通过调节血小板-内皮细胞粘附分子-1 / CD31表位参与的协同增强纳米载体的内皮靶向。,ACS Nano

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通过调节血小板-内皮细胞粘附分子-1 / CD31表位参与的协同增强纳米载体的内皮靶向。
ACS Nano ( IF 15.8 ) Pub Date : 2015-07-13 00:00:00 , DOI: 10.1021/nn505672x
Ann-Marie Chacko , Jingyan Han , Colin F. Greineder , Blaine J. Zern , John L. Mikitsh , Madhura Nayak , Divya Menon , Ian H. Johnston ₁ , Mortimer Poncz ₁ , David M. Eckmann , Peter F. Davies , Vladimir R. Muzykantov

Affiliation

涂有针对跨膜糖蛋白PECAM（血小板内皮细胞粘附分子-1 / CD31）的细胞外表位的抗体（Abs）的纳米载体（NCs）可以将药物靶向递送至血管内皮细胞。最近的研究表明，针对PECAM相邻但不同表位的成对抗体在体外和体内均能刺激彼此与内皮细胞的结合（“协作增强”）。该现象改善了治疗性融合蛋白的靶向性，但尚未解决其在靶向多价NCs中的潜在作用。本文中，我们研究了Ab介导的协同增强作用对涂有PECAM Abs（Ab / NC，直径约180 nm）的多价NC球体的影响。我们发现PECAM Abs确实增强了成对但不是“自身” Ab包被的Ab / NC的内皮细胞结合。体外，成对的Abs协同增强Ab / NC的内皮结合的能力受Ab / NC亲和力，抗原决定簇选择和血流的调节。细胞固定而不是阻止内吞作用消除了Ab / NC结合的协同增强作用，表明该作用是由内皮细胞膜中PECAM分子的分子重组介导的。在体内证实了Ab / NC结合的协同增强。配对的Abs的血管内注射可将Ab / NC对小鼠肺血管的靶向性提高一个数量级。这种刺激作用大大超过了成对的Abs对Ab靶向的增强作用，表明与较大的多价载体相比，“协同增强”作用更为明显游离抗体，可能是由于表位可及性的积极改变所带来的更深远的后果。该现象为优化治疗剂的靶向内皮的纳米载体的输送提供了潜在的范例。

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Collaborative Enhancement of Endothelial Targeting of Nanocarriers by Modulating Platelet-Endothelial Cell Adhesion Molecule-1/CD31 Epitope Engagement

Nanocarriers (NCs) coated with antibodies (Abs) to extracellular epitopes of the transmembrane glycoprotein PECAM (platelet endothelial cell adhesion molecule-1/CD31) enable targeted drug delivery to vascular endothelial cells. Recent studies revealed that paired Abs directed to adjacent, yet distinct epitopes of PECAM stimulate each other’s binding to endothelial cells in vitro and in vivo (“collaborative enhancement”). This phenomenon improves targeting of therapeutic fusion proteins, yet its potential role in targeting multivalent NCs has not been addressed. Herein, we studied the effects of Ab-mediated collaborative enhancement on multivalent NC spheres coated with PECAM Abs (Ab/NC, ∼180 nm diameter). We found that PECAM Abs do mutually enhance endothelial cell binding of Ab/NC coated by paired, but not “self” Ab. In vitro, collaborative enhancement of endothelial binding of Ab/NC by paired Abs is modulated by Ab/NC avidity, epitope selection, and flow. Cell fixation, but not blocking of endocytosis, obliterated collaborative enhancement of Ab/NC binding, indicating that the effect is mediated by molecular reorganization of PECAM molecules in the endothelial plasmalemma. The collaborative enhancement of Ab/NC binding was affirmed in vivo. Intravascular injection of paired Abs enhanced targeting of Ab/NC to pulmonary vasculature in mice by an order of magnitude. This stimulatory effect greatly exceeded enhancement of Ab targeting by paired Abs, indicating that ‘“collaborative enhancement”’ effect is even more pronounced for relatively large multivalent carriers versus free Abs, likely due to more profound consequences of positive alteration of epitope accessibility. This phenomenon provides a potential paradigm for optimizing the endothelial-targeted nanocarrier delivery of therapeutic agents.

更新日期：2015-07-13

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