Inhibitor-GCPII Interaction: Selective and Robust System for Targeting Cancer Cells with Structurally Diverse Nanoparticles
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- GCPII, PSMA, cell, click chemistry, inhibitor, multivalent binding, nanodiamond, nonspecific interaction, polymer, targeting, virus-like particle,
- MeSH
- Antigens, Surface metabolism MeSH
- Click Chemistry MeSH
- Chemistry, Pharmaceutical MeSH
- Glutamate Carboxypeptidase II antagonists & inhibitors metabolism MeSH
- Hydrophobic and Hydrophilic Interactions MeSH
- Enzyme Inhibitors administration & dosage MeSH
- Humans MeSH
- Ligands MeSH
- Cell Line, Tumor MeSH
- Neoplasms drug therapy pathology MeSH
- Nanoconjugates chemistry MeSH
- Antineoplastic Agents administration & dosage MeSH
- Recombinant Proteins metabolism MeSH
- Thiazolidines chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 2-mercaptothiazoline MeSH Browser
- Antigens, Surface MeSH
- FOLH1 protein, human MeSH Browser
- Glutamate Carboxypeptidase II MeSH
- Enzyme Inhibitors MeSH
- Ligands MeSH
- Nanoconjugates MeSH
- Antineoplastic Agents MeSH
- Recombinant Proteins MeSH
- Thiazolidines MeSH
Glutamate carboxypeptidase II (GCPII) is a membrane protease overexpressed by prostate cancer cells and detected in the neovasculature of most solid tumors. Targeting GCPII with inhibitor-bearing nanoparticles can enable recognition, imaging, and delivery of treatments to cancer cells. Compared to methods based on antibodies and other large biomolecules, inhibitor-mediated targeting benefits from the low molecular weight of the inhibitor molecules, which are typically stable, easy-to-handle, and able to bind the enzyme with very high affinity. Although GCPII is established as a molecular target, comparing previously reported results is difficult due to the different methodological approaches used. In this work, we investigate the robustness and limitations of GCPII targeting with a diverse range of inhibitor-bearing nanoparticles (various structures, sizes, bionanointerfaces, conjugation chemistry, and surface densities of attached inhibitors). Polymer-coated nanodiamonds, virus-like particles based on bacteriophage Qβ and mouse polyomavirus, and polymeric poly(HPMA) nanoparticles with inhibitors attached by different means were synthesized and characterized. We evaluated their ability to bind GCPII and interact with cancer cells using surface plasmon resonance, inhibition assay, flow cytometry, and confocal microscopy. Regardless of the diversity of the investigated nanosystems, they all strongly interact with GCPII (most with low picomolar Ki values) and effectively target GCPII-expressing cells. The robustness of this approach was limited only by the quality of the nanoparticle bionanointerface, which must be properly designed by adding a sufficient density of hydrophilic protective polymers. We conclude that the targeting of cancer cells overexpressing GCPII is a viable approach transferable to a broad diversity of nanosystems.
References provided by Crossref.org
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