Neuropilin-1-Targeted Cell-Penetrating Tandem Peptide–Drug Conjugate Exhibits Potent In Vivo Antiglioma and Antiangiogenic Activity
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
Authors
- Szilvia Bősze (ORCID: https://orcid.org/0000-0001-9555-699X)
- Előd Méhes (ORCID: https://orcid.org/0000-0003-2697-907X)
- Bálint Jezsó (ORCID: https://orcid.org/0000-0002-1306-4797)
- Zsuzsa Baranyai (ORCID: https://orcid.org/0000-0002-2174-6747)
- Beáta Biri‐Kovács (ORCID: https://orcid.org/0000-0001-5803-9969)
- József Tóvári (ORCID: https://orcid.org/0000-0002-5543-3204)
- Ivan Ranđelović (ORCID: https://orcid.org/0000-0003-0161-0022)
- Bence Stipsicz
- Levente Lakatos
- Sára Surguta (ORCID: https://orcid.org/0000-0002-8735-3962)
- Lilla Horváth
Institutions
- Semmelweis University (HU)
- Eötvös Loránd University (HU)
- Universidad de Zaragoza (ES)
- Laboratory of Molecular Genetics (PL)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (ES)
- National Center for Tumor Diseases (DE)
- Department of Physics, Mathematics and Informatics (BY)
- Károly Róbert University College (HU)
- National Institute of Oncology (HU)
- National Public Health Laboratory (NP)
- Instituto de Nanociencia y Materiales de Aragón (ES)
- Momentum Research (US)
- Institute of Molecular Life Sciences (HU)
- Institute of Physics of the Slovak Academy of Sciences (SK)
- Hungarian Academy of Sciences (HU)
- HUN-REN Research Centre for Natural Sciences (HU)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-04-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03835
- Primary Topic
- Angiogenesis and VEGF in Cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00