1. Academic Validation
  2. An orally available PD-1/PD-L1 blocking peptide OPBP-1-loaded trimethyl chitosan hydrogel for cancer immunotherapy

An orally available PD-1/PD-L1 blocking peptide OPBP-1-loaded trimethyl chitosan hydrogel for cancer immunotherapy

  • J Control Release. 2021 Jun 10:334:376-388. doi: 10.1016/j.jconrel.2021.04.036.
Wanqiong Li 1 Xueqin Zhu 2 Xiuman Zhou 2 Xiaoxi Wang 2 Wenjie Zhai 2 Bingyu Li 2 Jiangfeng Du 2 Guodong Li 2 Xinghua Sui 3 Yahong Wu 2 Mingxia Zhai 2 Yuanming Qi 2 Guanyu Chen 4 Yanfeng Gao 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China; School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 2 School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 3 School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China.
  • 4 School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China. Electronic address: chengy239@mail.sysu.edu.cn.
  • 5 School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China; School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: gaoyf29@mail.sysu.edu.cn.
Abstract

Blockade of the immune checkpoint PD-1/PD-L1 with monoclonal Antibodies demonstrated unprecedented clinical efficacies in many cancers. But the orally available low molecular weight inhibitors remain infancy. Compared to small molecules, peptide exhibits better selectivity and fewer side effects, but poor half-life and a big challenge to be orally administrated. Here, we developed a proteolysis-resistant D peptide OPBP-1 (Oral PD-L1 Binding Peptide 1) which could selectively bind PD-L1, significantly block PD-1/PD-L1 interaction and enhance IFN-γ (interferon γ) secretion from CD8+ T cells in human PBMCs (Peripheral blood mononuclear cells). OPBP-1 could significantly inhibit tumor growth in murine colorectal CT26 and melanoma B16-OVA models at a relatively low dose of 0.5 mg/kg, with enhancing the infiltration and function of CD8+ T cells. More interestingly, oral delivery of OPBP-1 loaded TMC (N, N, N-trimethyl chitosan) hydrogel (OPBP-1@TMC) showed promising OPBP-1 oral bioavailability (52.8%) and prolonged half-life (14.55 h) in rats, and also significantly inhibited tumor growth in CT26 model. In conclusion, we discovered and optimized a PD-1/PD-L1 blocking peptide OPBP-1, and subsequently loaded into a TMC based hydrogel oral delivery system, in order to maximally elevate the oral bioavailability of the peptide drug and effectively inhibit tumor growth. These results opened up a new prospect for oral drug development in Cancer Immunotherapy.

Keywords

Cancer immunotherapy; Oral drug delivery; PD-1/PD-L1; Peptide optimization; Trimethyl chitosan.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P10424
    PD-1/PD-L1阻断肽