title: Branched Polymer-Drug Conjugates for Multivalent Blockade of Angiotensin II Receptors.
abstract: 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 ARB molecules to branched polymers could vastly augment their therapeutic efficacy. EXP3174, a potent non-peptide ARB, 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 AT1R 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.
authors.affiliation: Department of Pharmaceutical Technology, University of Regensburg , Regensburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Hennig
authors.affiliation: Department of Pharmaceutical Technology, University of Regensburg , Regensburg, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Veser
authors.affiliation: Department of Pharmaceutical Technology, University of Regensburg , Regensburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kirchhof
authors.affiliation: Department of Pharmaceutical Technology, University of Regensburg , Regensburg, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Goepferich
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D006207:Half-Life; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D019808:Losartan; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D011945:Receptors, Angiotensin / Q000737:chemistry*; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D050091:Dendrimers; D004337:Drug Carriers; D007093:Imidazoles; D008024:Ligands; C104700:PAMAM Starburst; D011073:Polyamines; D011108:Polymers; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D011092:Polyethylene Glycols; C066026:losartan carboxylic acid; D019808:Losartan
keywords: EXP3174; PAMAM dendrimers; PEGylation; angiotensin receptor blocker; half-life extension; multivalency