{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:06:54Z","timestamp":1789020414428,"version":"build-2803163510"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:p>\n                    Doxorubicin (DOX) is a cornerstone anthracycline in breast cancer therapy, but its use is constrained by cumulative cardiotoxicity. We asked whether conjugation to a guanidinium-rich cell-penetrating peptidomimetic widens the window between anticancer activity and cardiomyocyte toxicity, or merely rescales potency. DOX was linked by azide\u2013alkyne click chemistry to an eight-guanidinium peptidomimetic, H-O2Oc-[Dap(GO\n                    <jats:sub>2<\/jats:sub>\n                    )]\n                    <jats:sub>8<\/jats:sub>\n                    -O2Oc-NH\n                    <jats:sub>2<\/jats:sub>\n                    , through either a hexynoyl linker (CuAAC; DOX-ACA-HEX-G8) or a dibenzocyclooctyne linker (SPAAC; DOX-ACA-DBCO-G8), so that the pair differs in a single variable. Both conjugates and free DOX were tested in three-dimensional spheroids of HER2-positive SKBR3, triple-negative MDA-MB-231, non-tumorigenic mammary epithelium (HB2) and human AC16 cardiomyocytes (0.5\u201350\u00a0\u03bcM; 24, 48 and 72\u00a0h; CellTiter-Glo 3D), and in a three-read-out control panel (LDH, ATP, DNA). Free DOX was potent but non-selective, killing SKBR3, HB2 and AC16 with comparable 72\u00a0h IC\n                    <jats:sub>50<\/jats:sub>\n                    values (&amp;lt;0.5, 0.78 and &amp;lt;0.5\u00a0\u00b5M) and leaving no meaningful window. DOX-ACA-HEX-G8 matched DOX against SKBR3 at 48\u201372\u00a0h (IC\n                    <jats:sub>50<\/jats:sub>\n                    &amp;lt; 0.5\u00a0\u00b5M) while being 15-fold (HB2) and &amp;gt;18-fold (AC16) less toxic to the non-malignant lines. Because the SKBR3 IC\n                    <jats:sub>50<\/jats:sub>\n                    is censored for both DOX and DOX-ACA-HEX-G8, their selectivity indices cannot be compared; the window is therefore established directly at matched concentration, without extrapolation: at 0.5 \u00b5M\/72\u00a0h free DOX left SKBR3 at 6% and AC16 at 14% of control (an 8-percentage-point separation), whereas DOX-ACA-HEX-G8 left SKBR3 at 32% and AC16 at 122% (90 percentage points). The linker-matched DOX-ACA-DBCO-G8 was less selective, showing the effect tracks with linker chemistry. In the triple-negative model, DOX-ACA-HEX-G8 gave no window at all, and DOX-ACA-DBCO-G8 only a marginal one (selectivity index 1.6 for AC16 and 2.3 for HB2, both versus MDA-MB-231), although both conjugates were internalized. Both produced a pronounced low-dose hormetic signal in the non-malignant lines; a cell-free spike-recovery control excluded an artifact of the luminescence read-out, and the biomass read-out excluded proliferation, so the effect is metabolic and its mechanism remains open. DOX-ACA-HEX-G8 is a lead for anthracycline delivery with reduced acute cardiomyocyte toxicity, contingent on mechanistic studies of uptake and drug release.\n                  <\/jats:p>","DOI":"10.3389\/fchem.2026.1945333","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:31:33Z","timestamp":1789018293000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Guanidinium-rich cell-penetrating peptidomimetic\u2013doxorubicin conjugates show linker-dependent, reduced acute toxicity to cardiomyocytes and normal breast epithelium while retaining activity against a HER2-positive breast cancer model (SKBR3 spheroids)"],"prefix":"10.3389","volume":"14","author":[{"given":"Wiktoria","family":"Mallek","sequence":"first","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk","place":["Gda\u0144sk, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Bublewicz","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk","place":["Gda\u0144sk, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Mirecka","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk","place":["Gda\u0144sk, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kajetan","family":"Godzi\u0105tkowski","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk","place":["Gda\u0144sk, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Piwkowska","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences","place":["Gda\u0144sk, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Lesner","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk","place":["Gda\u0144sk, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Wysocka","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Gda\u0144sk","place":["Gda\u0144sk, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"93","DOI":"10.3390\/mps8040093","article-title":"Optimizing cell density and unveiling cytotoxic profiles of DMSO and ethanol in six cancer cell lines: experimental and in silico insights","volume":"8","author":"Asiri","year":"2025","journal-title":"Methods Protoc."},{"key":"B2","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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