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.

• Authors: Fan Gao, Chi Zhang, Wen-Xiu Qiu, Xue Dong, Di-Wei Zheng, Wei Wu, Xian-Zheng Zhang
• Journal: Small (Weinheim an der Bergstrasse, Germany) (Small) Vol. 14 Issue 37 Pg. e1802403 (09 2018) ISSN: 1613-6829 [Electronic] Germany
• PMID: 30129176 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Polymers
• Prodrugs
• Programmed Cell Death 1 Receptor
• Doxorubicin
• Interferon-gamma
• Hyaluronic Acid

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Doxorubicin (pharmacokinetics, pharmacology)
• Female
• Hyaluronic Acid (chemical synthesis, chemistry)
• Immunotherapy
• Interferon-gamma (metabolism)
• Melanoma, Experimental (pathology)
• Mice, Inbred C57BL
• Nanoparticles (chemistry, ultrastructure)
• Neoplasm Metastasis
• Polymers (chemistry)
• Prodrugs (pharmacokinetics, pharmacology)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, metabolism)
• T-Lymphocytes, Cytotoxic (drug effects)