Skip to content
2000
Volume 15, Issue 3
  • ISSN: 2210-3031
  • E-ISSN: 2210-304X

Abstract

Introduction

The development of novel drug carriers is invaluable to maximize therapeutic efficiency and improve specificity. Dioctadecyl-dimethylammonium bromide (DODAB): monoolein (MO) (1:2) liposomes exhibit non-lamellar phases in their core that improve the encapsulation ability of both hydrophobic and hydrophilic molecules. This study explores the use of this nanosystem for the therapeutic delivery of cytokines, specifically of leukemia inhibitory factor (LIF). Nanocarriers can overcome the drawbacks of direct cytokine administration, like poor bioavailability.

Methods

DODAB:MO (1:2) liposomes were produced by lipid film hydration, followed by extrusion, and used for encapsulating 0.125 and 0.25 µM LIF. The produced nanoparticles were characterized in terms of size and zeta potential, FTIR and STEM. LIF was quantified with an optimized Bradford method to determine encapsulation efficiencies, drug loading, and release profile. Cytotoxicity was assessed by hemolysis, and mouse myoblasts were used to validate bioactivity .

Results

Neither the extrusion nor the protein incorporation steps promoted significant alterations in cytokine structure. LIF-containing liposomes DODAB (1:2) nanosystem were small (~200-300nm), positively charged (~50-60mV), non-toxic, and stable at physiological pH. Biophysical characterization identified liposomal formulation of 200 µM DODAB:MO (1:2) at 0.25 µM as the most efficient system. The bioactivity analysis showed an increase of ~20% in cell proliferation after 48h of incubation when compared to free mLIF. Also, the LIF-containing DODAB:MO (1:2) liposomal formulation, when exposed to serum, revealed a capacity to protect its cargo for up to 6 h.

Conclusion

The DODAB:MO (1:2) nanosystem was found to be efficient for cytokine delivery, stabilizing mLIF, and promoting its bioactivity with multiple applications.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ddl/10.2174/0122103031336363250109091243
2025-01-14
2025-12-20

  • From This Site

    /content/journals/ddl/10.2174/0122103031336363250109091243
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. PagoniP. Korologou-LindenR.S. HoweL.D. Davey SmithG. Ben-ShlomoY. StergiakouliE. AndersonE.L. Causal effects of circulating cytokine concentrations on risk of Alzheimer’s disease and cognitive function.Brain Behav. Immun.2022104546410.1016/j.bbi.2022.05.00635580794
     [Google Scholar]
  2. JiangS.S. WangY.L. XuQ.H. GuL.Y. KangR.Q. YangW.Y. ZhangB.R. TianJ. PuJ.L. Cytokine and chemokine map of peripheral specific immune cell subsets in Parkinson’s disease.NPJ Parkinsons Dis.20239111710.1038/s41531‑023‑00559‑037491350
     [Google Scholar]
  3. NikovicsK. FavierA.L. RocherM. MayingaC. GomezJ. Dufour-GaumeF. RiccobonoD. In situ identification of both IL-4 and IL-10 cytokine–receptor interactions during tissue regeneration.Cells20231211152210.3390/cells1211152237296643
     [Google Scholar]
  4. TsarouchasT.M. WehnerD. CavoneL. MunirT. KeatingeM. LambertusM. UnderhillA. BarrettT. KassapisE. OgryzkoN. FengY. van HamT.J. BeckerT. BeckerC.G. Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages in zebrafish spinal cord regeneration.Nat. Commun.201891467010.1038/s41467‑018‑07036‑w30405119
     [Google Scholar]
  5. BorsiniA. Di BenedettoM.G. GiacobbeJ. ParianteC.M. Pro- and anti-inflammatory properties of interleukin (IL6) in vitro: Relevance for major depression and for human hippocampal neurogenesis.Int. J. Neuropsychopharmacol.2020231173875010.1093/ijnp/pyaa05532726406
     [Google Scholar]
  6. SantollaniL. WittrupK.D. Spatiotemporally programming cytokine immunotherapies through protein engineering.Immunol. Rev.20233201102810.1111/imr.1323437409481
     [Google Scholar]
  7. SaxtonR.A. GlassmanC.R. GarciaK.C. Emerging principles of cytokine pharmacology and therapeutics.Nat. Rev. Drug Discov.2023221213710.1038/s41573‑022‑00557‑636131080
     [Google Scholar]
  8. AkbarianM. ChenS.H. Instability challenges and stabilization strategies of pharmaceutical proteins.Pharmaceutics20221411253310.3390/pharmaceutics1411253336432723
     [Google Scholar]
  9. DeckersJ. AnbergenT. HokkeA.M. de DreuA. SchrijverD.P. de BruinK. TonerY.C. BeldmanT.J. SpanglerJ.B. de GreefT.F.A. GrisoniF. van der MeelR. JoostenL.A.B. MerkxM. NeteaM.G. MulderW.J.M. Engineering cytokine therapeutics.Nat. Revi. Bioenginee.20231428630310.1038/s44222‑023‑00030‑y37064653
     [Google Scholar]
  10. GonçalvesA. MachadoR. GomesA.C. CostaA. Nanotechnology solutions for controlled cytokine delivery: An applied perspective.Appl. Sci. (Basel)20201020709810.3390/app10207098
     [Google Scholar]
  11. JonesS.A. JenkinsB.J. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer.Nat. Rev. Immunol.2018181277378910.1038/s41577‑018‑0066‑730254251
     [Google Scholar]
  12. CostaA. Franco-DuarteR. MachadoR. GomesA.C. Uncovering the promiscuous activity of IL-6 proteins: A multi-dimensional analysis of phylogeny, classification and residue conservation.Protein Sci.20223111e446910.1002/pro.446936222303
     [Google Scholar]
  13. PinhoV. FernandesM. da CostaA. MachadoR. GomesA.C. Leukemia inhibitory factor: Recent advances and implications in biotechnology.Cytokine Growth Factor Rev.202052253310.1016/j.cytogfr.2019.11.00531870618
     [Google Scholar]
  14. LiuC. ZhouH. ZhongJ. TangT. CuiH. ZhouJ. ZhangQ. MeiZ. Leukemia inhibitory factor decreases neurogenesis and angiogenesis in a rat model of intracerebral hemorrhage.Curr. Med. Sci.201939229830410.1007/s11596‑019‑2034‑231016525
     [Google Scholar]
  15. LinJ. NiimiY. ClausiM.G. KanalH.D. LevisonS.W. Neuroregenerative and protective functions of Leukemia Inhibitory Factor in perinatal hypoxic-ischemic brain injury.Exp. Neurol.202033011332410.1016/j.expneurol.2020.11332432320698
     [Google Scholar]
  16. KandaM. NagaiT. TakahashiT. LiuM.L. KondouN. NaitoA.T. AkazawaH. SashidaG. IwamaA. KomuroI. KobayashiY. Leukemia inhibitory factor enhances endogenous cardiomyocyte regeneration after myocardial infarction.PLoS One2016115e015656210.1371/journal.pone.015656227227407
     [Google Scholar]
  17. HennøL.T. StorjordE. ChristiansenD. BergsethG. LudviksenJ.K. FureH. BareneS. NielsenE.W. MollnesT.E. BrekkeO.L. Effect of the anticoagulant, storage time and temperature of blood samples on the concentrations of 27 multiplex assayed cytokines – Consequences for defining reference values in healthy humans.Cytokine201797869510.1016/j.cyto.2017.05.01428595117
     [Google Scholar]
  18. VincentF.B. NimH.T. LeeJ.P.W. MorandE.F. HarrisJ. Effect of storage duration on cytokine stability in human serum and plasma.Cytokine201911345345710.1016/j.cyto.2018.06.00929909979
     [Google Scholar]
  19. ZhaoW. OskeritzianC.A. PozezA.L. SchwartzL.B. Cytokine production by skin-derived mast cells: Endogenous proteases are responsible for degradation of cytokines.J. Immunol.200517542635264210.4049/jimmunol.175.4.263516081839
     [Google Scholar]
  20. GaggeroS. Martinez-FabregasJ. CozzaniA. FyfeP.K. LeprohonM. YangJ. ThomasenF.E. WinkelmannH. MagnezR. ContiA.G. WilmesS. PohlerE. van Gijsel BonnelloM. ThuruX. QuesnelB. SoncinF. PiehlerJ. Lindorff-LarsenK. RoychoudhuriR. MoragaI. MitraS. IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein.Sci. Immunol.2022778eade568610.1126/sciimmunol.ade568636459543
     [Google Scholar]
  21. HiltonD.J. NicolaN.A. WaringP.M. MetcalfD. Clearance and fate of leukemia-inhibitory factor (LIF) after injection into mice.J. Cell. Physiol.1991148343043910.1002/jcp.10414803151918172
     [Google Scholar]
  22. LianH. MaS. ZhaoD. ZhaoW. CuiY. HuaY. ZhangZ. Cytokine therapy combined with nanomaterials participates in cancer immunotherapy.Pharmaceutics20221412260610.3390/pharmaceutics1412260636559100
     [Google Scholar]
  23. OliveiraA.C.N. FernandesJ. GonçalvesA. GomesA.C. OliveiraM.E.C.D.R. Lipid-based nanocarriers for siRNA delivery: Challenges, strategies and the lessons learned from the DODAX: MO liposomal system.Curr. Drug Targets2018201295010.2174/138945011966618070314541029968536
     [Google Scholar]
  24. OliveiraA.C.N. MartensT.F. RaemdonckK. AdatiR.D. FeitosaE. BotelhoC. GomesA.C. BraeckmansK. Real OliveiraM.E.C.D. Dioctadecyldimethylammonium:monoolein nanocarriers for efficient in vitro gene silencing.ACS Appl. Mater. Interfaces2014696977698910.1021/am500793y24712543
     [Google Scholar]
  25. CarneiroC. CorreiaA. CollinsT. VilanovaM. PaisC. GomesA.C. Real OliveiraM.E.C.D. SampaioP. DODAB:monoolein liposomes containing Candida albicans cell wall surface proteins: A novel adjuvant and delivery system.Eur. J. Pharm. Biopharm.20158919020010.1016/j.ejpb.2014.11.02825499956
     [Google Scholar]
  26. CarneiroC. CorreiaA. LimaT. VilanovaM. PaisC. GomesA.C. Real OliveiraM.E.C.D. SampaioP. Protective effect of antigen delivery using monoolein-based liposomes in experimental hematogenously disseminated candidiasis.Acta Biomater.20163913314510.1016/j.actbio.2016.05.00127150234
     [Google Scholar]
  27. SilvaJ.P.N. OliveiraI.M.S.C. OliveiraA.C.N. LúcioM. GomesA.C. CoutinhoP.J.G. OliveiraM.E.C.D.R. Structural dynamics and physicochemical properties of pDNA/DODAB:MO lipoplexes: Effect of pH and anionic lipids in inverted non-lamellar phases versus lamellar phases.Biochim. Biophys. Acta Biomembr.20141838102555256710.1016/j.bbamem.2014.06.01424976292
     [Google Scholar]
  28. SilvaJ.P.N. OliveiraA.C.N. LúcioM. GomesA.C. CoutinhoP.J.G. OliveiraM.E.C.D.R. Tunable pDNA/DODAB:MO lipoplexes: The effect of incubation temperature on pDNA/DODAB:MO lipoplexes structure and transfection efficiency.Colloids Surf. B Biointerfaces201412137137910.1016/j.colsurfb.2014.06.01925023903
     [Google Scholar]
  29. NicolaN.A. BabonJ.J. Leukemia inhibitory factor (LIF).Cytokine Growth Factor Rev.201526553354410.1016/j.cytogfr.2015.07.00126187859
     [Google Scholar]
  30. BoulangerM.J. BankovichA.J. KortemmeT. BakerD. GarciaK.C. Convergent mechanisms for recognition of divergent cytokines by the shared signaling receptor gp130.Mol. Cell200312357758910.1016/S1097‑2765(03)00365‑414527405
     [Google Scholar]
  31. HuytonT. ZhangJ.G. LuoC.S. LouM.Z. HiltonD.J. NicolaN.A. GarrettT.P.J. An unusual cytokine:Ig-domain interaction revealed in the crystal structure of leukemia inhibitory factor (LIF) in complex with the LIF receptor.Proc. Natl. Acad. Sci. USA200710431127371274210.1073/pnas.070557710417652170
     [Google Scholar]
  32. Plun-FavreauH. PerretD. DiveuC. FrogerJ. ChevalierS. LelièvreE. GascanH. ChabbertM. Leukemia inhibitory factor (LIF), cardiotrophin-1, and oncostatin M share structural binding determinants in the immunoglobulin-like domain of LIF receptor.J. Biol. Chem.200327829271692717910.1074/jbc.M30316820012707269
     [Google Scholar]
  33. OliveiraA.C.N. SárriaM.P. MoreiraP. FernandesJ. CastroL. LopesI. Côrte-RealM. Cavaco-PauloA. Real OliveiraM.E.C.D. GomesA.C. Counter ions and constituents combination affect DODAX : MO nanocarriers toxicity in vitro and in vivo.Toxicol. Res. (Camb.)2016541244125510.1039/C6TX00074F30090429
     [Google Scholar]
  34. OwczarekC.M. ZhangY. LaytonM.J. MetcalfD. RobertsB. NicolaN.A. The unusual species cross-reactivity of the leukemia inhibitory factor receptor α-chain is determined primarily by the immunoglobulin-like domain.J. Biol. Chem.199727238239762398510.1074/jbc.272.38.239769295349
     [Google Scholar]
  35. JoC. KimH. JoI. ChoiI. JungS.C. KimJ. KimS.S. JoS.A. Leukemia inhibitory factor blocks early differentiation of skeletal muscle cells by activating ERK.Biochim. Biophys. Acta Mol. Cell Res.20051743318719710.1016/j.bbamcr.2004.11.00215843032
     [Google Scholar]
  36. ParkJ. GaoW. WhistonR. StromT.B. MetcalfeS. FahmyT.M. Modulation of CD4+ T lymphocyte lineage outcomes with targeted, nanoparticle-mediated cytokine delivery.Mol. Pharm.20118114315210.1021/mp100203a20977190
     [Google Scholar]
  37. DavisS.M. ReichelD. BaeY. PennypackerK.R. Leukemia inhibitory factor-loaded nanoparticles with enhanced cytokine metabolic stability and anti-inflammatory activity.Pharm. Res.2018351610.1007/s11095‑017‑2282‑429294201
     [Google Scholar]
  38. StrombergZ.R. JacobsenD.E. KocherilP.A. Kubicek-SutherlandJ.Z. Biological toxicity and environmental hazards associated with PLGA nanoparticles.Poly(Lactic-Co-Glycolic Acid) Nanoparticles Drug DeliveryElsevier202345747510.1016/B978‑0‑323‑91215‑0.00006‑6
     [Google Scholar]
  39. LopesI. C N OliveiraA. P SárriaM. P Neves SilvaJ. GonçalvesO. GomesA.C. Real OliveiraM.E.C.D. Monoolein-based nanocarriers for enhanced folate receptor-mediated RNA delivery to cancer cells.J. Liposome Res.201626319921010.3109/08982104.2015.107646326340109
     [Google Scholar]
  40. GasteigerE. GattikerA. HooglandC. IvanyiI. AppelR.D. BairochA. ExPASy: The proteomics server for in-depth protein knowledge and analysis.Nucleic Acids Res.200331133784378810.1093/nar/gkg56312824418
     [Google Scholar]
  41. FernandesM. LopesI. MagalhãesL. SárriaM.P. MachadoR. SousaJ.C. BotelhoC. TeixeiraJ. GomesA.C. Novel concept of exosome-like liposomes for the treatment of Alzheimer’s disease.J. Control. Release202133613014310.1016/j.jconrel.2021.06.01834126168
     [Google Scholar]
  42. VakakisN. BowerJ. AustinL. in vitro myoblast to myotube transformations in the presence of leukemia inhibitory factor.Neurochem. Int.1995274-532933510.1016/0197‑0186(95)00014‑Y8845733
     [Google Scholar]
/content/journals/ddl/10.2174/0122103031336363250109091243
Loading
Pleiotropic Leukemia Inhibitory Factor Encapsulated in DODAB:MO Liposomes for Multiple Biomedical Applications
Drug Deliv Lett 15, 334 (2025); https://doi.org/10.2174/0122103031336363250109091243
/content/journals/ddl/10.2174/0122103031336363250109091243
/content/journals/ddl/10.2174/0122103031336363250109091243
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): dioctadecyl-dimethylammonium bromide; Leukemia inhibitory factor; liposomes; monoolein; myoblasts, novel drug carriers

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test