期刊
MOLECULAR PHARMACEUTICS
卷 12, 期 9, 页码 3292-3302出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.5b00301
关键词
angiotensin receptor blocker; half-life extension; PEGylation; PAMAM dendrimers; EXP3174; multivalency
资金
- Deutsche Forschungsgemeinschaft: DFG [GO565/18-1]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据