Protease-activated CendR peptides targeting tenascin-C: mitigating off-target tissue accumulation.

Autor: Tobi A; Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, 50411, Tartu, Estonia., Haugas M; Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, 50411, Tartu, Estonia., Rabi K; Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, 50411, Tartu, Estonia., Sethi J; Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, 50411, Tartu, Estonia., Põšnograjeva K; Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, 50411, Tartu, Estonia., Paiste P; Department of Geology, Institute of Ecology and Earth Sciences, University of Tartu, Ravila 14A, 50411, Tartu, Estonia., Jagomäe T; Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, 50411, Tartu, Estonia., Pleiko K; Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, 50411, Tartu, Estonia., Lingasamy P; Competence Centre on Health Technologies, Teaduspargi 13, 50411, Tartu, Estonia., Teesalu T; Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, 50411, Tartu, Estonia. tambet.teesalu@ut.ee.; Materials Research Laboratory, University of California, Santa Barbara, CA, 93106, USA. tambet.teesalu@ut.ee.
Jazyk: angličtina
Zdroj: Drug delivery and translational research [Drug Deliv Transl Res] 2024 Oct; Vol. 14 (10), pp. 2945-2961. Date of Electronic Publication: 2024 Jul 16.
DOI: 10.1007/s13346-024-01670-2
Abstrakt: To achieve precision and selectivity, anticancer compounds and nanoparticles (NPs) can be targeted with affinity ligands that engage with malignancy-associated molecules in the blood vessels. While tumor-penetrating C-end Rule (CendR) peptides hold promise for precision tumor delivery, C-terminally exposed CendR peptides can accumulate undesirably in non-malignant tissues expressing neuropilin-1 (NRP-1), such as the lungs. One example of such promiscuous peptides is PL3 (sequence: AGRGRLVR), a peptide that engages with NRP-1 through its C-terminal CendR element, RLVR.Here, we report the development of PL3 derivatives that bind to NRP-1 only after proteolytic processing by urokinase-type plasminogen activator (uPA), while maintaining binding to the other receptor of the peptide, the C-domain of tenascin-C (TNC-C). Through a rational design approach and screening of a uPA-treated peptide-phage library (PL3 peptide followed by four random amino acids) on the recombinant NRP-1, derivatives of the PL3 peptide capable of binding to NRP-1 only post-uPA processing were successfully identified. In vitro cleavage, binding, and internalization assays, along with in vivo biodistribution studies in orthotopic glioblastoma-bearing mice, confirmed the efficacy of two novel peptides, PL3uCendR (AGRGRLVR↓SAGGSVA) and SKLG (AGRGRLVR↓SKLG), which exhibit uPA-dependent binding to NRP-1, reducing off-target binding to healthy NRP-1-expressing tissues. Our study not only unveils novel uPA-dependent TNC-C targeting CendR peptides but also introduces a broader paradigm and establishes a technology for screening proteolytically activated tumor-penetrating peptides.
(© 2024. The Author(s).)
Databáze: MEDLINE
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