Three-Dimensional Directionality Is a Pivotal Structural Feature for the Bioactivity of Azabisphosphonate-Capped Poly(PhosphorHydrazone) Nanodrug Dendrimers,Biomacromolecules

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Three-Dimensional Directionality Is a Pivotal Structural Feature for the Bioactivity of Azabisphosphonate-Capped Poly(PhosphorHydrazone) Nanodrug Dendrimers
Biomacromolecules ( IF 5.5 ) Pub Date : 2018-02-14 00:00:00 , DOI: 10.1021/acs.biomac.7b01398
Myriam Hayder ₁ , Matteo Garzoni ₂ , Davide Bochicchio ₂ , Anne-Marie Caminade _{3,

4} , François Couderc ₅ , Varravaddheay Ong-Meang ₅ , Jean-Luc Davignon ₁ , Cédric-Olivier Turrin _{3,

4} , Giovanni M. Pavan ₂ , Rémy Poupot ₁

Affiliation

Dendrimers are nanosized, nonlinear, hyperbranched polymers whose overall 3D shape is key for their biological activity. Poly(PhosphorHydrazone) (PPH) dendrimers capped with aza-bisphosphonate (ABP) end groups are known to have anti-inflammatory properties enabling the control of inflammatory diseases in different mouse models. Here we screen the anti-inflammatory activity of a series of PPH dendrimers bearing between 2 and 16 ABP end groups in a mouse model of arthritis and confront the biological results with atomistic simulations of the dendrimers. We show that only the PPH dendrimers capped with 10 and 12 ABP end groups can control the flare of the inflammatory disease. All-atom accelerated molecular dynamics simulations show that dendrimers with a low number of ABP end groups are directional but highly flexible/dynamic and have thereby limited efficiency in establishing multivalent interactions. The largest dendrimer appears as nondirectional, having 16 ABP end groups forming patches all over the dendrimer surface. Conversely, intermediate dendrimers having 10 or 12 ABP end groups reach the best compromise between the number of surface groups and their stable directional gathering, a real maximization of multivalency.

中文翻译：

三维方向性是Azabisphosphonate封端的聚（Ph）纳米药物树状聚合物的生物活性的关键结构特征。

树枝状聚合物是纳米级，非线性，超支化聚合物，其整体3D形状是其生物活性的关键。已知被氮杂双膦酸酯（ABP）端基封端的聚（PhosphorHydrazone）（PPH）树状聚合物具有抗炎特性，可以控制不同小鼠模型中的炎性疾病。在这里，我们筛选了关节炎小鼠模型中一系列带有2至16个ABP端基的PPH树状聚合物的抗炎活性，并通过树状分子的原子模拟来面对生物学结果。我们显示，只有以10和12个ABP端基封端的PPH树状聚合物才能控制发炎性疾病的发作。全原子加速的分子动力学模拟表明，具有少量ABP端基的树状聚合物具有方向性，但具有高度的柔韧性/动态性，因此建立多价相互作用的效率受到限制。最大的树枝状聚合物表现为无方向性，具有16个ABP端基，在整个树枝状聚合物表面上形成斑块。相反，具有10个或12个ABP端基的中间树枝状聚合物在表面基团的数量与其稳定的方向聚集之间达到了最佳折衷，这是多价的真正最大化。

更新日期：2018-02-14

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