PD‐1 Blockade for Improving the Antitumor Efficiency of Polymer–Doxorubicin Nanoprodrug

Abstract

Chemotherapy is well recognized to induce immune responses during some chemotherapeutic drugs-mediated tumor eradication. Here, a strategy involving blocking programmed cell death protein 1 (PD-1) to enhance the chemotherapeutic effect of a doxorubicin nanoprodrug HA-Psi-DOX is proposed and the synergetic mechanism between them is further studied. The nanoprodrugs are fabricated by conjugating doxorubicin (DOX) to an anionic polymer hyaluronic acid (HA) via a tumor overexpressed matrix metalloproteinase sensitive peptide (CPLGLAGG) for tumor targeting and enzyme-activated drug release. Once accumulated at the tumor site, the nanoprodrug can be activated to release antitumor drug by tumor overexpressed MMP-2. It is found that HA-Psi-DOX nanoparticles can kill tumor cells effectively and initiate an antitumor immune response, leading to the upregulation of interferon-γ. This cytokine promotes the expression of programmed cell death protein-ligand 1 (PD-L1) on tumor cells, which will cause immunosuppression after interacting with PD-1 on the surface of lymphocytes. The results suggest that the therapeutic efficiency of HA-Psi-DOX nanoparticles is significantly improved when combined with checkpoint inhibitors anti-PD-1 antibody (α-PD1) due to the neutralization of immunosuppression by blocking the interaction between PD-L1 and PD-1. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between conventional tumor therapies and immunotherapy.

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

“…Long-term expression of IFN-γ in tumor tissues upregulates the expression of PD-L1 on the tumor cells, resulting in immunosuppression to promote tumor growth 4 . PD-L1 inactivates lymphocytes after interacting with PD-l present on the surface of various immune cells 7 , 9 . We evaluated the expression of PD-L1 in tumor tissues by flow cytometry.…”

“…However, prolonged IFN-γ signaling may also have an immunosuppressive role by promoting programmed cell death protein-ligand 1 (PD-L1) expression on tumor cells 4 - 6 . PD-L1 interacts with programmed cell death protein 1 (PD-1), inactivating lymphocytes 7 - 9 . Therefore, combination treatment of immunogenic chemotherapy agent DOX and PD-1/PD-L1 inhibitors can recruit T cells by blocking the PD-1/PD-L1 interaction, to achieve synergic therapy effect 7 , 10 .…”

“…PD-L1 interacts with programmed cell death protein 1 (PD-1), inactivating lymphocytes 7 - 9 . Therefore, combination treatment of immunogenic chemotherapy agent DOX and PD-1/PD-L1 inhibitors can recruit T cells by blocking the PD-1/PD-L1 interaction, to achieve synergic therapy effect 7 , 10 .…”

“…However, DOX and PD-1/PD-L1 inhibitor need to be delivered to different sites of cells; DOX must be released inside the tumor cells while PD-1/PD-L1 inhibitor should be delivered out of the tumor cells to block the interaction between T cells and tumor cells. Previously, PD-1/PD-L1 antibodies and chemotherapy agents were generally administrated via different routes in mice with an intraperitoneal injection of PD-1/PD-L1 antibodies, while chemotherapy agents were intravenously injected 7 , 11 - 13 . Although PD-L1 is expressed mainly on tumor cells to regulate T-cell response, it is also expressed on other cells, such as macrophages.…”

<p>Doxorubicin Delivered Using Nanoparticles Camouflaged with Mesenchymal Stem Cell Membranes to Treat Colon Cancer</p>

“…Mice were sacrificed at 24 h post-injection and major organs (heart, liver, spleen, lung, kidney, and tumor) harvested for ex vivo imaging and semi-quantitative biodistribution analysis. [23][24][25]…”