Ligand accessibility and bioactivity of a hormone?dendrimer conjugate depend on pH and pH history [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 547.7 Macromolecules and related compounds
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2015
• Mô tả vật lý: Size: p. 10326-10335 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 261127
• Chủ đề: 1. 37 inorganic, organic, physical, and analytical chemistry; 2. 60 applied life sciences; 3. Er?-pmapk complex; 4. Estrogen receptor; 5. Estrogen-dendrimer conjugate; 6. Et al; 7. Genomic gene expression; 8. Non-genomic gene expression; 9. Pamam dendrimer; 10. Ph dependent estrogenic effect; 11. Proximity-ligated er? and pmapk complex

Tóm tắt

 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 (17?-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?-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.