{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T05:35:59Z","timestamp":1774071359269,"version":"3.50.1"},"reference-count":80,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T00:00:00Z","timestamp":1752451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Russian Science Foundation","award":["24-25-00104"],"award-info":[{"award-number":["24-25-00104"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>L-asparaginase (L-ASNase) remains a vital chemotherapeutic agent for acute lymphoblastic leukemia (ALL), primarily due to its mechanism of depleting circulating asparagine essential for leukemic cell proliferation. However, existing ASNases (including pegylated ones) face limitations including immunogenicity, rapid clearance, and off-target toxicities. Earlier, we have shown that the conjugation of L-ASNase with the polyamines and their copolymers results in significant enhancement of the antiproliferative activity due to accumulation in tumor cells. We suggested that this effect is probably mediated by polyamine transport system (PTS) receptors that are overexpressed in ALL cells. Here, we investigated the effect of competitive inhibitors of PTS receptors to the L-ASNase interaction with cancer cells (L5178Y, K562 and A549). L-ASNase from Rhodospirillum rubrum (RrA), Erwinia carotovora (EwA), and Escherichia coli (EcA) were conjugated with natural polyamines (spermine\u2014spm, spermidine\u2014spd, putrescine\u2014put) and a synthetic branched polymer, polyethyleneimine 2 kDa (PEI2 ), using carbodiimide chemistry. Polyamine conjugation with L-ASNase significantly increased enzyme binding and cellular uptake, as quantified by fluorimetry and confocal microscopy. This increased cellular uptake translated into increased cytotoxicity of L-ASNase conjugates. The presence of competitive ligands to PTS receptors decreased the uptake of polyamine-conjugated enzymes-fatty acid derivatives of polyamines produced the strongest suppression. Simultaneously with this suppression, in some cases, competitive ligands to PTS significantly promoted the uptake of the native unconjugated enzymes, \u201cequalizing\u201d the cellular access for native vs conjugated ASNase. The screening for competing inhibitors of PTS receptor-mediated endocytosis revealed spermine and caproate\/lipoate derivatives as the most potent inhibitors or antagonists, significantly reducing the cytostatic efficacy of polyamine-conjugated ASNases. The results obtained emphasize the complex, cell-type-dependent and inhibitor-specific nature of these interactions, which highlights the profound involvement of PTS in L-ASNase internalization and cytotoxic activity. These findings support the viability of polyamine conjugation as a strategy to enhance L-ASNase delivery and therapeutic efficacy by targeting the PTS.<\/jats:p>","DOI":"10.3390\/ijms26146749","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T09:45:52Z","timestamp":1752572752000},"page":"6749","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Receptor-Mediated Internalization of L-Asparaginase into Tumor Cells Is Suppressed by Polyamines"],"prefix":"10.3390","volume":"26","author":[{"given":"Igor D.","family":"Zlotnikov","sequence":"first","affiliation":[{"name":"Faculty of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1\/3, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6221-3093","authenticated-orcid":false,"given":"Alexander A.","family":"Ezhov","sequence":"additional","affiliation":[{"name":"Faculty of Physics, Lomonosov Moscow State University, Leninskie Gory, 1\/2, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9761-7757","authenticated-orcid":false,"given":"Elena V.","family":"Kudryashova","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1\/3, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1002\/cncr.25489","article-title":"L-asparaginase Treatment in Acute Lymphoblastic Leukemia","volume":"117","author":"Pieters","year":"2011","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1007\/s00280-014-2402-3","article-title":"a Asparaginase in the Treatment of Non-ALL Hematologic Malignancies","volume":"73","author":"Emadi","year":"2014","journal-title":"Cancer Chemother. 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