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

Journal Article · · Journal of the American Chemical Society
DOI:https://doi.org/10.1021/jacs.5b05952· OSTI ID:1345983
 [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)
+ Show Author Affiliations

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.

Research Organization:
Univ. of Illinois at Urbana-Champaign, 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, Vol. 137, Issue 32; ISSN 0002-7863
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 14 works
Citation information provided by
Web of Science

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Cited By (2)

Polymer–drug conjugate therapeutics: advances, insights and prospects journal December 2018
Designing Dendrimer and Miktoarm Polymer Based Multi-Tasking Nanocarriers for Efficient Medical Therapy journal September 2015

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Related Subjects

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