experiments,and the surface of PMO was successfully modified with Cy5.5 by near-infrared fluorescence imaging of water,supernatant and PMO-Cy5.5 and UV–visible absorption spectrum.The Zeta potential of PMO,PMO-Cy5.5,PMO-Cy5.5-ICAM,DOX@PMO-Cy5.5-ICAM was measured to verify whether the Cy5.5 and ICAM-1 antibodies were successfully modified on the PMO surface and the DOX was successfully loaded into the PMO pore.The biocompatibility of PMO-Cy5.5-ICAM nanomaterials was verified by in vitro MTT assay and in vivo mouse assay.The targeting of PMO-Cy5.5-ICAM on TNBC cells was verified by confocal microscopy.The toxicity of DOX@PMO-Cy5.5-ICAM to MDA-MB-231cell was verified by cck-8 assay.A TNBC nude mouse model was established,and DOX,PBS,DOX@PMO-Cy5.5,DOX@PMO-Cy5.5-ICAM were injected into the tail vein,followed by ex vivo near-infrared fluorescence imaging to verify the distribution of DOX@PMO-Cy5.5-ICAM in vivo.The therapeutic effect of DOX@PMO-Cy5.5-ICAM nanoparticles on TNBC was verified by measuring tumor volume changes after 30 days of treatment.In the experiment,SPSS18.0 software was used for statistical analysis of data,and t test was used for comparison of quantitative data.P<0.05 meant statistical difference.Results1.The TEM images showed that the thioether-bridged PMOs are 70 nm in diameter with a uniform spherical shape and good dispersion in ethanol and the PMOs have radially oriented mesochannels,which are favored for the adsorption and release of drug molecules.The diameter of PMOs measured by dynamic light scattering?DLS?was 90 nm.Nitrogen sorption isotherms of the PMOs showed the characteristics of the mesoporous materials.The surface area and pore size of PMOs were up to 1146m²/g and 3.0 nm,respectively.2.The IVIS optical imaging system demonstrated that PMOs-Cy5.5 had a strong fluorescence signal.PMO-Cy5.5 exhibited characteristic absorption peaks for Cy5.5on the UV–visible absorption spectrum,demonstrating that Cy5.5 was connected to the PMOs.FT-IR of the DOX@PMO-Cy5.5-ICAM showed a 1650cm^-1 amide I band?red arrow?suggesting that the ICAM-1 antibody was successfully modified on the PMOs.The results of zeta potential change indicate that Cy5.5 and ICAM-1antibodies have been successfully modified on PMOs and DOX has been loaded into the PMOs channel.Quantitative analysis indicated that the loading capacity of PMO-Cy5.5-ICAM for DOX was as high as 400 mg/g.3.In vitro MTT assay and in vivo mouse test results showed that PMO-Cy5.5-ICAM had good biocompatibility.Confocal laser microscopy showed that PMO-Cy5.5-ICAM can effectively target and enter TNBC cells.Drug release experiments showed obvious acidic pH sensitivity.Cytotoxicity experiments showed that DOX@PMO-Cy5.5-ICAM had higher killing effect on MDA-MB-231 cells than other control groups.In vitro near infrared fluorescence imaging,the results showed that DOX@PMO-Cy5.5-ICAM accumulation in TNBC was higher than that in other control groups.DOX@PMO-Cy5.5-ICAM showed a better therapeutic effect on TNBC after 30 days of treatment.Conclusion We prepared an ICAM-1-targeted drug delivery system for the treatment of TNBC by conjugating ICAM-1 antibody and Cy5.5 to thiother-bridged PMOs.This is the first study on the active targeted drug delivery system for the treatment of triple-negative breast cancer,providing a new idea for the treatment of TNBC breast cancer.