Delivery of cisplatin and resiquimod in nanomicelles for the chemoimmunotherapy of ovarian cancer

Abstract

BackgroundTo explore the effect and mechanism of delivery of cisplatin (CDDP) and resiquimod in nanomicelles for the chemoimmunotherapy of ovarian cancer in vivo and in vitro.MethodsPoly(l-glutamic acid)-graft-methoxypolyethylene glycols (PLG-g-mPEG) was used to carry cisplatin and resiquimod for the preparation of CDDP/resiquimod/PLG-g-mPEG. We determined the loading content (LC) and encapsulation efficiency (EE), and then observed the particle shape, particle size distribution and zeta potential. In this study, we recruited 30 healthy adult participants and isolated mononuclear cells, and they were randomly classified into a control group, a CDDP group, a resiquimod group, a CDDP/resiquimod/PLG-g-mPEG group and a IFN-γ + LPS group to identify macrophages markers in different polarization states. We conducted microprobe synchrotron radiation X-ray fluorescence (SRXRF) imaging to observe the cell uptake. Furthermore, we observed the effects of CDDP/resiquimod/PLG-g-mPEG on the growth and colony formation of SW626 cells and the expressions of apoptosis-associated genes and proteins. Tumor-bearing mouse models of ovarian cancer were prepared and randomized into a negative control group, a PLG-g-mPEG group, a CDDP group, a resiquimod group and a CDDP/resiquimod/PLG-g-mPEG group, so as to analyze the anti-cancer effect of CDDP/resiquimod/PLG-g-mPEG in vivo.ResultsThe LC and EE of CDDP/resiquimod/PLG-g-mPEG were 19.42% and 90.12%, respectively. Nanoparticles were uniform spherical in shape and closely arranged together, with a typical core–shell structure, and their average particle size and zeta potential were 82.36 nm and − 23.69 mV, respectively. When CDDP/resiquimod/PLG-g-mPEG group was compared with the control group, the positive expression rate of CD16 in the CDDP/resiquimod/PLG-g-mPEG group highly increased, whereas the positive expression rate of CD163 dramatically decreased. In the meantime, Arg1 and Mrc1 mRNA expressions significantly decreased whereas IL-12 and NOS2 mRNA expressions dramatically increased (P < 0.05). Elemental mapping of cells exhibited notable internalization of cisplatin delivered by CDDP/resiquimod/PLG-g-mPEG to cytoplasm. We compared the cell survival rate between the CDDP/resiquimod/PLG-g-mPEG group and the control group, the CDDP/resiquimod/PLG-g-mPEG group sharply reduced (P < 0.05). What’s more, the inhibitory effect got strengthened as the reaction time was prolonged, with the synergy coefficient of 0.31.ConclusionPLG-g-mPEG-loaded CDDP and resiquimod effectively achieves the targeted delivery of chemotherapy and immunotherapy, with a strong synergistic anti-cancer effect.