Skip to main content
SpringerLink
Log in

Micelles of Different Morphologies—Advantages of Worm-like Filomicelles of PEO-PCL in Paclitaxel Delivery

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Worm-like and spherical micelles are both prepared here from the same amphiphilic diblock copolymer, poly(ethylene oxide)-b-poly (ε-caprolactone) (PEO [5 kDa]–PCL [6.5 kDa]) in order to compare loading and delivery of hydrophobic drugs.

Materials and Methods

Worm-like micelles of this degradable copolymer are nanometers in cross-section and spontaneously assemble to stable lengths of microns, resembling filoviruses in some respects and thus suggesting the moniker ‘filomicelles’. The highly flexible worm-like micelles can also be sonicated to generate kinetically stable spherical micelles composed of the same copolymer.

Results

The fission process exploits the finding that the PCL cores are fluid, rather than glassy or crystalline, and core-loading of the hydrophobic anticancer drug delivery, paclitaxel (TAX) shows that the worm-like micelles load and solubilize twice as much drug as spherical micelles. In cytotoxicity tests that compare to the clinically prevalent solubilizer, Cremophor® EL, both micellar carriers are far less toxic, and both types of TAX-loaded micelles also show fivefold greater anticancer activity on A549 human lung cancer cells.

Conclusion

PEO–PCL based worm-like filomicelles appear to be promising pharmaceutical nanocarriers with improved solubilization efficiency and comparable stability to spherical micelles, as well as better safety and efficacy in vitro compared to the prevalent Cremophor® EL TAX formulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. M. J. Vicent, R. Duncan. Polymer conjugates: nanosized medicines for treating cancer. Trends Biotechnol. 24:39–47 (2006).

    Article  PubMed  CAS  Google Scholar 

  2. A. Malugin, P. Kopeckova, and J. Kopecek. HPMA copolymer-bound doxorubicin induces apoptosis in ovarian carcinoma cells by the disruption of mitochondrial function. Mol. Pharmacol. 3:351–361 (2006).

    Article  CAS  Google Scholar 

  3. Y. Luo, M. R. Ziebell, and G. D. Prestwich. A hyaluronic acid–taxol antitumor bioconjugate targeted to cancer cells. Biomacromolecules. 1:208–218 (2000).

    Article  PubMed  CAS  Google Scholar 

  4. L. E. van Vlerkenand, and M. M. Amiji. Multi-functional polymeric nanoparticles for tumour-targeted drug delivery. Expert Opin. Drug Deliv. 3:205–216 (2006).

    Article  Google Scholar 

  5. B. Liu, S. Jiang, W. Zhang, F. Ye, Y. H. Wang, J. Wu, and D. Y. Zhang. Novel biodegradable HSAM nanoparticle for drug delivery. Oncol. Rep. 15:957–961 (2006).

    PubMed  CAS  Google Scholar 

  6. V. P. Torchilin. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. 4:145–160 (2005).

    Article  PubMed  CAS  Google Scholar 

  7. X. Guo, and F. C. Szoka, Jr. Chemical approaches to triggerable lipid vesicles for drug and gene delivery. Acc. Chem. Res. 36:335–341 (2003).

    Article  PubMed  CAS  Google Scholar 

  8. F. Ahmed, R. I. Pakunlu, G. Srinivas, A. Brannan, F. Bates, M. L. Klein, T. Minko, and D. E. Discher. Shrinkage of a rapidly growing tumor by drug-loaded polymersomes: pH-triggered release through copolymer degradation. Mol. Pharmacol. 3:340–350 (2006).

    Article  CAS  Google Scholar 

  9. F. Ahmed, R. I. Pakunlu, A. Brannan, F. Bates, T. Minko, and D. E. Discher. Biodegradable polymersomes loaded with both paclitaxel and doxorubicin permeate and shrink tumors, inducing apoptosis in proportion to accumulated drug. J. Control. Release. 116:150–158 (2006).

    Article  PubMed  CAS  Google Scholar 

  10. J. P. Xu, J. Ji, W. D. Chen, and J. C. Shen. Novel biomimetic polymersomes as polymer therapeutics for drug delivery. J. Control. Release. 107:502–512 (2005).

    Article  PubMed  CAS  Google Scholar 

  11. Y. Bae, W. D. Jang, N. Nishiyama, S. Fukushima, and K. Kataoka. Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery. Mol. BioSyst. 1:242–250 (2005).

    Article  PubMed  CAS  Google Scholar 

  12. J. Wang, D. Mongayt, and V. P. Torchilin. Polymeric micelles for delivery of poorly soluble drugs: preparation and anticancer activity in vitro of paclitaxel incorporated into mixed micelles based on poly(ethylene glycol)–lipid conjugate and positively charged lipids. J. Drug Target. 13:73–80 (2005).

    Article  PubMed  CAS  Google Scholar 

  13. Y. Geng, P. Dalhaimer, S. Cai, R. Tsai, M. Tewari, T. Minko, and D. E. Discher. Shape effects of filaments versus spherical particles in flow and drug delivery. Nat. Nanotech. 2:249–255 (2007).

    Article  Google Scholar 

  14. X. Tong, J. Zhou, and Y. Tan. Liquid chromatography/tandem triple-quadrupole mass spectrometry for determination of paclitaxel in rat tissues. Rapid Commun. Mass Spectrom. 20:1905–1912 (2006).

    Article  PubMed  CAS  Google Scholar 

  15. T. Y. Kim, D. W. Kim, J. Y. Chung, S. G. Shin, S. C. Kim, D. S. Heo, N. K. Kim, and Y. J. Bang. Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clin. Cancer Res. 10:3708–3716 (2004).

    Article  PubMed  CAS  Google Scholar 

  16. S. C. Kim, J. Yu, J. W. Lee, E. S. Park, and S. C. Chi. Sensitive HPLC method for quantitation of paclitaxel (Genexol in biological samples with application to preclinical pharmacokinetics and biodistribution. J. Pharm. Biomed. Anal. 39:170–176 (2005).

    Article  PubMed  CAS  Google Scholar 

  17. L. M. Han, J. Guo, L. J. Zhang, Q. S. Wang, and X. L. Fang. Pharmacokinetics and biodistribution of polymeric micelles of paclitaxel with Pluronic P123. Acta Pharmacol. Sin. 27:747–753 (2006).

    Article  PubMed  CAS  Google Scholar 

  18. O. Soga, C. F. van Nostrum, M. Fens, C. J. Rijcken, R. M. Schiffelers, G. Storm, and W. E. Hennink. Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery. J. Control. Release. 103:341–353 (2005).

    Article  PubMed  CAS  Google Scholar 

  19. R. T. Liggins, W. L. Hunter, and H. M. Burt. Solid-state characterization of paclitaxel. J. Pharm. Sci. 86:1458–1463 (1997).

    Article  PubMed  CAS  Google Scholar 

  20. S. C. Kim, D. W. Kim, Y. H. Shim, J. S. Bang, H. S. Oh, S. Wan Kim, and M. H. Seo. In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy. J. Control. Release. 72:191–202 (2001).

    Article  PubMed  CAS  Google Scholar 

  21. S. Cheon Lee, C. Kim, I. Chan Kwon, H. Chung, and S. Young Jeong. Polymeric micelles of poly(2-ethyl-2-oxazoline)-block-poly(epsilon-caprolactone) copolymer as a carrier for paclitaxel. J. Control. Release. 89:437–446 (2003).

    Article  PubMed  Google Scholar 

  22. T. Meyer, D. Waidelich, and A. W. Frahm. Separation and first structure elucidation of Cremophor EL-components by hyphenated capillary electrophoresis and delayed extraction-matrix assisted laser desorption/ionization-time of flight-mass spectrometry. Electrophoresis. 23:1053–1062 (2002).

    Article  PubMed  CAS  Google Scholar 

  23. Y. Mo, and L. Y. Lim. Preparation and in vitro anticancer activity of wheat germ agglutinin (WGA)-conjugated PLGA nanoparticles loaded with paclitaxel and isopropyl myristate. J. Control. Release. 107:30–42 (2005).

    Article  PubMed  CAS  Google Scholar 

  24. S. Q. Liu, Y. W. Tong, and Y. Y. Yang. Thermally sensitive micelles self-assembled from poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-b-poly(d,l-lactide-c o-glycolide) for controlled delivery of paclitaxel. Mol. BioSyst. 1:158–165 (2005).

    Article  PubMed  CAS  Google Scholar 

  25. J. Xie, C. H. Wang. Self-assembled biodegradable nanoparticles developed by direct dialysis for the delivery of paclitaxel. Pharm. Res. 22:2079–2090 (2005).

    Article  PubMed  CAS  Google Scholar 

  26. G. Gaucher, M. H. Dufresne, V. P. Sant, N. Kang, D. Maysinger, and J. C. Leroux. Block copolymer micelles: preparation, characterization and application in drug delivery. J. Control. Release. 109:169–188 (2005).

    Article  PubMed  CAS  Google Scholar 

  27. F. Yoshii, D. Darwis, H. Mitomo, and K. Makuuchi. Crosslinking of poly(beta-caprolactone) by radiation technique and its biodegradability. Radiat. Phys. Chem. 57:417–420 (2000).

    Article  CAS  Google Scholar 

  28. R. T. Liggins, T. Cruz, W. Min, L. Liang, W. L. Hunter, and H. M. Burt. Intra-articular treatment of arthritis with microsphere formulations of paclitaxel: biocompatibility and efficacy determinations in rabbits. Inflamm. Res. 53:363–372 (2004).

    Article  PubMed  CAS  Google Scholar 

  29. Z. G. Gao, D. H. Lee, D. I. Kim, and Y. H. Bae. Doxorubicin loaded pH-sensitive micelle targeting acidic extracellular pH of human ovarian A2780 tumor in mice. J. Drug Target. 13:391–397 (2005).

    Article  PubMed  CAS  Google Scholar 

  30. Y. Geng, and D. E. Discher. Hydrolytic degradation of poly(ethylene oxide)-block-polycaprolactone worm micelles. J. Am. Chem. Soc. 127:12780–12781 (2005).

    Article  PubMed  CAS  Google Scholar 

  31. P. Dalhaimer, F. S. Bates, and D. E. Discher. Single molecule visualization of stable, stiffness-tunable, flow-conforming worm micelles. Macromolecules. 36:6873–6877 (2003).

    Article  CAS  Google Scholar 

  32. Y. Kim, P. Dalhaimer, D. A. Christian, and D. E. Discher. Polymeric worm micelles as nano-carriers for drug delivery. Nanotechnology. 16:S484–S491 (2005).

    Article  Google Scholar 

  33. Y. Geng, F. Ahmed, N. Bhasin, and D. E. Discher. Visualizing worm micelle dynamics and phase transitions of a charged diblock copolymer in water. J. Phys. Chem., B Condens. Mater. Surf. Interfaces Biophys. 109:3772–3779 (2005).

    CAS  Google Scholar 

  34. P. Dalhaimer, A. J. Engler, R. Parthasarathy, and D. E. Discher. Targeted worm micelles. Biomacromolecules. 5:1714–1719 (2004).

    Article  PubMed  CAS  Google Scholar 

  35. S. D. Webb, J. A. Sherratt, and R. G. Fish. Alterations in proteolytic activity at low pH and its association with invasion: a theoretical model. Clin. Exp. Metastasis. 17:397–407 (1999).

    Article  PubMed  CAS  Google Scholar 

  36. K. Vijayan, and D. E. Discher. Block copolymer worm micelles in dilution: mechanochemical metrics of robustness as a basis for novel linear assemblies. J. Polym. Sci., B, Polym. Phys. 44:3431–3433 (2006).

    Article  CAS  Google Scholar 

  37. L. Luo, J. Tam, D. Maysinger, and A. Eisenberg. Cellular internalization of poly(ethylene oxide)-b-poly(epsilon-caprolactone) diblock copolymer micelles. Bioconjug. Chem. 13:1259–1265 (2002).

    Article  PubMed  CAS  Google Scholar 

  38. P. Skoglund, and A. Fransson. Continuous cooling and isothermal crystallization of polycaprolactone. J. Appl. Polym. Sci. 61:2455–2465 (1996).

    Article  CAS  Google Scholar 

  39. V. Balsamo, C. U. de Navarro, and G. Gil. Microphase separation vs crystallization in polystyrene-b-polybutadiene-b-poly(epsilon-caprolactone) ABC triblock copolymers. Macromolecules 36:4507–4514 (2003).

    Article  CAS  Google Scholar 

  40. Y. Geng, D. E. Discher, J. Justynska, and H. Schlaad. Grafting short peptides onto polybutadiene-block-poly(ethylene oxide): a platform for self-assembling hybrid amphiphiles. Angew. Chem., Int. Ed. Engl. 45:7578–7581 (2006).

    Article  CAS  Google Scholar 

  41. M. A. Hillmyerand, F. S. Bates. Synthesis and characterization of model polyalkane-poly(ethylene oxide) block copolymers. Macromolecules. 29:6994–7002 (1996).

    Article  Google Scholar 

  42. J. H. Kim, K. Emoto, M. Lijima, Y. Nagasaki, T. Aoyagi, T. Okano, Y. Sakurai, and K. Kataoka. Core-stabilized polymeric micelle as potential drug carrier: increased solubilization of taxol. Polym. Adv. Technol. 10:647–654 (1999).

    Article  CAS  Google Scholar 

  43. G. L. Li and J. X. Tang. Diffusion of actin filaments within a thin layer between two walls. Phys. Rev., E Stat. Nonlin. Soft Matter Phys. 69: Art. No. 061921 Part 1:(2004).

Download references

Acknowledgements

This study was supported by grants from NIH-NIBIB and NSF-MRSEC.

Author information

Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, University of Pennsylvania Philadelphia, Pennsylvania, 19104, USA

    Shenshen Cai, Kandaswamy Vijayan, Debbie Cheng, Eliana M. Lima & Dennis E. Discher

Authors
  1. Shenshen Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kandaswamy Vijayan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Debbie Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eliana M. Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dennis E. Discher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dennis E. Discher.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cai, S., Vijayan, K., Cheng, D. et al. Micelles of Different Morphologies—Advantages of Worm-like Filomicelles of PEO-PCL in Paclitaxel Delivery. Pharm Res 24, 2099–2109 (2007). https://doi.org/10.1007/s11095-007-9335-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-007-9335-z

Key words

Search

Navigation