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Abstract Peptides are an emerging class of biologics for cancer immunotherapy; however, their clinical translation is hindered by poor binding kinetics, bioavailability, and short plasma half‐life compared to their corresponding antibodies. Nanoparticles present potential solutions but face scale‐up difficulties due to complexity. Here, a translatable, modular nanoparticle scaffold is presented for peptide‐based immune checkpoint inhibitors (ICIs). This platform is based on a simple structure of generation 7 (G7) poly(amidoamine) (PAMAM) dendrimers conjugated with engineered peptides (dendrimer‐peptide conjugates, DPCs). DPCs functionalized with multiple copies of a programmed death‐ligand 1 (PD‐L1)‐binding peptide exhibited significantly enhanced avidity‐based binding kinetics and in vitro specificity, in addition to the substantially prolonged plasma half‐life in vivo. Notably, a series of in vivo experiments revealed that DPCs displayed selective tumor accumulation and high efficacy, without apparent toxicity, when applied to a syngeneic mouse model bearing mouse oral carcinoma (MOC1) tumors. The results indicate that the DPC platform significantly improves the antagonistic effect and in vivo behaviors of the PD‐L1‐binding peptides, which can be potentially applied to virtually any peptide‐based ICIs. The DPC platform's simplicity and modular nature will likely increase the potential of its clinical translation and ultimately enable precision/personalized cancer immunotherapy.
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This content will become publicly available on May 19, 2026
The toxicity, uptake, and impact on galectin-3 mediated apoptosis of lactose functionalized PAMAM dendrimers
Poly(amidoamine) (PAMAM) dendrimers functionalized with ligands that are designed to interact with biological receptors are important macromolecules for the elucidation and mediation of biological recognition processes. Specifically, carbohydrate functionalized dendrimers are useful synthetic multivalent systems for the study of multivalent protein–carbohydrate interactions. For example, lactose functionalized glycodendrimers can be used to discern the function of galectins, galactoside-binding proteins that are often over-expressed during cancer progression. In order to effectively interpret cancer cellular assays using glycodendrimers, however, their properties in the presence of cells must first be assessed. Macromolecules that are taken up by cells would be expected to have access to many different cell signaling pathways and modes of action that solely extracellular macromolecules cannot utilize. In addition, macromolecules that display cellular toxicity could not be used as drug delivery vehicles. Here, we report fundamental studies of cellular toxicity, viability, and uptake with four generations of lactose functionalized PAMAM dendrimers. In all cases, the dendrimers are readily taken up by the cells but do not display any significant cellular toxicity. The glycodendrimers also increase cellular apoptosis, suggesting that they may abrogate the antiapoptotic protections afforded by galectin- 3 to cancer cells. The results reported here indicate that appropriately functionalized PAMAM dendrimers can be used as nontoxic tools for the study and mediation of both extra and intracellular cancer processes.
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- Award ID(s):
- 1214134
- PAR ID:
- 10633202
- Publisher / Repository:
- Royal Society of Chemistry
- Date Published:
- Journal Name:
- Materials Advances
- Volume:
- 6
- Issue:
- 10
- ISSN:
- 2633-5409
- Page Range / eLocation ID:
- 3171 to 3184
- Subject(s) / Keyword(s):
- glycodendrimers galectin-3 galectins apoptosis lactose-functionalized dendrimers confocal scanning laser microscopy
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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