A pH-responsive Pickering Nanoemulsion for specified spatial delivery of Immune Checkpoint Inhibitor and Chemotherapy agent to Tumors

Abstract

Rationale: Immune checkpoint (ICP) blockade therapy combined with chemotherapy is a promising treatment strategy for tumors. Chemotherapeutic agents usually function inside the tumor cells, while ICP inhibitors are efficacious out of the tumor cells. It is desirable to effectively co-deliver an ICP inhibitor and a chemotherapy agent to different sites of a tumor. We have designed an effective drug delivery system to accomplish both objectives. Methods: We designed a Pickering nanoemulsion (PNE) using multi-sensitive nanogels with pH-responsive, hydrophilicity-hydrophobicity switch, and redox-responding properties as an oil/water interfacial stabilizer. The D/HY@PNE was employed for specified spatial delivery of the chemotherapy agent doxorubicin (DOX) and ICP inhibitor HY19991 (HY). We systematically investigated the pH-responsive disassembly of PNE, the release of DOX and HY from D/HY@PNE in the tumor microenvironment, enhanced tumor penetration of DOX, immunogenic cell death (ICD), antitumor efficacy, and the immune response induced by D/HY@PNE in vitro and in vivo . Results: D/HY@PNE disassembled to release the ICP inhibitor HY and DOX-loaded nanogels due to the hydrophilicity-hydrophobicity reversal of nanogels in the acidic tumor microenvironment. Quantitative analysis indicates that D/HY@PNE presents enhanced tumor penetration behavior and effectively induces ICD. The strong immune response induced by D/HY@PNE was due to the efficient synergetic combination of chemotherapy and immunotherapy and resulted in enhanced antitumor efficacy in 4T1 tumor-bearing mice. Conclusion: This novel strategy highlights the promising potential of a universal platform to co-deliver different therapeutic or diagnostic reagents with spatial regulation to improve the anti-tumor effect.

In situ tumor-triggered subcellular precise delivery of multi-drugs for enhanced chemo-photothermal-starvation combination antitumor therapy

“…The tumor microenvironment is often acidic, and acidic metabolites such as lactic acid produced by anaerobic glycolysis during hypoxia, appear to be the main underlying cause 39 , 40 . Therefore, the acidic pH of tumors is often designated as a target stimulus trigger for the controlled release of antitumor drugs 9 , 41 . When the pH of the solution containing P60-ICG-THP was buffered close to 6.5, green sediments were separated and precipitated at the bottom of the centrifuge tube after a few minutes, and the supernatant became red (pH 6.5, Figure 3 A).…”

Based on the identification of tumor antigens and immune subtypes in renal clear cell carcinoma for mRNA vaccine development

“…This indicated that IS5 and IS6 are immunological “hot”, and IS1-4 are immunological “cold” phenotypes, which is the lack or paucity of tumor T cell infiltration. Since the presence of immune checkpoints affects the immune response of tumors, ICBs combined with other tumor therapies can induce ICD in tumors, thereby enhancing the anti-tumor effect [42]. The high expressions of ICPs in IS6 tumors in GEO cohort and in TCGA cohort suggest an immunosuppressive tumor microenvironment, which may inhibit the mRNA vaccine from eliciting an effective immune response.…”

Advanced and Innovative Nano-Systems for Anticancer Targeted Drug Delivery

“…Besides, the combined application of immune checkpoint (ICP) blockade and chemotherapeutic drugs have also been proposed as a promising strategy for tumor treatment [ 139 ]. For instance, Jia’s group constructed a pH-responsive pickering nanoemulsion (PNE) to deliver both ICP inhibitor HY19991 and DOX, which was termed D/HY@PNE [ 34 ]. HY19991 was a small molecule inhibitor, which could block the PD-1/PD-L1 interaction between T cells and tumor cells, resulting in the activation of T cells.…”