Preparation, Biosafety, and Cytotoxicity Studies of a Newly Tumor-Microenvironment-Responsive Biodegradable Mesoporous Silica Nanosystem Based on Multimodal and Synergistic Treatment

Abstract

Patients with triple negative breast cancer (TNBC) often suffer relapse, and clinical improvements offered by radiotherapy and chemotherapy are modest. Although targeted therapy and immunotherapy have been a topic of significant research in recent years, scientific developments have not yet translated to significant improvements for patients with TNBC. In view of these current clinical treatment shortcomings, we designed a silica nanosystem (SNS) with Nano-Ag as the core and a complex of MnO2 and doxorubicin (Dox) as the surrounding mesoporous silica shell. This system was coated with anti-PD-L1 to target the PD-L1 receptor, which is highly expressed on the surface of tumor cells. MnO2 itself has been shown to act as chemodynamic therapy (CDT), and Dox is cytotoxic. Thus, the full SNS system presents a multimodal, potentially synergistic strategy for the treatment of TNBC. Given potential interest in the clinical translation of SNS, the biological safety and antitumor activity of SNS were evaluated in a series of studies that included physicochemical characterization, particle stability, blood compatibility, and cytotoxicity. We found that the particle size and zeta potential of SNS were 94.6 nm and -22.1 mV, respectively. Ultraviolet spectrum analysis showed that Nano-Ag, Dox, and MnO2 were successfully loaded into SNS, and the drug loading ratio of Dox was about 10.2%. Stability studies found that the particle size of SNS did not change in different solutions. Hemolysis tests showed that SNS, at levels far exceeding the anticipated physiologic concentrations, did not induce red blood cell lysis. Further in vitro and in vivo experiments found that SNS did not activate platelets or cause coagulopathy and had no significant effects on the total number of blood cells or hepatorenal function. Cytotoxicity experiments suggested that SNS significantly inhibited the growth of tumor cells by damaging cell membranes, increasing intracellular ROS levels, inhibiting the release of TGF-β1 cytokines by macrophages, and inhibiting intracellular protein synthesis. In general, SNS appeared to have favorable biosafety and antitumor effects and may represent an attractive new therapeutic approach for the treatment of TNBC.

Nanoparticle-Mediated Immunotherapy in Triple-Negative Breast Cancer

“…The cytotoxicity assays indicated that the system effectively suppressed tumor cell development by damaging CMs, elevating intracellular levels of ROS, and impeding the production of TGF-β1 cytokines by macrophages. 98 The CXCR4 receptor, found on the surface of cells, is highly expressed in TNBC and stimulates cell growth and movement toward chemical signals. 99 Research has demonstrated that the chemokine (C-X-C motif) ligand 12 (CXCL12) hinders the presence of T cells within a tumor.…”

“…For instance, He et al designed a SNS with Nano-Ag as the core and a complex of MnO 2 and doxorubicin as the surrounding mesoporous silica shell, with anti-PD-L1 as a targeting group. 98 Periodic mesoporous organosilica nanoparticles (PMOs) are inorganic−organic hybrids and optimized mesoporous silica nanoparticles that have attracted attention as potential nanocarriers for drug delivery. 57 PMOs bore TRAIL on their surfaces, and their inner cores were loaded with DOX, which were designed by Feng et al 57 In their study, the problem of PMOs low level of targeting tumors in vivo has been solved.…”

“…He et al developed a silica nanosystem consisting of a nano-Ag core and a mesoporous silica shell that contains a compound of MnO 2 and DOX. The cytotoxicity assays indicated that the system effectively suppressed tumor cell development by damaging CMs, elevating intracellular levels of ROS, and impeding the production of TGF-β1 cytokines by macrophages …”

“…Silica nanosystem (SNS) can be designed as a drug codelivery nanoplatform. For instance, He et al designed a SNS with Nano-Ag as the core and a complex of MnO 2 and doxorubicin as the surrounding mesoporous silica shell, with anti-PD-L1 as a targeting group …”

Research Progress on Improving the Efficiency of CDT by Exacerbating Tumor Acidification

“… 4–8 Its excellent therapeutic effect on tumors has been verified in laboratory studies. 9 Chemotherapy and radiotherapy, as treatments for cancer, have serious side effects, including toxicity and immunosuppression, which limit their anti-tumor efficacy and increase the risk of infection. 10 , 11 Compared to them, CDT agents are less prone to serious side effects and drug resistance.…”