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Title: Ligand accessibility and bioactivity of a hormone–dendrimer conjugate depend on pH and pH history

Estrogen conjugates with a polyamidoamine (PAMAM) dendrimer have shown remarkably selective regulation of the nongenomic actions of estrogens in target cells in this paper. In response to pH changes, however, these estrogen–dendrimer conjugates (EDCs) display a major morphological transition that alters the accessibility of the estrogen ligands that compromises the bioactivity of the EDC. A sharp break in dynamic behavior near pH 7 occurs for three different ligands on the surface of a PAMAM-G6 dendrimer: a fluorophore (tetramethylrhodamine [TMR]) and two estrogens (17α-ethynylestradiol and diphenolic acid). Collisional quenching and time-resolved fluorescence anisotropy experiments with TMR–PAMAM revealed high ligand shielding above pH 7 and low shielding below pH 7. Furthermore, when the pH was cycled from 8.5 (conditions of ligand–PAMAM conjugation) to 4.5 (e.g., endosome/lysosome) and through 6.5 (e.g., hypoxic environment) back to pH 8.5, the 17α-ethynylestradiol– and diphenolic acid–PAMAM conjugates experienced a dramatic, irreversible loss in cell stimulatory activity; dynamic NMR studies indicated that the hormonal ligands had become occluded within the more hydrophobic core of the PAMAM dendrimer. Thus, the active state of these estrogen–dendrimer conjugates appears to be metastable. Finally, this pH-dependent irreversible masking of activity is of considerable relevance to the design of drug conjugates with amine-bearingmore » PAMAM dendrimers.« less
 [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [2] ;  [1] ;  [1]
  1. Univ. of Illinois at Urbana-Champaign, Urbana, IL (United States)
  2. IBS Center for Soft and Living Matter and UNIST, Ulsan (South Korea)
Publication Date:
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Journal of the American Chemical Society
Additional Journal Information:
Journal Volume: 137; Journal Issue: 32; Journal ID: ISSN 0002-7863
American Chemical Society (ACS)
Research Org:
Univ. of Illinois at Urbana-Champaign, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES; PAMAM dendrimer; estrogen receptor; estrogen-dendrimer conjugate; non-genomic gene expression; genomic gene expression; pH dependent estrogenic effect; proximity-ligated ERα and pMAPK complex; ERα-pMAPK complex; proximity ligation assay
OSTI Identifier: