Hennig, Robert and Veser, Anika and Kirchhof, Susanne and Goepferich, Achim (2015) Branched Polymer-Drug Conjugates for Multivalent Blockade of Angiotensin II Receptors. MOLECULAR PHARMACEUTICS, 12 (9). pp. 3292-3302. ISSN 1543-8384,
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The use of angiotensin receptor blockers (ARBs) for treatment of ocular diseases associated with neovascularizations, such as proliferative diabetic retinopathy, shows tremendous promise but is presently limited due to short intravitreal half-life. Conjugation of ARE molecules to branched polymers could vastly augment their therapeutic efficacy. EXP3174, a potent non-peptide ARE, was conjugated to branched poly(ethylene glycol) (PEG) and poly(amido amine) (PAMAM) dendrimers: 7.8 ligand molecules were tethered to each 40 kDa PEG molecule whereas 16.7 ligand molecules were linked to each PAMAM generation 5 dendrimer. The multivalent PEG and PAMAM conjugates blocked AT(1)R signaling with an IC50 of 224 and 36.3 nM, respectively. The 6-fold higher affinity of the multivalent ligand-conjugated PAMAM dendrimers was due to their unique microarchitecture and ability to suppress polymer-drug interactions. Remarkably, both polymer-drug conjugates exhibited no cytotoxicity, in stark contrast to plain PAMAM dendrimers. With sufficiently long vitreous half-lives, both synthesized polymer-ARB conjugates have the potential to pave a new path for the therapy of ocular diseases accompanied by retinal neovascularizations.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ENDOTHELIAL GROWTH-FACTOR; PRELIMINARY BIOLOGICAL EVALUATION; PAMAM DENDRIMERS; POLY(AMIDOAMINE) DENDRIMERS; RETINAL NEOVASCULARIZATION; TYPE-1 RECEPTOR; HUMAN PLASMA; BINDING; PHARMACOKINETICS; FLUORESCENCE; angiotensin receptor blocker; half-life extension; PEGylation; PAMAM dendrimers; EXP3174; multivalency |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical Technology (Prof. Göpferich) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Jun 2019 13:23 |
| Last Modified: | 12 Jun 2019 13:23 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4918 |
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