Dendrimers and hyperbranched polymers for controlling nuclear hormone receptor localization

Date
2017
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Publisher
University of Delaware
Abstract
Nuclear hormone receptors (NHR) are transcription factors that activate gene expression in the presence of hormones. Misregulation of NHRs has been associated with certain types of cancer. Treatment often involves the use of drugs which bind to the receptor, but disrupt gene transcription in some way, hindering proliferation. While these treatments are often effective initially, they are susceptible to resistance. In some instances, resistance caused by NHR mutations can lead to antagonists having agonist effects, increasing cell viability and proliferation instead of suppressing it. Previous studies in the Koh group have demonstrated that controlling the cellular localization of the nuclear hormone receptor, Androgen Receptor, to favor cytoplasmic localization, was possible and effective as a new previously unexplored therapeutic strategy. This was accomplished by attaching AR binding ligands to the surface of PAMAM dendrimers. PAMAM dendrimers are hyperbranched polymers that enter cells but are excluded from the nucleus. PAMAM-antiandrogen conjugates kept the Androgen Receptor in the cytoplasm, away from the nucleus, preventing the receptor from activating growth and survival genes and decreasing cell viability of androgen-dependent cancer cells. ☐ In this work, localization experiments were attempted on Estrogen Receptor (ER), to test if similar results could be obtained on a related biological system. Though structurally and functionally similar to AR, unliganded ER is found in the nucleus instead of the cytoplasm. While the ligands used for ER had a binding affinity several fold better than those used with AR, treatment with dendrimer conjugates was unsuccessful in affecting the cellular localization of ER. However, the use of smaller dendrimers which can enter the nucleus may still prove effective as ER modulators worthy of future study. ☐ Additionally, hyperbranched polyglycerol was investigated as a possible substitute for expensive PAMAM dendrimers for localization experiments. The surface groups of hyperbranched polyglycerol were modified from hydroxyl to amine groups and then covalently modified to contain rhodamine to image by microscopy. It was found that the hyperbranched polymers studied could enter cells and were of appropriate size to be excluded from the nucleus. These preliminary results suggest hyperbranched polyglycerol could potentially be used as a less expensive and more versatile PAMAM dendrimer substitute.
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Pure sciences
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