Skip to main content
SpringerLink
Log in

PEG-poly(amino acid) Block Copolymer Micelles for Tunable Drug Release

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

ABSTRACT

Purpose

To achieve tunable pH-dependent drug release in tumor tissues.

Methods

Poly(ethylene glycol)-poly(aspartic acid) [PEG-p(Asp)] containing 12 kDa PEG and pAsp (5, 15, and 35 repeating units) were prepared. Hydrazide linkers with spacers [glycine (Gly) and 4-aminobenzoate (Abz)] were introduced to PEG-p(Asp), followed by drug conjugation [doxorubicin (DOX)]. The block copolymer-drug conjugates were either reconstituted or dialyzed in aqueous solutions to prepare micelles. Drug release patterns were observed under sink conditions at pH 5.0 and 7.4, 37°C, for 48 h.

Results

A collection of six block copolymers with different chain lengths and spacers was synthesized. Drug binding yields were 13–43.6%. The polymer-drug conjugates formed <50 nm polymer micelles irrespective of polymer compositions. Gly-introduced polymer micelles showed marginal change in particle size (40 ± 10 nm), while the size of Abz-micelles increased gradually from 10 to 40 nm as the polymer chain lengths increased. Drug release patterns of both Gly and Abz micelles were pH-dependent and tunable. The spacers appear to play a crucial role in controlling drug release and stability of polymer micelles in combination with block copolymer chain lengths.

Conclusion

A drug delivery platform for tunable drug release was successfully developed with polymer micelles possessing spacer-modified hydrazone drug-binding linkers.

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. Scripture CD, Figg WD. Drug interactions in cancer therapy. Nat Rev, Cancer. 2006;6:546–58.

    Article  CAS  Google Scholar 

  2. Atkins JH, Gershell LJ. Selective anticancer drugs. Nat Rev, Cancer. 2002;1:645–6.

    Article  Google Scholar 

  3. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  CAS  PubMed  Google Scholar 

  4. Duncan R. Polymer conjugates as anticancer nanomedicines. Nat Rev, Cancer. 2006;6:688–701.

    Article  CAS  Google Scholar 

  5. Senter PD, Kopecek J. Drug carriers in medicine and biology. Mol Pharmacol. 2004;1:395–8.

    Article  CAS  Google Scholar 

  6. Jain RK RK, Munn LL, Fukumura D. Dissecting tumour pathophysiology using intravital microscopy. Nat Rev, Cancer. 2002;2:266–76.

    Article  Google Scholar 

  7. Yamaoka T, Tabata Y, Ikada Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci. 1994;83:601–6.

    Article  CAS  PubMed  Google Scholar 

  8. Maeda H, Matsumura Y. Tumoritropic and lymphotropic principles of macromolecular drugs. Crit Rev Ther Drug Carrier Syst. 1989;6:193–210.

    CAS  PubMed  Google Scholar 

  9. Kwon G, Kataoka K. Block copolymer micelles as long-circulating drug vehicles. Adv Drug Deliv Rev. 1995;16:295–309.

    Article  CAS  Google Scholar 

  10. Putnam D, Kopecek J. Polymer conjugates with anticancer activity. Adv Polym Sci. 1995;122:55–123.

    CAS  Google Scholar 

  11. Duncan R. The dawning era of polymer therapeutics. Nature Rev Drug Discov. 2003;2:347–60.

    Article  CAS  Google Scholar 

  12. Tsukioka Y, Matsumura Y, Hamaguchi T, Koike H, Moriyasu F, Kakizoe T. Pharmaceutical and biomedical differences between micellar doxorubicin (NK911) and liposomal doxorubicin (Doxil). Jpn J Cancer Res. 2002;93:1145–53.

    CAS  PubMed  Google Scholar 

  13. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res. 1986;46:6387–92.

    CAS  PubMed  Google Scholar 

  14. Stella B, Arpicco S, Peracchia MT, Desmaele D, Hoebeke J, Renoir M et al. Design of folic acid-conjugated nanoparticles for drug targeting. J Pharm Sci. 2000;89:1452–64.

    Article  CAS  PubMed  Google Scholar 

  15. Takakura Y, Hashida M. Macromolecular carrier systems for targeted drug delivery: pharmacokinetic considerations on biodistribution. Pharm Res. 1996;13:820–31.

    Article  CAS  PubMed  Google Scholar 

  16. Benelli R, Monteghirfo S, Balbi C, Barboro P, Ferrari N. Novel antivascular efficacy of metronomic docetaxel therapy in prostate cancer: hnRNP K as a player. Int J Cancer. 2009;124:2989–96.

    Article  CAS  PubMed  Google Scholar 

  17. Mayer LD, Harasym TO, Tardi PG, Harasym NL, Shew CR, Johnstone SA et al. Ratiometric dosing of anticancer drug combinations: controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice. Mol Cancer Ther. 2006;5:1854–63.

    Article  CAS  PubMed  Google Scholar 

  18. Patel M, Ardalan K, Hochman I, Tian EM, Ardalan B. Cytotoxic effects and mechanisms of an alteration in the dose and duration of 5-fluorouracil. Anticancer Res. 2003;23:447–52.

    CAS  PubMed  Google Scholar 

  19. Ma J, Waxman DJ. Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib. Mol Cancer Ther. 2008;7:79–89.

    Article  CAS  PubMed  Google Scholar 

  20. Bae Y, Kataoka K. Intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) block copolymers. Adv Drug Deliv Rev. 2009;61:768–84.

    Article  CAS  PubMed  Google Scholar 

  21. Lavasanifar A, Samuel J, Kwon G. Poly(ethylene oxide)-block-poly(L-amino acid) micelles for drug delivery. Adv Drug Deliv Rev. 2002;54:169–90.

    Article  CAS  PubMed  Google Scholar 

  22. Kataoka K, Yokoyama M, Kwon GS, Okano T, Sakurai Y. Block copolymer micelles as vehicles for drug delivery. J Control Release. 1993;24:119–32.

    Article  CAS  Google Scholar 

  23. Blanco E, Kessinger CW, Sumer BD, Gao J. Multifunctional micellar nanomedicine for cancer therapy. Exp Biol Med. 2009;234:123–31.

    Article  CAS  Google Scholar 

  24. Bae Y, Jang W-D, Nishiyama N, Fukushima S, Kataoka K. Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery. Mol BioSyst. 2005;1:242–50.

    Article  CAS  PubMed  Google Scholar 

  25. Bae Y, Nishiyama N, Kataoka K. In vivo antitumor activity of the folate-conjugated pH-sensitive polymeric micelle selectively releasing adriamycin in the intracellular acidic compartments. Bioconjug Chem. 2007;18:1131–9.

    Article  CAS  PubMed  Google Scholar 

  26. Bae Y, Nishiyama N, Fukushima S, Koyama H, Matsumura Y, Kataoka K. Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy. Bioconjug Chem. 2005;16:122–30.

    Article  CAS  PubMed  Google Scholar 

  27. Nakanishi T, Fukushima S, Okamoto K, Suzuki M, Matsumura Y, Yokoyama M et al. Development of the polymer micelle carrier system for doxorubicin. J Control Release. 2001;74:295–302.

    Article  CAS  PubMed  Google Scholar 

  28. Suzuki H, Nakai D, Seita T, Sugiyama Y. Design of a drug delivery system for targeting based on pharmacokinetic consideration. Adv Drug Deliv Rev. 1996;19:335–57.

    Article  CAS  Google Scholar 

  29. Kaneko T, Willner D, Monkovic I, Knipe JO, Braslawsky GR, Greenfield RS et al. New hydrazone derivatives of adriamycin and their immunoconjugates—a correlation between acid stability and cytotoxicity. Bioconjug Chem. 1991;2:133–41.

    Article  CAS  PubMed  Google Scholar 

  30. West KR, Otto S. Reversible covalent chemistry in drug delivery. Curr Drug Discov Technol. 2005;2:123–60.

    Article  CAS  PubMed  Google Scholar 

  31. Kratz F, Beyer U, Schutte MT. Drug-polymer conjugates containing acid-cleavable bonds. Crit Rev Ther Drug. 1999;16:245–88.

    Article  CAS  Google Scholar 

  32. Lee ES, Gao Z, Bae YH. Recent progress in tumor pH targeting nanotechnology. J Control Release. 2008;132:164–70.

    Article  CAS  PubMed  Google Scholar 

  33. Callahan J, Kopeckova P, Kopecek J. Intracellular trafficking and subcellular distribution of a large array of HPMA copolymers. Biomacromolecules. 2009;10:1704–14.

    Article  CAS  Google Scholar 

  34. Jones AT, Gumbleton M, Duncan R. Understanding endocytic pathways and intracellular trafficking: a prerequisite for effective design of advanced drug delivery systems. Adv Drug Deliv Rev. 2003;55:1353–7.

    Article  CAS  PubMed  Google Scholar 

  35. Bae Y, Fukushima S, Harada A, Kataoka K. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew Chem Int Ed. 2003;42:4640–3.

    Article  CAS  Google Scholar 

  36. Cammas S, Kataoka K. Functional poly (ethylene oxide)-co-(β-benzyl-L-aspartate) polymeric micelles: block copolymer synthesis and micelles formation. Macromol Chem Phys. 1995;196:1899–905.

    Article  CAS  Google Scholar 

  37. Yokoyama M, Miyauchi M, Yamada N, Okano T, Kataoka K, Inoue S. Polymer micelles as novel drug carriers: adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer. J Control Release. 1990;11:269–78.

    Article  CAS  Google Scholar 

  38. Allen C, Maysinger D, Eisenberg A. Nano-engineering block copolymer aggregates for drug delivery. Colloids Surf, B Biointerfaces. 1999;16:3–27.

    Article  CAS  Google Scholar 

  39. Kataoka K, Matsumoto T, Yokoyama M, Okano T, Sakurai Y, Fukushima S et al. Doxorubicin-loaded poly(ethylene glycol)-poly(β-benzyl-L-aspartate) copolymer micelles: their pharmaceutical characteristics and biological significance. J Control Release. 2000;64:143–53.

    Article  CAS  PubMed  Google Scholar 

  40. Fukushima S, Machida M, Akutsu T, Shimizu K, Tanaka S, Okamoto K et al. Roles of adriamycin and adriamycin dimer in antitumor activity of the polymeric micelle carrier system. Colloids Surf, B Biointerfaces. 1999;16:227–36.

    Article  CAS  Google Scholar 

  41. Yokoyama M, Satoh A, Sakurai Y, Okano T, Matsumura Y, Kakizoe T et al. Incorporation of water-insoluble anticancer drug into polymeric micelles and control of their particle size. J Control Release. 1998;55:219–29.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGEMENTS

Authors acknowledge financial support provided by the Kentucky Lung Cancer Research Program.

Author information

Authors and Affiliations

  1. Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky, 40536, USA

    Andrei Ponta & Younsoo Bae

Authors
  1. Andrei Ponta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Younsoo Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Younsoo Bae.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ponta, A., Bae, Y. PEG-poly(amino acid) Block Copolymer Micelles for Tunable Drug Release. Pharm Res 27, 2330–2342 (2010). https://doi.org/10.1007/s11095-010-0120-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0120-z

KEY WORDS

Search

Navigation