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첨단연성물질 연구단
첨단연성물질 연구단
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Ligand Accessibility and Bioactivity of a Hormone-Dendrimer Conjugate Depend on pH and pH History

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Title
Ligand Accessibility and Bioactivity of a Hormone-Dendrimer Conjugate Depend on pH and pH History
Author(s)
Kim, SH; Madak-Erdogan, Z; Sung Chul Bae; Carlson, KE; Mayne, CG; Steve Granick; Katzenellenbogen, BS; Katzenellenbogen, JA
Publication Date
2015-08
Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.137, no.32, pp.10326 - 10335
Publisher
AMER CHEMICAL SOC
Abstract
Estrogen conjugates with a polyamidoamine (PAMAM) dendrimer have shown remarkably selective regulation of the nongenomic actions of estrogens in target cells. 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 (17 alpha-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 17 alpha-ethynylestradiol- and diphenolic acid-PAMAM conjugates experienced a draniatic, 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. This pH-dependent irreversible masking of activity is of considerable relevance to the design of drug conjugates with amine-bearing PAMAM dendrimers
URI
https://pr.ibs.re.kr/handle/8788114/1915
ISSN
0002-7863
Appears in Collections:
Center for Soft and Living Matter(첨단연성물질 연구단) > Journal Papers (저널논문)
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