{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T01:02:23Z","timestamp":1791162143576,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Tumor extracellular matrix (ECM) is a high-capacity target for the precision delivery of affinity ligand-guided drugs and imaging agents. Recently, we developed a PL1 peptide (sequence: PPRRGLIKLKTS) for systemic targeting of malignant ECM. Here, we map the dynamics of PL1 binding to its receptors Fibronectin Extra Domain B (FN-EDB) and Tenascin C C-isoform (TNC-C) by computational modeling and cell-free binding studies on mutated receptor proteins, and study cellular binding and internalization of PL1 nanoparticles in cultured cells. Molecular dynamics simulation and docking analysis suggested that the engagement of PL1 peptide with both receptors is primarily driven by electrostatic interactions. Substituting acidic amino acid residues with neutral amino acids at predicted PL1 binding sites in FN-EDB (D52N-D49N-D12N) and TNC-C (D39N-D45N) resulted in the loss of binding of PL1 nanoparticles. Remarkably, PL1-functionalized nanoparticles (NPs) were not only deposited on the target ECM but bound the cells and initiated a robust cellular uptake via a pathway resembling macropinocytosis. Our studies establish the mode of engagement of the PL1 peptide with its receptors and suggest applications for intracellular delivery of nanoscale payloads. The outcomes of this work can be used for the development of PL1-derived peptides with improved stability, affinity, and specificity for precision targeting of the tumor ECM and malignant cells.<\/jats:p>","DOI":"10.3390\/pharmaceutics13121998","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T23:22:56Z","timestamp":1638314576000},"page":"1998","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["PL1 Peptide Engages Acidic Surfaces on Tumor-Associated Fibronectin and Tenascin Isoforms to Trigger Cellular Uptake"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8826-4531","authenticated-orcid":false,"given":"Prakash","family":"Lingasamy","sequence":"first","affiliation":[{"name":"Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"P\u00f5\u0161nograjeva","sequence":"additional","affiliation":[{"name":"Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1756-9327","authenticated-orcid":false,"given":"Sergei","family":"Kopanchuk","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Tartu, Ravila 14, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan","family":"Tobi","sequence":"additional","affiliation":[{"name":"Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7238-749X","authenticated-orcid":false,"given":"Ago","family":"Rinken","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Tartu, Ravila 14, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8346-6978","authenticated-orcid":false,"given":"Ignacio J.","family":"General","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8931-027X","authenticated-orcid":false,"given":"Eliana K.","family":"Asciutto","sequence":"additional","affiliation":[{"name":"School of Science and Technology, National University of San Martin (UNSAM), ICIFI and CONICET, 25 de Mayo y Francia, San Mart\u00edn 1650, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9458-6385","authenticated-orcid":false,"given":"Tambet","family":"Teesalu","sequence":"additional","affiliation":[{"name":"Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia"},{"name":"Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1124\/pr.109.001289","article-title":"Extracellular matrix molecules: Potential targets in pharmacotherapy","volume":"61","author":"Sainio","year":"2009","journal-title":"Pharmacol. 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