Potential of Dendrimer-like Silica Nanoparticles Loaded with Cisplatin and Immune-checkpoint Inhibitors for Direct and Indirect Tumor Regression

Since the development of cancer immunotherapy using immune checkpoint inhibitors (ICIs), significant improvements have been made in cancer treatment. However, there are still limitations in their clinical effectiveness, particularly in terms of low delivery to target sites. To address these limitations, we aimed to enhance the existing ICI-based immunotherapy strategies by combining them with chemotherapeutic agents.<br/>To achieve this goal, we employed a one-pot sol-gel reaction to prepare dendrimer-like porous silica nanoparticles (DPSNs). These DPSNs possess a larger surface area compared to spherical particles of the same size, resulting in enhanced stability during long-term storage. Initially, we focused on conjugating cisplatin, a widely used chemotherapeutic anti-cancer agent, onto the surface of DPSNs. By modifying the DPSNs with carboxyl groups and loading cisplatin as a model anticancer drug, we investigated the release behavior of the drug molecules. Our findings revealed that cisplatin remained intact under neutral conditions but was released under acidic conditions, indicating the successful development of pH-responsive DPSNs (referred to as DPSN-cis).<br/>Furthermore, we performed an EDC/NHS-sulfo reaction to modify aPD-1, one of the ICIs, onto the surface of DPSN-cis. This allowed us to create DPSN-ICIS, where both cisplatin and aPD-1 were simultaneously conjugated. Importantly, DPSN-ICIS exhibited no cytotoxicity even after three days of cell culture and demonstrated long-term physicochemical stability. To evaluate the effectiveness of DPSN-ICIS, we conducted in vitro experiments to assess its binding to PD-1 on T cells and its ability to induce cancer cell death. Subsequently, we validated these findings in vivo by demonstrating that DPSN-ICIS effectively performed both functions and led to tumor eradication. These results were further supported by analyzing immune responses to examine the behavior of DPSN-ICIS within a living organism.<br/>Overall, our study highlights the potential of next-generation cancer immunotherapy by simultaneously loading chemotherapeutic agents capable of directly killing tumors and functionalizing various immune enhancers. The development of DPSN-ICIS addresses the limitations of current immunotherapy approaches, offering a promising strategy for more effective cancer treatment.