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A thermal analysis and physicochemical study on thermoresponsive chimeric liposomal nanosystems

  • Nikolaos Naziris
  • Athanasios Skandalis
  • Aleksander Forys
  • Barbara Trzebicka
  • Stergios Pispas
  • Costas DemetzosEmail author
Article
  • 25 Downloads

Abstract

Thermoresponsive nanomaterials have led to a plethora of new applications in the fields of Nanobiotechnology, Biomedicine and Therapeutics. Since liposomal membranes are lyotropic liquid crystals, the development of thermoresponsive liposomes for drug delivery has been recognized as an attractive scientific field. Additionally, plenty of studies utilizing the temperature-dependent response of certain synthetic polymers are conducted, alone or in combination with liposomes. In the present study, we combined the liposomal and thermoresponsive polymer technologies, in order to create functional chimeric/mixed liposomal nanosystems with innovative properties. Initially, differential scanning calorimetry was applied on chimeric/mixed bilayers to evaluate the effect of polymeric guests on the thermotropic behavior of lipidic membranes. Thereafter, chimeric/mixed liposomes were built and their physicochemical properties, as well as their colloidal stability were measured and evaluated. The nature of the self-assembled structures and the lipidic membrane morphology were investigated through cryo-transmission electron microscopy, while their thermoresponsiveness and its consequences on the lipidic membrane properties were assessed, through a simple heating protocol. The presence of a new thermodynamic phase on the lipidic membrane acts as an agglomeration and aggregation inducer, affecting the whole colloidal chimeric/mixed nanosystem. This mechanism might be characterized as “phase functionality” and may be utilized for drug delivery purposes and also in other applications. Biophysics and thermodynamics are very important tools to study the self-assembly process, as well as the stability and bio-functionality of drug delivery systems.

Keywords

Chimeric liposomes Thermoresponsiveness Thermal analysis Light scattering Cryo-TEM Phase functionality 

Notes

Acknowledgements

The research work was supported by the Hellenic Foundation for Research and Innovation (HFRI) and the General Secretariat for Research and Technology (GSRT), under the HFRI PhD Fellowship grant (GA. no. 392). We would also like to thank Dimitrios Fessas, Associate Professor in the Department of Food, Environmental and Nutritional Sciences—DeFENS, University of Milan, for his valuable advice on interpreting the DSC results and thermodynamic behavior of thermoresponsive chimeric nanosystems. In Poland, this work was supported by state funds for the Centre of Polymer and Carbon Materials, Polish Academy of Science.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10973_2019_9049_MOESM1_ESM.docx (96 kb)
Supplementary material 1 (DOCX 96 kb)

References

  1. 1.
    Demetzos C, Pippa N. Advanced drug delivery nanosystems (aDDnSs): a mini-review. Drug Deliv. 2014;21:250–7.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Naziris N, Pippa N, Pispas S, Demetzos C. Stimuli-responsive drug delivery nanosystems: from bench to clinic. Curr Nanomed. 2016;6:1–20.CrossRefGoogle Scholar
  3. 3.
    Dou Y, Hynynen K, Allen C. To heat or not to heat: challenges with clinical translation of thermosensitive liposomes. J Control Release. 2017;249:63–73.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Kneidl B, Peller M, Winter G, Lindner LH, Hossann M. Thermosensitive liposomal drug delivery systems: state of the art review. Int J Nanomed. 2014;9:4387–98.Google Scholar
  5. 5.
    Lee Y, Thompson DH. Stimuli-responsive liposomes for drug delivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2017.  https://doi.org/10.1002/wnan.1450.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Lee SM, Nguyen ST. Smart nanoscale drug delivery platforms from stimuli-responsive polymers and liposomes. Macromolecules. 2013;46:9169–80.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Sánchez-Moreno P, de Vicente J, Nardecchia S, Marchal JA, Boulaiz H. Thermo-sensitive nanomaterials: recent advance in synthesis and biomedical applications. Nanomaterials (Basel). 2018;8:935–66.PubMedCentralCrossRefGoogle Scholar
  8. 8.
    Hongshua B, Jianxiu X, Hong J, Shan G, Dongjuan T, Yan F, Kai S. Current developments in drug delivery with thermosensitive liposomes. Asian J Pharm. 2019;14:365–79.Google Scholar
  9. 9.
    Heskins M, Guillet JE. Solution properties of poly(n-isopropylacrylamide). J Macromol Sci. 1968;2:1441–55.CrossRefGoogle Scholar
  10. 10.
    Futscher MH, Philipp M, Müller-Buschbaum P, Schulte A. The role of backbone hydration of poly(n-isopropyl acrylamide) across the volume phase transition compared to its monomer. Sci Rep. 2017;7:17012–31.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Pelton R. Poly(N-isopropylacrylamide) (PNIPAM) is never hydrophobic. J Colloid Interface Sci. 2010;348:673–4.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Southall NT, Dill KA, Haymet ADJ. A view of the hydrophobic effect. J Phys Chem B. 2002;106:521–33.CrossRefGoogle Scholar
  13. 13.
    Liu P, Song L, Li N, Lin J, Huang D. Time dependence of phase separation enthalpy recovery behavior in aqueous poly(N-isopropylacrylamide) solution. J Therm Anal Calorim. 2017;130:843–50.CrossRefGoogle Scholar
  14. 14.
    Lanzalaco S, Armelin E. Poly(n-isopropylacrylamide) and copolymers: a review on recent progresses in biomedical applications. Gels. 2017;3:36–67.PubMedCentralCrossRefGoogle Scholar
  15. 15.
    Ward MA, Georgiou TK. Thermoresponsive polymers for biomedical applications. Polymers. 2011;3:1215–42.CrossRefGoogle Scholar
  16. 16.
    Liu R, Fraylich M, Saunders BR. Thermoresponsive copolymers: from fundamental studies to applications. Colloid Polym Sci. 2009;287:627–43.CrossRefGoogle Scholar
  17. 17.
    Eeckman F, Moës AJ, Amighi K. Synthesis and characterization of thermosensitive copolymers for oral controlled drug delivery. Eur Polym J. 2004;40:873–81.CrossRefGoogle Scholar
  18. 18.
    Demetzos C. Differential scanning calorimetry (DSC): a tool to study the thermal behavior of lipid bilayers and liposomal stability. J Liposome Res. 2008;18:159–73.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Naziris N, Pippa N, Stellas D, Chrysostomou V, Pispas S, Demetzos C, Libera M, Trzebicka B. Development and evaluation of stimuli-responsive chimeric nanostructures. AAPS PharmSciTech. 2018;19:2971–89.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Naziris N, Demetzos C. The role of the information/entropy balance in self-assembly. The structural hierarchy of chimeric drug delivery nanosystems. Pharmakeftiki. 2017;19:77–82.Google Scholar
  21. 21.
    Pippa N, Pispas S, Demetzos C. The metastable phases as modulators of biophysical behavior of liposomal membranes. J Therm Anal Calorim. 2015;120:937–45.CrossRefGoogle Scholar
  22. 22.
    Pippa N, Stellas D, Skandalis A, Pispas S, Demetzos C, Libera M, Marcinkowski A, Trzebicka B. Chimeric lipid/block copolymer nanovesicles: physico-chemical and bio-compatibility evaluation. Eur J Pharm Biopharm. 2016;107:295–309.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Ionov M, Klajnert B, Gardikis K, Hatziantoniou S, Palecz B, Salakhutdinov B, Cladera J, Zamaraeva M, Demetzos C, Bryszewska M. Effect of amyloid beta peptides Aβ1–28 and Aβ25–40 on model lipid membranes. J Therm Anal Calorim. 2010;99:741–7.CrossRefGoogle Scholar
  24. 24.
    Gardikis K, Hatziantoniou S, Signorelli M, Pusceddu M, Micha-Screttas M, Schiraldi A, Demetzos C, Fessas D. Thermodynamic and structural characterization of Liposomal-Locked in-Dendrimers as drug carriers. Colloids Surf B Biointerfaces. 2010;81:11–9.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Kolman I, Pippa N, Meristoudi A, Pispas S, Demetzos C. A dual-stimuli-responsive polymer into phospholipid membranes. J Therm Anal Calorim. 2016;123:2257–71.CrossRefGoogle Scholar
  26. 26.
    Pippa N, Chronopoulos DD, Stellas D, Fernández-Pacheco R, Arenal R, Demetzos C, Tagmatarchis N. Design and development of multi-walled carbon nanotube-liposome drug delivery platforms. Int J Pharm. 2017;528:429–39.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Pippa N, Meristoudi A, Pispas S, Demetzos C. Temperature-dependent drug release from DPPC:C12H25-PNIPAM-COOH liposomes: control of the drug loading/release by modulation of the nanocarriers’ components. Int J Pharm. 2015;485:374–82.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Demetzos C. Biophysics and thermodynamics: the scientific building blocks of bio-inspired drug delivery nano systems. AAPS PharmSciTech. 2015;16:491–5.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Ali S, Minchey S, Janoff A, Mayhew E. A differential scanning calorimetry study of phosphocholines mixed with paclitaxel and its bromoacylated taxanes. Biophys J. 2000;78:246–56.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Bruggemann EP, Melchior DL. Alterations in the organization of phosphatidylcholine/cholesterol bilayers by tetrahydrocannabinol. J Biol Chem. 1983;258:8298–303.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Fujisawa S, Kadoma Y, Ishihara M, Atsumi T, Yokoe I. Dipalmitoylphosphatidylcholine (DPPC) and DPPC/cholesterol liposomes as predictors of the cytotoxicity of bis-GMA related compounds. J Liposome Res. 2004;14:39–49.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Koynova R, Caffrey M. Phases and phase transitions of the phosphatidylcholines. Biochim Biophys Acta. 1998;1376:91–145.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Sadozai H, Saeidi D. Recent developments in liposome-based veterinary therapeutics. ISRN Vet Sci. 2013;2013.Google Scholar
  34. 34.
    Pippa N, Gardikis K, Pispas S, Demetzos C. The physicochemical/thermodynamic balance of advanced drug liposomal delivery systems. J Therm Anal Calorim. 2014;116:99–105.CrossRefGoogle Scholar
  35. 35.
    Kono K. Thermosensitive polymer-modified liposomes. Adv Drug Deliv Rev. 2001;53:307–19.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Spěváček J, Konefał R, Dybal J, Čadová E, Kovářová J. Thermoresponsive behavior of block copolymers of PEO and PNIPAm with different architecture in aqueous solutions: a study by NMR, FTIR, DSC and quantum-chemical calculations. Eur Pol J. 2017;94:471–83.CrossRefGoogle Scholar
  37. 37.
    Zhang Y, Furyk S, Sagle LB, Cho Y, Bergbreiter DE, Cremer PS. Effects of Hofmeister anions on the LCST of PNIPAM as a function of molecular weight. J Phys Chem C Nanomater Interfaces. 2007;111:8916–24.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Binder WH, Barragan V, Menger FM. Domains and rafts in lipid membranes. Angew Chem Int Ed Engl. 2003;42:5802–27.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Matsingou C, Demetzos C. Calorimetric study on the induction of interdigitated phase in hydrated DPPC bilayers by bioactive labdanes and correlation to their liposome stability: the role of chemical structure. Chem Phys Lipids. 2007;145:45–62.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Itel F, Chami M, Najer A, Lörcher S, Wu D, Dinu IA, Meier W. Molecular organization and dynamics in polymersome membranes: a lateral diffusion study. Macromolecules. 2014;47:7588–96.CrossRefGoogle Scholar
  41. 41.
    Attwood D, Florence AT. Physical pharmacy. 2nd ed. London: Pharmaceutical Press; 2012.Google Scholar
  42. 42.
    Kono K, Nakai R, Morimoto K, Takagishi T. Thermosensitive polymer-modified liposomes that release contents around physiological temperature. Biochim Biophys Acta. 1999;1416:239–50.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Naziris N, Pippa N, Chrysostomou V, Pispas S, Demetzos C, Libera M, et al. Morphological diversity of block copolymer/lipid chimeric nanostructures. J Nanopart Res. 2017;19:347–57.CrossRefGoogle Scholar
  44. 44.
    Kaiser N, Kimpfler A, Massing U, Burger AM, Fiebig HH, Brandl M, Schubert R. 5-Fluorouracil in vesicular phospholipid gels for anticancer treatment: entrapment and release properties. Int J Pharm. 2003;256:123–31.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Bowick MJ, Sknepnek R. Pathways to faceting of vesicles. Soft Matter. 2013;9:8088–95.CrossRefGoogle Scholar
  46. 46.
    Dao TPT, Fernandes F, Er-Rafik M, Salva R, Schmutz M, Brûlet A, Prieto M, Sandre O, Le Meins JF. Phase separation and nanodomain formation in hybrid polymer/lipid vesicles. ACS Macro Lett. 2015;4:182–6.CrossRefGoogle Scholar
  47. 47.
    Fox CB, Mulligan SK, Sung J, Dowling QM, Fung HW, Vedvick TS, Coler RN. Cryogenic transmission electron microscopy of recombinant tuberculosis vaccine antigen with anionic liposomes reveals formation of flattened liposomes. Int J Nanomed. 2014;9:1367–77.CrossRefGoogle Scholar
  48. 48.
    Le Meins JF, Schatz C, Lecommandoux S, Sandre O. Hybrid polymer/lipid vesicles: state of the art and future perspectives. Mater Today. 2013;16:397–402.CrossRefGoogle Scholar
  49. 49.
    Chemin M, Brun PM, Lecommandoux S, Sandre O, Le Meins JF. Hybrid polymer/lipid vesicles: fine control of the lipid and polymer distribution in the binary membrane. Soft Matter. 2012;8:2867–74.CrossRefGoogle Scholar
  50. 50.
    Lim SK, Wong ASW, de Hoog HPM, Rangamani P, Parikh AN, Nallani M, Sandin S, Liedberg B. Spontaneous formation of nanometer scale tubular vesicles in aqueous mixtures of lipid and block copolymer amphiphiles. Soft Matter. 2017;13:1107–15.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Rangelov S, Edwards K, Almgren M, Karlsson G. Steric stabilization of egg-phosphatidylcholine liposomes by copolymers bearing short blocks of lipid-mimetic units. Langmuir. 2003;19:172–81.CrossRefGoogle Scholar
  52. 52.
    Kuntsche J, Horst JC, Bunjes H. Cryogenic transmission electron microscopy (cryo-TEM) for studying the morphology of colloidal drug delivery systems. Int J Pharm. 2011;417:120–37.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Le Meins JF, Sandre O, Lecommandoux S. Recent trends in the tuning of polymersomes’ membrane properties. Eur Phys J E Soft Matter. 2011;34:14–31.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Schulz M, Binder WH. Mixed hybrid lipid/polymer vesicles as a novel membrane platform. Macromol Rapid Commun. 2015;36:2031–41.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Roy B, Guha P, Bhattarai R, Nahak P, Karmakar G, Chettri P, Panda AK. Influence of lipid composition, pH, and temperature on physicochemical properties of liposomes with curcumin as model drug. J Oleo Sci. 2016;65:399–411.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Nichols G, Byard S, Bloxham MJ, Botterill J, Dawson NJ, Dennis A, Diart V, North NC, Sherwood JD. A review of the terms agglomerate and aggregate with a recommendation for nomenclature used in powder and particle characterization. J Pharm Sci. 2002;91:2103–9.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Akadémiai Kiadó, Budapest, Hungary 2019

Authors and Affiliations

  • Nikolaos Naziris
    • 1
  • Athanasios Skandalis
    • 2
  • Aleksander Forys
    • 3
  • Barbara Trzebicka
    • 3
  • Stergios Pispas
    • 2
  • Costas Demetzos
    • 1
    Email author
  1. 1.Section of Pharmaceutical Technology, Department of Pharmacy, School of Health SciencesNational and Kapodistrian University of AthensAthensGreece
  2. 2.Theoretical and Physical Chemistry InstituteNational Hellenic Research FoundationAthensGreece
  3. 3.Centre of Polymer and Carbon Materials, Polish Academy of SciencesZabrzePoland

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