Collaborative Enhancement of Endothelial Targeting of Nanocarriers by Modulating Platelet-Endothelial Cell Adhesion Molecule-1/CD31 Epitope Engagement
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- 作者：Ann-Marie Chacko ; Jingyan Han ; Colin F. Greineder ; Blaine J. Zern ; John L. Mikitsh ; Madhura Nayak ; Divya Menon ; Ian H. Johnston ; Mortimer Poncz ; David M. Eckmann ; Peter F. Davies ; Vladimir R. Muzykantov
- 刊名：ACS Nano
- 出版年：2015
- 出版时间：July 28, 2015
- 年：2015
- 卷：9
- 期：7
- 页码：6785-6793
- 全文大小：574K
- ISSN：1936-086X
文摘
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鈥檚 binding to endothelial cells in vitro and in vivo (鈥渃ollaborative enhancement鈥?. 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, 鈭?80 nm diameter). We found that PECAM Abs do mutually enhance endothelial cell binding of Ab/NC coated by paired, but not 鈥渟elf鈥?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 鈥樷€渃ollaborative enhancement鈥濃€?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.