Branched Polymer-Drug Conjugates for Multivalent Blockade of Angiotensin II Receptors.
Branched Polymer-Drug Conjugates for Multivalent Blockade of Angiotensin II Receptors.
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DOI：
10.1021/acs.molpharmaceut.5b00301
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发表时间：
2015-08
影响因子：
4.9
通讯作者：
R. Hennig;Anika Veser;S. Kirchhof;A. Goepferich
中科院分区：
文献类型：
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作者：
R. Hennig;Anika Veser;S. Kirchhof;A. Goepferich
血管紧张素受体阻滞剂(ARB)用于治疗与新生血管相关的眼部疾病，如增殖性糖尿病视网膜病变，显示出巨大的前景，但由于玻璃体内半衰期较短，目前受到限制。ARB分子与支化聚合物的偶联可以极大地提高它们的治疗效果。EXP3174是一种有效的非肽ARB，它与支化的聚乙二醇(PEG)和聚酰胺胺(PAMAM)树枝状大分子偶联：每40 kDa的聚乙二醇分子上连接7.8个配体分子，而每个PAMAM第五代树枝状大分子上连接16.7个配体分子。多价聚乙二醇胺和PAMAM结合物阻断AT1R信号转导，其IC50分别为224和36.3 nM。多价配体偶联的PAMAM树状大分子的亲和力提高了6倍，这是由于它们独特的微结构和抑制聚合物-药物相互作用的能力。值得注意的是，这两种聚合物-药物结合物都没有细胞毒性，这与普通的PAMAM树枝状大分子形成鲜明对比。由于具有足够长的玻璃体半衰期，两种合成的聚合物-ARB结合物都有可能为伴随视网膜新生血管的眼部疾病的治疗铺平一条新的道路。
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.