Inhibiting Endothelial Cell-Mediated T Lymphocyte Apoptosis with Integrin-Targeting Peptide-Drug Conjugate Filaments for Chemoimmunotherapy of Triple-Negative Breast Cancer.
Ying CaiBinyu ZhuXiaoting ShanLingli ZhouXujie SunAnqi XiaBinhao WuYang YuHelen He ZhuPengcheng ZhangHaijun YuPublished in: Advanced materials (Deerfield Beach, Fla.) (2023)
Tumor-associated endothelial cells (TECs) limit anti-tumor immunity via inducing apoptosis of infiltrating T lymphocytes through a Fas ligand (FasL)-mediated mechanism. Herein, we create a peptide-drug conjugate (PDC) by linking 7-ethyl-10-hydroxycamptothecin (SN38) to hydrophilic segments with either RGDR or HKD motif at their C-terminus through a glutathione-responsive linker. The PDCs spontaneously assemble into filaments in aqueous solution. The PDC filaments containing 1% of SN38-RGDR (SN38-HKD/RGDR) effectively target triple-negative breast cancer (TNBC) cells and TECs with upregulated expression of integrin, and induce immunogenic cell death (ICD) of tumor cells and FasL down-regulation of TECs. SN38-HKD/RGDR increases infiltration, activity, and viability of CD8 + T cells, and thus inhibits the growth of primary tumors and pulmonary metastasis. This study highlights the synergistic modulation of cancerous cells and TECs with integrin-targeting PDC filaments as a promising strategy for TNBC chemoimmunotherapy. This article is protected by copyright. All rights reserved.
Keyphrases
- cell cycle arrest
- cell death
- cancer therapy
- endothelial cells
- induced apoptosis
- pi k akt
- endoplasmic reticulum stress
- oxidative stress
- aqueous solution
- signaling pathway
- drug delivery
- poor prognosis
- pulmonary hypertension
- high glucose
- drug induced
- liquid chromatography
- high resolution
- simultaneous determination
- tandem mass spectrometry