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This study aimed to investigate the cytotoxic activity, antitrypanosomal efficacy, and combination effects with benznidazole of hybrid silver nanoparticles (AgNPs) synthesized with miltefosine against\n                      <jats:italic>T. cruzi<\/jats:italic>\n                      epimastigotes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, a hybrid miltefosine (Mil)-silver nanoparticle (OA-MilAg-NP) complex was synthesized. The nanoparticles were characterized using FT-IR spectroscopy, transmission electron microscopy (TEM), and scanning electron microscopy (SEM) analyses. The cytotoxicity of the nanoparticles was assessed in L929 fibroblast cells, while their antitrypanosomal activity was evaluated against a\n                      <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                      ATCC 50828 strain using the broth microdilution method. The interaction between the nanoparticle complex or miltefosine and benznidazole was analyzed using the checkerboard method.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>FT-IR analysis demonstrated that the amylose surface was successfully coated with silver and miltefosine, confirming the successful synthesis of the hybrid complex. SEM analysis revealed that the nanoparticles exhibited a spherical morphology with varying sizes, while TEM analysis determined their sizes ranged between 10.14 and 18.42\u00a0nm. The OA-MilAg-NP complex exhibited high antitrypanosomal activity and a selectivity index twice as high as that of miltefosine. Synergistic interactions were observed in the combinations of the OA-MilAg-NP complex or miltefosine with benznidazole.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The development of novel bioactive compounds with lower toxicity compared to traditional drugs has become essential for the treatment of Chagas disease. Drug repurposing combined with nanotechnology applications holds significant potential for improving therapeutic outcomes. The hybridization of miltefosine with silver nanoparticles, demonstrating strong antitrypanosomal activity and synergistic effects with benznidazole, may fill critical gaps in the literature.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                    <jats:p>\n                      In this study, oxidized amylose-miltefosine-silver (OA-MilAg-NP) hybrid nanoparticles were synthesized. The characterization of the nanoparticles was performed using FTIR, SEM, and TEM analyses. The cytotoxicity of the hybrid OA-MilAg-NPs was evaluated on the L929 fibroblast cell line. The antitrypanosomal activity of the synthesized nanoparticles against\n                      <jats:italic>T. cruzi<\/jats:italic>\n                      isolates was determined using the in vitro broth microdilution method, while their synergy with benznidazole was assessed using the checkerboard method.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11686-025-01074-3","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T06:33:31Z","timestamp":1749710011000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis and Evaluation of a Hybrid Miltefosine-Silver Nanoparticle Complex: Synergistic Interaction with Benznidazole Against Trypanosoma cruzi"],"prefix":"10.1007","volume":"70","author":[{"given":"Yener","family":"\u00d6zel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0130brahim","family":"\u00c7avu\u015f","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feyzullah","family":"Tokay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sema","family":"Ba\u011fdat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet","family":"\u00d6zbilgin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"1074_CR1","unstructured":"WHO. 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