{
  "abstract": "Background The advancement of precision oncology has highlighted biologic therapies that modulate the immune system to suppress tumor growth across various cancers, including head and neck squamous cell carcinoma (HNSCC). While monoclonal antibodies (mAbs) remain the standard of care, they are limited by immune-related toxicities, high costs, poor tumor penetration, and manufacturing variability. Peptides provide a promising alternative due to their ease of manufacture, reduced immunogenicity, and enhanced tumor penetration. However, their clinical application remains challenging because of poor binding kinetics, low bioavailability, and rapid clearance. To overcome these issues, we present a modular nanoparticle platform based on generation 7 (G7) poly(amidoamine) (PAMAM) dendrimers conjugated with engineered peptides (dendrimer-peptide conjugates, DPCs), targeting programmed death ligand 1 (PD-L1) or epidermal growth factor receptor (EGFR), both overexpressed in HNSCC. We hypothesize that the multivalent binding effects mediated by dendrimers will enhance binding avidity, in vitro selectivity, and in vivo efficacy.Methods DPCs targeting PD-L1 (DPC PD-L1) or EGFR (DPCEGFR) were synthesized and characterized using 1H NMR and MALDI-TOF.1 Their binding kinetics were evaluated using biolayer interferometry and surface plasmon resonance. In vitro binding and cytotoxicity were examined using PD-L1/EGFR-expressing mouse oral squamous cell carcinoma (MOC1) cell line. Inhibition of oncogenic signaling was observed by Western blot. In vivo pharmacology was assessed in syngeneic MOC1 tumor-bearing mice treated intravenously with DPCs. Drug half-life, toxicity, and anti-tumor efficacy were examined, and ex vivo analyses, including flow cytometry, immunohistochemistry, and NanoString profiling, were performed to explore immune modulation.Results Successfully synthesized and characterized DPC PD-L1 and DPCEGFR exhibited up to 1,000-fold stronger binding avidity to their targets compared to free peptides, which translated to enhanced in vitro selectivity for MOC1 cells. In vivo, DPCs showed a 14-fold increase in plasma half-life and significantly enhanced anti-tumor efficacy. Mice treated with DPCPD-L1showed a 40% reduction in tumor volume after four IV injections at a dosage of 50 mg/kg, accompanied by increased CD4- and CD8-positive T cell in filtration, reduced regulatory T cells, and decreased tumor cell proliferation. Similarly, DPCEGFR exhibited anti-tumor efficacy comparable to anti-EGFR, correlating with reduced EGFR phosphorylation, inhibited downstream pMAPK signaling, and increased apoptosis in tumor tissues.Conclusions Together, these results highlight the therapeutic potential of our DPC platform in co-targeting immune checkpoint and oncogenic pathways. With its simplicity, modularity, and functional flexibility, this platform supports the feasibility of integrating multiple therapeutic and targeting components, offering a promising strategy for clinical translation and providing new treatment options for HNSCC.Reference Kim D, Lee J, Rawding PA, Iida M, Kim C, Kostecki KL, Poellmann MJ, Crossman B, Liu AS, Kim Y, Wheeler DL, and Hong S. Dendrimer conjugates with PD-L1-binding peptides enhance in vivo antitumor immune response. Adv Healthc Mater. 2025;2500551.",
  "authors": [
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Dawon Kim"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "JinWoong Lee"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Narsimha Mamidi"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Mari Iida"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Deric Wheeler"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Seungpyo Hong"
    }
  ],
  "title": "989 A multivalent dendrimer-peptide conjugate platform for co-targeting immune checkpoint and oncogenic pathways in HNSCC",
  "uid": "a4c74e61-5b9a-5277-8e5a-642a7688eb79"
}