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

Kim, Sung Hoon; Madak-Erdogan, Zeynep; Bae, Sung Chul; Carlson, Kathryn E.; Mayne, Christopher G.; Granick, Steve; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.

doi:10.1021/jacs.5b05952

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

Journal Article · Fri Jul 17 00:00:00 EDT 2015 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.5b05952· OSTI ID:1345983

Kim, Sung Hoon ^[1]; Madak-Erdogan, Zeynep ^[2]; Bae, Sung Chul ^[3]; Carlson, Kathryn E. ^[2]; Mayne, Christopher G. ^[2]; Granick, Steve ^[3]; Katzenellenbogen, Benita S. ^[2]; Katzenellenbogen, John A. ^[2]

Univ. of Illinois at Urbana-Champaign, Urbana, IL (United States); Office of Scientific and Technical Information (OSTI)
Univ. of Illinois at Urbana-Champaign, Urbana, IL (United States)
IBS Center for Soft and Living Matter and UNIST, Ulsan (South Korea)

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-bearing PAMAM dendrimers.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of Illinois, Urbana, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: FG02-02ER46019

OSTI ID:: 1345983

Journal Information:: Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 32 Vol. 137; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
ERα-pMAPK complex
PAMAM dendrimer
estrogen receptor
estrogen-dendrimer conjugate
genomic gene expression
non-genomic gene expression
pH dependent estrogenic effect
proximity ligation assay
proximity-ligated ERα and pMAPK complex

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

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References (39)

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