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DawWon Kim, Pharmsci graduate student (Hong Lab), will be defending her PhD research thesis:

Multivalent Dendrimer-Based Platforms for Targeted Cancer Therapy and Liquid Biopsy

Abstract:
The efficacy of cancer therapeutics and diagnostics is often limited by weak molecular interactions, resulting in poor binding affinity, rapid clearance, and low analytical sensitivity. To overcome these issues, dendrimer-based nanoparticles, particularly poly(amidoamine) (PAMAM) dendrimers, have emerged as a versatile platform for enhancing interactions with tumor cell-surface proteins through multivalent ligand presentation.

First, we applied the PAMAM platform to a therapeutic strategy using dendrimer-peptide conjugates (DPCs) designed to target the immune checkpoint programmed death ligand-1 (PD-L1). The multivalent presentation of PD-L1-binding peptides on generation 7 (G7) PAMAM dendrimers significantly enhanced binding avidity, prolonged serum half-life, and increased tumor accumulation. The conjugates not only improved target engagement but also blocked PD-1/PD-L1 pathway, reprogramming the tumor
microenvironment by recruiting cytotoxic T-cell infiltration while excluding immunosuppressive regulatory T cells. This immunomodulation resulted in delayed tumor growth in vivo without systemic toxicity. To expand the therapeutic potential of this platform, DPCs were further developed to target oncogenic epidermal growth factor receptor (EGFR). Multivalent EGFR engagement inhibited receptor activation and the downstream signaling pathway, leading to suppressed tumor cell proliferation and delayed tumor growth in vivo.

Beyond therapeutic applications, the dendrimer platform was adapted for diagnostics through the development of a biomimetic liquid biopsy system for circulating tumor cell (CTC) capture. By integrating E-selectin-mediated cell rolling with dendrimer-mediated multivalent capture, this system enabled highly sensitive detection of CTCs in patients with head and neck squamous cell carcinoma. Longitudinal monitoring of CTC abundance provided a minimally invasive evaluation of therapeutic response, in some cases, that surpassed conventional radiologic biomarkers.

In summary, these findings establish the PAMAM dendrimer as a unifying platform for targeting tumorcell surface proteins for both therapeutic modulation and diagnostic capture.