کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1423675 | 1509033 | 2015 | 13 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Immunoglobulin Fc-fused, neuropilin-1-specific peptide shows efficient tumor tissue penetration and inhibits tumor growth via anti-angiogenesis Immunoglobulin Fc-fused, neuropilin-1-specific peptide shows efficient tumor tissue penetration and inhibits tumor growth via anti-angiogenesis](/preview/png/1423675.png)
Neuropilin-1 (NRP1) receptor, involved in vascular endothelial growth factor (VEGF)-mediated vascular permeability and tumor angiogenesis, is targeted by peptides that bind to its VEGF-binding site. However, these peptides also cross-react with the structurally related receptor, NRP2. Here, we describe an immunoglobulin Fc-fused peptide, Fc-TPP11, which specifically binds to the VEGF-binding site of NRP1 with approximately 2 nM affinity, but negligibly to that of NRP2. Fc-TPP11 triggered NRP1-dependent signaling, enhanced vascular permeability via vascular endothelial (VE)-cadherin downregulation, and increased paracellular permeability via E-cadherin downregulation in tumor tissues. Fc-TPP11 also significantly enhanced the tumor penetration of co-injected anti-cancer drug, doxorubicin, leading to the improved in vivo anti-tumor efficacy. Fc-TPP11 was easily adapted to the full-length anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab (Erbitux), cetuximab-TPP11, exhibiting more than 2-fold improved tumor penetration than the parent cetuximab. Fc-TPP11 exhibited a similar whole-body half-life to that of intact Fc in tumor bearing mice. In addition to the tumor-penetrating activity, Fc-TPP11 suppressed VEGF-dependent angiogenesis by blocking VEGF binding to NRP1, thereby inhibiting tumor growth without promoting metastasis in the mouse model. Our results show that NRP1-specific, high-affinity binding of Fc-TPP11, is useful to validate NRP1 signaling, independent of NRP2. Thus, Fc-TPP11 can be used as a tumor penetration-promoting agent with anti-angiogenic activity or directly adapted to mAb-TPP11 format for more potent anti-cancer antibody therapy.
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Journal: Journal of Controlled Release - Volume 216, 28 October 2015, Pages 56–68