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Protein Kinase C-delta Inhibitor Peptide Formulation using Gold Nanoparticles
Published on: March 9, 2019
Peptides-functionalized gold nanostars enhanced degradation of PD-L1 for improved prostate cancer immunotherapy
Liangjun Tao1, Yifei Zhang1, Jingwei Zhang1
1Department of Urology, The First Affiliated Hospital of Wannan Medical College, Wuhu, People's Republic of China.
Abstract:
Blockage of the interaction between programmed death receptor-1 (PD-1) and programmed death ligand-1 (PD-L1) can restore T-cell activity and enhance antitumor immunity. PD-1/PD-L1 pathway inhibitors have promising applications in the treatment of advanced prostate cancer (PCa). We successfully developed a peptides-functionalized gold nanoconstruct (P-AuNS) consisted of PD-L1-binding peptide (PD-L1pep, P) and gold nanostar (AuNS), which could bind to cell-surface PD-L1 specifically and deliver PD-L1 into PCa cells with high efficiency. In PCa cells, P-AuNS can efficiently degrade PD-L1 in a lysosomal-dependent manner. In the co-culture system of Jurkat cells and DU145 cells, P-AuNS restored the proliferative capacity and interferon-gamma (IFN-γ) secretion level of Jurkat cells inhibited by co-cultured DU145 cells, indicating that P-AuNS effectively hampered the interaction between PD-1 and PD-L1. In addition, in PCa-bearing mice, P-AuNS can effectively inhibit tumor growth and down-regulate PD-L1 protein levels, and in vivo experimental results show that P-AuNS has no systemic toxicity. P-AuNS block the interaction between PD-1 and PD-L1 by efficiently degrading PD-L1, thus restoring the antitumor activity of T cells and inhibiting tumor progression of PCa. In all, P-AuNS has great promise as a potential immunotherapy strategy in the treatment of advanced PCa and even other solid tumors.
Insights
A novel peptide-functionalized gold nanoconstruct (P-AuNS) effectively degrades Programmed Death-Ligand 1 (PD-L1) in prostate cancer cells. This approach restores T-cell antitumor immunity and inhibits tumor growth with no observed systemic toxicity.
Area of Science:
- Biomedical Engineering
- Immunology
- Oncology
Background:
- The programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway suppresses T-cell activity, hindering antitumor immune responses.
- Inhibitors of the PD-1/PD-L1 pathway show potential for treating advanced prostate cancer (PCa).
Purpose of the Study:
- To develop and evaluate a novel peptides-functionalized gold nanoconstruct (P-AuNS) for targeted PD-L1 degradation in prostate cancer.
- To assess the efficacy of P-AuNS in restoring T-cell activity and inhibiting tumor progression in preclinical models.
Main Methods:
- A P-AuNS was synthesized, comprising a PD-L1-binding peptide and a gold nanostar.
- P-AuNS were used to deliver and degrade cell-surface PD-L1 in PCa cells via a lysosomal-dependent mechanism.
- In vitro co-culture assays and in vivo studies in PCa-bearing mice were conducted to evaluate P-AuNS efficacy and toxicity.
Main Results:
- P-AuNS specifically bound to and efficiently degraded PD-L1 in PCa cells.
- In vitro, P-AuNS restored T-cell proliferation and interferon-gamma secretion, indicating effective blockade of PD-1/PD-L1 interaction.
- In vivo, P-AuNS significantly inhibited tumor growth in PCa-bearing mice and downregulated PD-L1 levels without systemic toxicity.
Conclusions:
- P-AuNS effectively blocks the PD-1/PD-L1 interaction by degrading PD-L1, thereby restoring antitumor T-cell activity.
- P-AuNS demonstrates significant potential as a novel immunotherapy strategy for advanced prostate cancer and other solid tumors.
