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Micelles with ultralow critical micelle concentration as carriers for drug delivery

Nature Biomedical Engineering volume 2, pages 318–325 (2018)Cite this article

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Abstract

Conventional micellar carriers disassemble into free surfactants when diluted at concentrations below the critical micelle concentration (CMC). This limits the bioavailability in vivo of injected hydrophobic drugs encapsulated in micellar systems. Here, we show that a micelle comprising a superhydrophilic zwitterionic polymer domain and a superhydrophobic lipid domain has an undetectable CMC below 10−6 mM—a value that is orders of magnitude lower than the CMCs (>10−3 mM) of typical micellar systems. We also show that zwitterionic moieties or zwitterionic polymers added to a micelle solution stabilize the micelles at concentrations below their inherent CMC. In a mouse model of melanoma, ultralow-CMC micelles encapsulating docetaxel led to the complete eradication of tumours, whereas conventional docetaxel micellar formulations did not reverse tumour growth. Ultralow-CMC micelles might become next-generation carriers for drug delivery.

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Fig. 1: Ultralow-CMC micelles and their unusual ability to stabilize cargoes in extremely diluted conditions with micelle concentrations far below the CMC of conventional micelles.
Fig. 2: TEM and DLS measurements for DSPE-PCB 5K micelles.
Fig. 3: Diluting–concentrating method to probe CMCs for micelles.
Fig. 4: Effect of supplying zwitterionic moieties on the CMC of conventional micelles, and impact of the zwitterionic PCB MW on the CMC of DSPE-PCB.
Fig. 5: Stability of ultralow-CMC micelles and conventional micelles with gold NP probes encapsulated at a 5.5 × 10–2 mM micelle concentration in 100% FBS over 72 h at room temperature.
Fig. 6: Stability of docetaxel/DSPE-PCB 5K formulation and its antitumour performance compared with control formulations.

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References

  1. O’Reilly, R. K., Hawker, C. J. & Wooley, K. L. Cross-linked block copolymer micelles: functional nanostructures of great potential and versatility. Chem. Soc. Rev. 35, 1068–1083 (2006).

    Article  PubMed  CAS  Google Scholar 

  2. Rodriguez-Hernandez, J., Checot, F., Gnanou, Y. & Lecommandoux, S. Toward ‘smart’ nano-objects by self-assembly of block copolymers in solution. Progress Polym. Sci. 30, 691–724 (2005).

    Article  CAS  Google Scholar 

  3. Kim, S., Shi, Y. Z., Kim, J. Y., Park, K. & Cheng, J. X. Overcoming the barriers in micellar drug delivery: loading efficiency, in vivo stability, and micelle–cell interaction. Expert Opin. Drug Deliv. 7, 49–62 (2010).

    Article  PubMed  CAS  Google Scholar 

  4. Ahmad, Z., Shah, A., Siddiq, M. & Kraatz, H. B. Polymeric micelles as drug delivery vehicles. RSC Adv. 4, 17028–17038 (2014).

    Article  CAS  Google Scholar 

  5. Verma, G. & Hassan, P. A. Self assembled materials: design strategies and drug delivery perspectives. Phys. Chem. Chem. Phys. 15, 17016–17028 (2013).

    Article  PubMed  CAS  Google Scholar 

  6. Kamaly, N., Xiao, Z. Y., Valencia, P. M., Radovic-Moreno, A. F. & Farokhzad, O. C. Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem. Soc. Rev. 41, 2971–3010 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Service, R. F. Nanotechnology. Nanoparticle Trojan horses gallop from the lab into the clinic. Science 330, 314–315 (2010).

    Article  PubMed  CAS  Google Scholar 

  8. Zhang, L. et al. Nanoparticles in medicine: therapeutic applications and developments. Clin. Pharmacol. Ther. 83, 761–769 (2008).

    Article  PubMed  CAS  Google Scholar 

  9. Service, R. F. Nanotechnology takes aim at cancer. Science 310, 1132–1134 (2005).

    Article  PubMed  Google Scholar 

  10. Yoo, J. W., Irvine, D. J., Discher, D. E. & Mitragotri, S. Bio-inspired, bioengineered and biomimetic drug delivery carriers. Nat. Rev. Drug Discov. 10, 521–535 (2011).

    Article  PubMed  CAS  Google Scholar 

  11. Scheinberg, D. A., Villa, C. H., Escorcia, F. E. & McDevitt, M. R. Conscripts of the infinite armada: systemic cancer therapy using nanomaterials. Nat. Rev. Clin. Oncol. 7, 266–276 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Petros, R. A. & DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nat. Rev. Drug Discov. 9, 615–627 (2010).

    Article  PubMed  CAS  Google Scholar 

  13. Kim, S., Kim, J. H., Jeon, O., Kwon, I. C. & Park, K. Engineered polymers for advanced drug delivery. Eur. J. Pharm. Biopharm. 71, 420–430 (2009).

    Article  PubMed  CAS  Google Scholar 

  14. Guo, S. & Huang, L. Nanoparticles containing insoluble drug for cancer therapy. Biotechnol. Adv. 32, 778–788 (2014).

    Article  PubMed  CAS  Google Scholar 

  15. Guo, S., Miao, L., Wang, Y. & Huang, L. Unmodified drug used as a material to construct nanoparticles: delivery of cisplatin for enhanced anti-cancer therapy. J. Control. Release 174, 137–142 (2014).

    Article  PubMed  CAS  Google Scholar 

  16. Tang, L. et al. Investigating the optimal size of anticancer nanomedicine. Proc. Natl Acad. Sci. USA 111, 15344–15349 (2014).

    Article  PubMed  CAS  Google Scholar 

  17. Tong, R. et al. Smart chemistry in polymeric nanomedicines. Chem. Soc. Rev. 43, 6982–7012 (2014).

    Article  PubMed  CAS  Google Scholar 

  18. Hu, C. M. J. et al. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc. Natl Acad. Sci. USA 108, 10980–10985 (2011).

    Article  PubMed  Google Scholar 

  19. Judd, J. et al. Tunable protease-activatable virus nanonodes. ACS Nano 8, 4740–4746 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Lee, J. et al. Caveolae-mediated endocytosis of conjugated polymer nanoparticles. Macromol. Biosci. 13, 913–920 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Wang, M., Alberti, K. A., Sun, S. & Xu, Q. Efficient intracellular protein delivery for cancer therapy using combinatorial lipid-like nanoparticles. Angew. Chem. Int. Ed. 53, 2893–2898 (2014).

    Article  CAS  Google Scholar 

  22. Shukla, S. & Steinmetz, N. F. Virus-based nanomaterials as positron emission tomography and magnetic resonance contrast agents: from technology development to translational medicine. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 7, 708–721 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Rosler, A., Vandermeulen, G. W. M. & Klok, H. A. Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Adv. Drug Deliv. Rev. 53, 95–108 (2001).

    Article  PubMed  CAS  Google Scholar 

  24. Feng, L. & Mumper, R. J. A critical review of lipid-based nanoparticles for taxane delivery. Cancer Lett. 334, 157–175 (2013).

    Article  PubMed  CAS  Google Scholar 

  25. Chen, H. et al. Release of hydrophobic molecules from polymer micelles into cell membranes revealed by Forster resonance energy transfer imaging. Proc. Natl Acad. Sci. USA 105, 6596–6601 (2008).

    Article  PubMed  Google Scholar 

  26. Montero, A., Fossella, F., Hortobagyi, G. & Valero, V. Docetaxel for treatment of solid tumours: a systematic review of clinical data. Lancet Oncol. 6, 229–239 (2005).

    Article  PubMed  CAS  Google Scholar 

  27. Vanoosterom, A. T. & Schriivers, D. Docetaxel (Taxotere), a review of preclinical and clinical experience. Part II. Clinical experience. Anticancer Drugs 6, 356–368 (1995).

    Article  CAS  Google Scholar 

  28. Bissery, M. C., Nohynek, G., Sanderink, G. J. & Lavelle, F. Docetaxel (Taxotere): a review of preclinical and clinical experience. Part I: preclinical experience. Anticancer Drugs 6, 339–355 (1995).

    Article  PubMed  CAS  Google Scholar 

  29. Sadhu, S. S. et al. In vitro and in vivo tumor growth inhibition by glutathione disulfide liposomes. Cancer Growth Metastasis https://doi.org/10.1177/1179064417696070 (2017).

  30. Cruz-Munoz, W., Man, S. & Kerbel, R. S. Effective treatment of advanced human melanoma metastasis in immunodeficient mice using combination metronomic chemotherapy regimens. Clin. Cancer Res. 15, 4867–4874 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Feleszko, W., Zagożdżon, R., Gołb, J. & Jakóbisiak, M. Potentiated antitumour effects of cisplatin and lovastatin against MmB16 melanoma in mice. Eur. J. Cancer 34, 406–411 (1998).

    Article  PubMed  CAS  Google Scholar 

  32. Gao, C. et al. Jolkinolide B induces apoptosis and inhibits tumor growth in mouse melanoma B16F10 cells by altering glycolysis. Sci. Rep. 6, 36114 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Jin, J.-l. et al. PTD4-apoptin protein and dacarbazine show a synergistic antitumor effect on B16-F1 melanoma in vitro and in vivo. Eur. J. Pharmacol. 654, 17–25 (2011).

    Article  PubMed  CAS  Google Scholar 

  34. Lee, C. et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med. 4, 124ra127 (2012).

    Article  Google Scholar 

  35. Cao, Z. Q., Zhang, L. & Jiang, S. Y. Superhydrophilic zwitterionic polymers stabilize liposomes. Langmuir 28, 11625–11632 (2012).

    Article  PubMed  CAS  Google Scholar 

  36. Cao, Z. Q. et al. Toward an understanding of thermoresponsive transition behavior of hydrophobically modified N-isopropylacrylamide copolymer solution. Polymer 46, 5268–5277 (2005).

    Article  CAS  Google Scholar 

  37. Imae, T. & Ikeda, S. Sphere-rod transition of micelles of tetradecyltrimethylammonium halides in aqueous sodium halide solutions and flexibility and entanglement of long rodlike micelles. J. Phys. Chem. 90, 5216–5223 (1986).

    Article  CAS  Google Scholar 

  38. Ananthapadmanabhan, K. P., Goddard, E. D., Turro, N. J. & Kuo, P. L. Fluorescence probes for critical micelle concentration. Langmuir 1, 352–355 (1985).

    Article  PubMed  Google Scholar 

  39. La, S. B., Okano, T. & Kataoka, K. Preparation and characterization of the micelle-forming polymeric drug indomethacin-incorporated poly(ethylene oxide)–poly(β-benzyl l-aspartate) block copolymer micelles. J. Pharm. Sci. 85, 85–90 (1996).

    Article  PubMed  CAS  Google Scholar 

  40. Allen, C., Yu, Y., Maysinger, D. & Eisenberg, A. Polycaprolactone-b-poly(ethylene oxide) block copolymer micelles as a novel drug delivery vehicle for neurotrophic agents FK506 and L-685,818. Bioconjug. Chem. 9, 564–572 (1998).

    Article  PubMed  CAS  Google Scholar 

  41. Lukyanov, A. N. & Torchilin, V. P. Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Adv. Drug Deliv. Rev. 56, 1273–1289 (2004).

    Article  PubMed  CAS  Google Scholar 

  42. Lee, J. H. et al. Polymeric nanoparticle composed of fatty acids and poly(ethylene glycol) as a drug carrier. Int. J. Pharm. 251, 23–32 (2003).

    Article  PubMed  CAS  Google Scholar 

  43. Nakagaki, M., Komatsu, H. & Handa, T. Estimation of critical micelle concentrations of lysolecithins with fluorescent probes. Chem. Pharm. Bull. 34, 4479–4485 (1986).

    Article  CAS  Google Scholar 

  44. Matsuzaki, K. et al. Quantitative analysis of hemolytic action of lysophosphatidylcholines in vitro: effect of acyl chain structure. Chem. Pharm. Bull. 36, 4253–4260 (1988).

    Article  PubMed  CAS  Google Scholar 

  45. Katsu, T. Reinvestigation of the critical micelle concentrations of cationic surfactants with the use of an ammonium 8-anilino-1-naphthalenesulphonate fluorescent probe. Colloid. Surf. 60, 199–202 (1991).

    Article  CAS  Google Scholar 

  46. Hadjichristidis, N., Pispas, S. & Floudas, G. A. Block Copolymers: Synthetic Strategies, Physical Properties, and Applications (Wiley, New York, 2003).

    Google Scholar 

  47. Topel, O., Cakir, B. A., Budama, L. & Hoda, N. Determination of critical micelle concentration of polybutadiene-block-poly(ethyleneoxide) diblock copolymer by fluorescence spectroscopy and dynamic light scattering. J. Mol. Liq. 177, 40–43 (2013).

    Article  CAS  Google Scholar 

  48. Carnero Ruiz, C. et al. Effect of ethylene glycol on the thermodynamic and micellar properties of Tween 20. Colloid Polym. Sci. 281, 531–541 (2003).

    Article  CAS  Google Scholar 

  49. Kramp, W., Pieroni, G., Pinckard, R. N. & Hanahan, D. J. Observations on the critical micellar concentration of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine and a series of its homologs and analogs. Chem. Phys. Lipids 35, 49–62 (1984).

    Article  PubMed  CAS  Google Scholar 

  50. Henriksen, J. R., Andresen, T. L., Feldborg, L. N., Duelund, L. & Ipsen, J. H. Understanding detergent effects on lipid membranes: a model study of lysolipids. Biophys. J. 98, 2199–2205 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Hoyrup, P., Davidsen, J. & Jorgensen, K. Lipid membrane partitioning of lysolipids and fatty acids: effects of membrane phase structure and detergent chain length. J. Phys. Chem. B 105, 2649–2657 (2001).

    Article  CAS  Google Scholar 

  52. Weltzien, H. U. Cytolytic and membrane-perturbing properties of lysophosphatidylcholine. Biochim. Biophys. Acta 559, 259–287 (1979).

    Article  PubMed  CAS  Google Scholar 

  53. Smith, R. & Tanford, C. Critical micelle concentration of l-α-dipalmitoylphosphatidylcholine in water and water/methanol solutions. J. Mol. Biol. 67, 75–83 (1972).

    Article  PubMed  CAS  Google Scholar 

  54. Berges, D. A. et al. Studies on the active site of succinyl-CoA:tetrahydrodipicolinate N-succinyltransferase. Characterization using analogs of tetrahydrodipicolinate. J. Biol. Chem. 261, 6160–6167 (1986).

    PubMed  CAS  Google Scholar 

  55. Ashok, B., Arleth, L., Hjelm, R. P., Rubinstein, I. & Onyuksel, H. In vitro characterization of PEGylated phospholipid micelles for improved drug solubilization: effects of PEG chain length and PC incorporation. J. Pharm. Sci. 93, 2476–2487 (2004).

    Article  PubMed  CAS  Google Scholar 

  56. Uster, P. S. et al. Insertion of poly(ethylene glycol) derivatized phospholipid into pre-formed liposomes results in prolonged in vivo circulation time. FEBS Lett. 386, 243–246 (1996).

    Article  PubMed  CAS  Google Scholar 

  57. Yu, D. F. et al. Effects of inorganic and organic salts on aggregation behavior of cationic gemini surfactants. J. Phys. Chem. B 114, 14955–14964 (2010).

    Article  PubMed  CAS  Google Scholar 

  58. Miyagishi, S., Okada, K. & Asakawa, T. Salt effect on critical micelle concentrations of nonionic surfactants, N-acyl-N-methylglucamides (MEGA-n). J. Colloid Interface Sci. 238, 91–95 (2001).

    Article  PubMed  CAS  Google Scholar 

  59. Cao, Z. Q. & Jiang, S. Y. Super-hydrophilic zwitterionic poly(carboxybetaine) and amphiphilic non-ionic poly(ethylene glycol) for stealth nanoparticles. Nano Today 7, 404–413 (2012).

    Article  CAS  Google Scholar 

  60. Ruiz, C. C. et al. Effect of ethylene glycol on the thermodynamic and micellar properties of Tween 20. Colloid Polym. Sci. 281, 531–541 (2003).

    Article  CAS  Google Scholar 

  61. Yusa, S., Fukuda, K., Yamamoto, T., Ishihara, K. & Morishima, Y. Synthesis of well-defined amphiphilic block copolymers having phospholipid polymer sequences as a novel biocompatible polymer micelle reagent. Biomacromolecules 6, 663–670 (2005).

    Article  PubMed  CAS  Google Scholar 

  62. Liu, H. et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519–522 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Anderson, J. M., Rodriguez, A. & Chang, D. T. Foreign body reaction to biomaterials. Semin. Immunol. 20, 86–100 (2008).

    Article  PubMed  CAS  Google Scholar 

  64. Hart, M. & Acott, S. Physical and chemical stability of Taxotere® (docetaxel) one-vial (20 mg/ml) infusion solution following refrigerated storage. Ecancermedicalscience 4, 202 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  65. Le Garrec, D. et al. Preparation, characterization, cytotoxicity and biodistribution of docetaxel-loaded polymeric micelle formulations. J. Drug Deliv. Sci. Technol. 15, 115–120 (2005).

    Article  CAS  Google Scholar 

  66. Jun, Y. J. et al. Stable and efficient delivery of docetaxel by micelle-encapsulation using a tripodal cyclotriphosphazene amphiphile. Int J. Pharm. 422, 374–380 (2012).

    Article  PubMed  CAS  Google Scholar 

  67. Chen, L. et al. Pluronic P105/F127 mixed micelles for the delivery of docetaxel against Taxol-resistant non-small cell lung cancer: optimization and in vitro, in vivo evaluation. Int. J. Nanomed. 8, 73–84 (2013).

    Google Scholar 

  68. Wang, Y. et al. PEG–PCL based micelle hydrogels as oral docetaxel delivery systems for breast cancer therapy. Biomaterials 35, 6972–6985 (2014).

    Article  PubMed  CAS  Google Scholar 

  69. Wack, C., Becker, J. C., Brocker, E. B., Lutz, W. K. & Fischer, W. H. Chemoimmunotherapy for melanoma with dacarbazine and 2,4-dinitrochlorobenzene: results from a murine tumour model. Melanoma Res. 11, 247–253 (2001).

    Article  PubMed  CAS  Google Scholar 

  70. Kerr, D. E. et al. Regressions and cures of melanoma xenografts following treatment with monoclonal antibody β-lactamase conjugates in combination with anticancer prodrugs. Cancer Res. 55, 3558–3563 (1995).

    PubMed  CAS  Google Scholar 

  71. Luke, J. J. & Schwartz, G. K. Chemotherapy in the management of advanced cutaneous malignant melanoma. Clin. Dermatol. 31, 290–297 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Saito Rde, F., Tortelli, T. C. Jr, Jacomassi, M. D. A., Otake, A. H. & Chammas, R. Emerging targets for combination therapy in melanomas. FEBS Lett. 589, 3438–3448 (2015).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the faculty start-up fund at Wayne State University, National Science Foundation (DMR-1410853) and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (DP2DK111910). This work made use of the JEOL 2010 transmission electron microscope supported by National Science Foundation Award 0216084. We thank C.-H. Liu and W. Zhang at Michigan State University for support with static-light-scattering measurements.

Author contributions

Z.C., Y.L. and Z.Y. designed the experiments. Y.L. performed the experiments. J.X. and W.W. helped with the TEM figures. E.Z. and H.Z. helped with the animal experiments. Z.C. and Y.L. outlined and wrote the paper. Z.C. supervised the study.

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  1. Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, USA

    Yang Lu, Zhanguo Yue, Jinbing Xie, Wei Wang, Hui Zhu, Ershuai Zhang & Zhiqiang Cao

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Lu, Y., Yue, Z., Xie, J. et al. Micelles with ultralow critical micelle concentration as carriers for drug delivery. Nat Biomed Eng 2, 318–325 (2018). https://doi.org/10.1038/s41551-018-0234-x

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