Neuropilin-1-Targeted Cell-Penetrating Tandem Peptide–Drug Conjugate Exhibits Potent In Vivo Antiglioma and Antiangiogenic Activity
Year: 2026
Type: article
Abstract: Most therapeutics for brain malignancies are limited by poor blood-brain barrier (BBB) transport and inadequate tumor penetration. Combining a BBB-penetrating peptide (SynB3) with a neuropilin-1 (NRP-1) receptor-targeting peptide (tuftsin) offers a promising strategy to enhance brain delivery, glioma targeting, and tumor penetration. This study demonstrated that SynB3, tuftsin, and their tandem construct bind in silico to the NRP-1 b1 pocket, corresponding to the C-end rule motif interaction site. Their cellular internalization likely involves macropinocytosis. The peptides penetrated 3D glioma spheroids, and the attached cargo did not significantly modulate their penetration. Dau-conjugates consistently inhibited proliferation in four glioblastoma cell lines and showed adequate in vitro stability in mouse plasma. In a subcutaneous murine model, Dau-SynB3 and the tandem conjugate reduced tumor volume and weight, prolonged tumor doubling time, and demonstrated improved tolerability compared with free Dau. Both conjugates exhibited antiproliferative effects, while the tandem construct additionally showed antiangiogenic activity ex vivo
Source: Journal of Medicinal Chemistry
Institutions: National Institute of Oncology, Eötvös Loránd University, Consejo Superior de Investigaciones Científicas, Universidad de Zaragoza, Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, Centro de Investigación Biomédica en Red, Instituto de Nanociencia y Materiales de Aragón, Hungarian Research Network, Viện Sinh học, Institute of Physics, Institute of Physics, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Semmelweis University
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W7155000231