Nanostructured Lipoxin A4: Understanding Its Biological Behavior and Impact on Alzheimer’s Disease (Proof of Concept)
<b>Background/Objectives</b>: Lipoxins, particularly Lipoxin A4 (LXA4), are endogenous lipid mediators with potent anti-inflammatory and pro-resolving properties, making them promising candidates for the treatment of inflammatory and neurodegenerative disorders. However, their therapeuti...
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| author | Natália Cristina Gomes-da-Silva Isabelle Xavier-de-Britto Marilia Amável Gomes Soares Natalia Mayumi Andrade Yoshihara Derya Ilem Özdemir Eduardo Ricci-Junior Pierre Basílio Almeida Fechine Luciana Magalhães Rebelo Alencar Maria das Graças Muller de Oliveira Henriques Thereza Christina Barja-Fidalgo Cristian Follmer Ralph Santos-Oliveira |
| author_facet | Natália Cristina Gomes-da-Silva Isabelle Xavier-de-Britto Marilia Amável Gomes Soares Natalia Mayumi Andrade Yoshihara Derya Ilem Özdemir Eduardo Ricci-Junior Pierre Basílio Almeida Fechine Luciana Magalhães Rebelo Alencar Maria das Graças Muller de Oliveira Henriques Thereza Christina Barja-Fidalgo Cristian Follmer Ralph Santos-Oliveira |
| author_sort | Natália Cristina Gomes-da-Silva |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: Lipoxins, particularly Lipoxin A4 (LXA4), are endogenous lipid mediators with potent anti-inflammatory and pro-resolving properties, making them promising candidates for the treatment of inflammatory and neurodegenerative disorders. However, their therapeutic application is limited by poor stability and bioavailability. This study aimed to develop and characterize nanomicelles encapsulating LXA4 (nano-lipoxin A4) to improve its pharmacological efficacy against Alzheimer’s disease (AD), a neurodegenerative condition marked by chronic inflammation and beta-amyloid (Aβ) accumulation. <b>Methods</b>: Nano-lipoxin A4 was synthesized using Pluronic F-127 as a carrier and characterized in terms of morphology, physicochemical stability, and in vitro activity against Aβ fibrils. Dissociation of Aβ fibrils was assessed via Thioflavin-T fluorescence assays and transmission electron microscopy. In vivo biodistribution and pharmacokinetic profiles were evaluated using technetium-99m-labeled nano-lipoxin A4 in rodent models. Hepatic biochemical parameters were also measured to assess potential systemic effects. <b>Results</b>: In vitro studies demonstrated that nano-lipoxin A4 effectively dissociated Aβ fibrils at concentrations of 50 nM and 112 nM. Electron microscopy confirmed the disruption of fibrillar structures. In vivo imaging revealed predominant accumulation in the liver and spleen, consistent with reticuloendothelial system uptake. Pharmacokinetic analysis showed a prolonged half-life (63.95 h) and low clearance rate (0.001509 L/h), indicating sustained systemic presence. Biochemical assays revealed elevated liver enzyme levels, suggestive of increased hepatic metabolism or potential hepatotoxicity. <b>Conclusions</b>: Nano-lipoxin A4 exhibits significant therapeutic potential for Alzheimer’s disease through effective modulation of Aβ pathology and favorable pharmacokinetic characteristics. However, the elevation in liver enzymes necessitates further investigation into systemic safety to support clinical translation. |
| format | Article |
| id | doaj-art-a00dbeefb3504d3296e447f7a65ad672 |
| institution | OA Journals |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-a00dbeefb3504d3296e447f7a65ad6722025-08-20T02:33:55ZengMDPI AGPharmaceutics1999-49232025-05-0117564910.3390/pharmaceutics17050649Nanostructured Lipoxin A4: Understanding Its Biological Behavior and Impact on Alzheimer’s Disease (Proof of Concept)Natália Cristina Gomes-da-Silva0Isabelle Xavier-de-Britto1Marilia Amável Gomes Soares2Natalia Mayumi Andrade Yoshihara3Derya Ilem Özdemir4Eduardo Ricci-Junior5Pierre Basílio Almeida Fechine6Luciana Magalhães Rebelo Alencar7Maria das Graças Muller de Oliveira Henriques8Thereza Christina Barja-Fidalgo9Cristian Follmer10Ralph Santos-Oliveira11Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro 21941906, RJ, BrazilLaboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro 21941906, RJ, BrazilLaboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro 21941906, RJ, BrazilLaboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro 21941906, RJ, BrazilFaculty of Pharmacy, Department of Radiopharmacy, Ege University, Bornova, Izmir 35040, TurkeySchool of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941900, RJ, BrazilGroup of Chemistry of Advanced Materials (GQMat), Department of Analytical Chemistry and Physical-Chemistry, Federal University of Ceará, Fortaleza 451970, CE, BrazilBiophysics and Nanosystems Laboratory, Department of Physics, Federal University of Maranhão, São Luis 65065690, MA, BrazilLaboratory of Cellular & Molecular Pharmacology, Department of Cell Biology, Instituto de Biologia Roberto Alcantara Gomes (IBRAG), Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20551030, RJ, BrazilLaboratory of Cellular & Molecular Pharmacology, Department of Cell Biology, Instituto de Biologia Roberto Alcantara Gomes (IBRAG), Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20551030, RJ, BrazilLaboratory of Biological Chemistry of Neurodegenerative Disorders, Department of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941909, RJ, BrazilLaboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro 21941906, RJ, Brazil<b>Background/Objectives</b>: Lipoxins, particularly Lipoxin A4 (LXA4), are endogenous lipid mediators with potent anti-inflammatory and pro-resolving properties, making them promising candidates for the treatment of inflammatory and neurodegenerative disorders. However, their therapeutic application is limited by poor stability and bioavailability. This study aimed to develop and characterize nanomicelles encapsulating LXA4 (nano-lipoxin A4) to improve its pharmacological efficacy against Alzheimer’s disease (AD), a neurodegenerative condition marked by chronic inflammation and beta-amyloid (Aβ) accumulation. <b>Methods</b>: Nano-lipoxin A4 was synthesized using Pluronic F-127 as a carrier and characterized in terms of morphology, physicochemical stability, and in vitro activity against Aβ fibrils. Dissociation of Aβ fibrils was assessed via Thioflavin-T fluorescence assays and transmission electron microscopy. In vivo biodistribution and pharmacokinetic profiles were evaluated using technetium-99m-labeled nano-lipoxin A4 in rodent models. Hepatic biochemical parameters were also measured to assess potential systemic effects. <b>Results</b>: In vitro studies demonstrated that nano-lipoxin A4 effectively dissociated Aβ fibrils at concentrations of 50 nM and 112 nM. Electron microscopy confirmed the disruption of fibrillar structures. In vivo imaging revealed predominant accumulation in the liver and spleen, consistent with reticuloendothelial system uptake. Pharmacokinetic analysis showed a prolonged half-life (63.95 h) and low clearance rate (0.001509 L/h), indicating sustained systemic presence. Biochemical assays revealed elevated liver enzyme levels, suggestive of increased hepatic metabolism or potential hepatotoxicity. <b>Conclusions</b>: Nano-lipoxin A4 exhibits significant therapeutic potential for Alzheimer’s disease through effective modulation of Aβ pathology and favorable pharmacokinetic characteristics. However, the elevation in liver enzymes necessitates further investigation into systemic safety to support clinical translation.https://www.mdpi.com/1999-4923/17/5/649neurodegenerativenanotechnologynanoparticlesneurology |
| spellingShingle | Natália Cristina Gomes-da-Silva Isabelle Xavier-de-Britto Marilia Amável Gomes Soares Natalia Mayumi Andrade Yoshihara Derya Ilem Özdemir Eduardo Ricci-Junior Pierre Basílio Almeida Fechine Luciana Magalhães Rebelo Alencar Maria das Graças Muller de Oliveira Henriques Thereza Christina Barja-Fidalgo Cristian Follmer Ralph Santos-Oliveira Nanostructured Lipoxin A4: Understanding Its Biological Behavior and Impact on Alzheimer’s Disease (Proof of Concept) Pharmaceutics neurodegenerative nanotechnology nanoparticles neurology |
| title | Nanostructured Lipoxin A4: Understanding Its Biological Behavior and Impact on Alzheimer’s Disease (Proof of Concept) |
| title_full | Nanostructured Lipoxin A4: Understanding Its Biological Behavior and Impact on Alzheimer’s Disease (Proof of Concept) |
| title_fullStr | Nanostructured Lipoxin A4: Understanding Its Biological Behavior and Impact on Alzheimer’s Disease (Proof of Concept) |
| title_full_unstemmed | Nanostructured Lipoxin A4: Understanding Its Biological Behavior and Impact on Alzheimer’s Disease (Proof of Concept) |
| title_short | Nanostructured Lipoxin A4: Understanding Its Biological Behavior and Impact on Alzheimer’s Disease (Proof of Concept) |
| title_sort | nanostructured lipoxin a4 understanding its biological behavior and impact on alzheimer s disease proof of concept |
| topic | neurodegenerative nanotechnology nanoparticles neurology |
| url | https://www.mdpi.com/1999-4923/17/5/649 |
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