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Release, Partitioning, and Conjugation Stability of Doxorubicin in Polymer Micelles Determined by Mechanistic Modeling

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ABSTRACT

Purpose

To better understand the mechanistic parameters that govern drug release from polymer micelles with acid-labile linkers.

Methods

A mathematical model was developed to describe drug release from block copolymer micelles composed of a poly(ethylene glycol) shell and a poly(aspartate) core, modified with drug binding linkers for pH-controlled release [hydrazide (HYD), aminobenzoate-hydrazide (ABZ), or glycine-hydrazide (GLY)]. Doxorubicin (Dox) was conjugated to the block copolymers through acid-labile hydrazone bonds. The polymer drug conjugates were used to prepare three polymer micelles (HYD-M, ABZ-M, and GLY-M). Drug release studies were performed to identify the factors governing pH-sensitive release of Dox. The effect of prolonged storage of copolymer material on release kinetics was also observed.

Results

Biphasic drug release kinetics were observed for all three micelle formulations. The developed model was able to quantify observed release kinetics upon the inclusion of terms for unconjugated Dox and two populations of conjugated Dox. Micelle/water partitioning of Dox was also incorporated into the model and found significant in all micelles under neutral conditions but reduced under acidic conditions. The drug binding linker played a major role in drug release as the extent of Dox release at specific time intervals was greater at pH 5.0 than at pH 7.4 (HYD-M > ABZ-M > GLY-M). Mathematical modeling was also able to correlate changes in release kinetics with the instability of the hydrazone conjugation of Dox during prolonged storage.

Conclusion

These results illustrate the potential utility of mechanistic modeling to better assess release characteristics intrinsic to a particular drug/nanoparticle system.

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REFERENCES

  1. Barenholz Y. Doxil (R)—the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117–34.

    Article  CAS  PubMed  Google Scholar 

  2. Drummond DC, Noble CO, Hayes ME, Park JW, Kirpotin DB. Pharmacokinetics and in vivo drug release rates in liposomal nanocarrier development. J Pharm Sci. 2008;97(11):4696–740.

    Article  CAS  PubMed  Google Scholar 

  3. Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer. 2005;5:161–71.

    Article  CAS  PubMed  Google Scholar 

  4. Domingo C, Saurina J. An overview of the analytical characterization of nanostructured drug delivery systems: towards green and sustainable pharmaceuticals: a review. Anal Chim Acta. 2012;744:8–22.

    Article  CAS  PubMed  Google Scholar 

  5. Mehnert W, Mäder K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev. 2012;64:83–101.

    Article  Google Scholar 

  6. Cho EJ, Holback H, Liu KC, Abouelmagd SA, Park J, Yeo Y. Nanoparticle characterization: state of the art, challenges, and emerging technologies. Mol Pharm. 2013;10(6):2093–110.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Modi S, Anderson BD. Determination of drug release kinetics from nanoparticles: overcoming pitfalls of the dynamic dialysis method. Mol Pharm. 2013;10(8):3076–89.

    Article  CAS  PubMed  Google Scholar 

  8. Fugit KD, Anderson BD. The role of pH and ring-opening hydrolysis kinetics on liposomal release of topotecan. J Control Release. 2014;174:88–97.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. 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(38):4640–3.

    Article  CAS  Google Scholar 

  10. Bae Y, Nishiyama N, Fukushima S, Koyama H, Yasuhiro M, 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. 2004;16(1):122–30.

    Article  Google Scholar 

  11. Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. J Control Release. 2001;73(2–3):137–72.

    Article  CAS  PubMed  Google Scholar 

  12. Kozlov MY, Melik-Nubarov NS, Batrakova EV, Kabanov AV. Relationship between pluronic block copolymer structure, critical micellization concentration and partitioning coefficients of low molecular mass solutes. Macromolecules. 2000;33(9):3305–13.

    Article  CAS  Google Scholar 

  13. Batrakova EV, Kabanov AV. Pluronic block copolymers: evolution of drug delivery concept from inert nanocarriers to biological response modifiers. J Control Release. 2008;130(2):98–106.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Frimpong RA, Fraser S, Zach HJ. Synthesis and temperature response analysis of magnetic-hydrogel nanocomposites. J Biomed Mater Res A. 2007;80A(1):1–6.

    Article  CAS  Google Scholar 

  15. Lu D-X, Wen X-T, Liang J, Zhang X-D, Gu Z-W, Fan Y-J. Novel pH-sensitive drug delivery system based on natural polysaccharide for doxorubicin release. Chin J Polym Sci. 2008;26(3):369–74.

    Article  Google Scholar 

  16. Haran G, Cohen R, Bar LK, Barenholz Y. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta. 1993;1151(2):201–15.

    Article  CAS  PubMed  Google Scholar 

  17. Gaber MH, Wu NZ, Hong K, Huang SK, Dewhirst MW, Papahadjopoulos D. Thermosensitive liposomes: extravasation and release of contents in tumor microvascular networks. Int J Radiat Oncol. 1996;36(5):1177–87.

    Article  CAS  Google Scholar 

  18. Kong G, Dewhirst MW. Review hyperthermia and liposomes. Int J Hyperther. 1999;15(5):345–70.

  19. Ono A, Takeuchi K, Sukenari A, Suzuki T, Adachi I, Ueno M. Reconsideration of drug release from temperature-sensitive liposomes. Biol Pharm Bull. 2002;25(1):97–101.

    Article  CAS  PubMed  Google Scholar 

  20. Joguparthi V, Feng S, Anderson BD. Determination of intraliposomal pH and its effect on membrane partitioning and passive loading of a hydrophobic camptothecin, DB-67. Int J Pharm. 2008;352(1–2):17–28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Tai L-A, Tsai P-J, Wang Y-C, Wang Y-J, Lo L-W, Yang C-S. Thermosensitive liposomes entrapping iron oxide nanoparticles for controllable drug release. Nanotechnology. 2009;20(13):1–9.

    Article  Google Scholar 

  22. Thomas CR, Ferris DP, Lee J-H, Choi E, Cho MH, Kim ES, et al. Noninvasive remote-controlled release of drug molecules in vitro using magnetic actuation of mechanized nanoparticles. J Am Chem Soc. 2010;132(31):10623–5.

    Article  CAS  PubMed  Google Scholar 

  23. Amstad E, Kohlbrecher J, Müller E, Schweizer T, Textor M, Reimhult E. Triggered release from liposomes through magnetic actuation of iron oxide nanoparticle containing membranes. Nano Lett. 2011;11(4):1664–70.

    Article  CAS  PubMed  Google Scholar 

  24. Bae Y, Kataoka K. Intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) block copolymers. Adv Drug Deliv Rev. 2009;61(10):768–84.

    Article  CAS  PubMed  Google Scholar 

  25. Ponta A, Bae Y. PEG-poly(amino acid) block copolymer micelles for tunable drug release. Pharm Res. 2010;27(11):2330–42.

    Article  CAS  PubMed  Google Scholar 

  26. Lee HJ, Bae Y. Pharmaceutical differences between block copolymer self-assembled and cross-linked nanoassemblies as carriers for tunable drug release. Pharm Res. 2013;30(2):478–88.

    Article  CAS  PubMed  Google Scholar 

  27. West KR, Otto S. Reversible covalent chemistry in drug delivery. Curr Drug Discov Technol. 2005;2(3):123–60.

    Article  CAS  PubMed  Google Scholar 

  28. Baker MA, Gray BD, Ohlsson-Wilhelm BM, Carpenter DC, Muirhead KA. Zyn-Linked colchicines: controlled-release lipophilic prodrugs with enhanced antitumor efficacy. J Control Release. 1996;40(1–2):89–100.

    Article  CAS  Google Scholar 

  29. Etrych T, Chytil P, Jelinkova M, Rihova B, Ulbrich K. Synthesis of HPMA copolymers containing doxorubicin bound via a hydrazone linkage. Macromol Biosci. 2002;2(1):43–52.

    Article  CAS  Google Scholar 

  30. Barbour N, Paborji M, Alexander T, Coppola W, Bogardus J. Stabilization of chimeric BR96-doxorubicin immunoconjugate. Pharm Res. 1995;12(2):215–22.

    Article  CAS  PubMed  Google Scholar 

  31. Fugit KD, Anderson BD. Dynamic, non-sink method for the simultaneous determination of drug permeability and binding coefficients in liposomes. Mol Pharm. 2014;11(4):1314–1325.

  32. Ponta A, Bae Y. Tumor-preferential sustained drug release enhances antitumor activity of block copolymer micelles. J Drug Target. 2014;22(7):619–628.

  33. Moreno-Bautista G, Tam KC. Evaluation of dialysis membrane process for quantifying the in vitro drug-release from colloidal drug carriers. Coll Surf A. 2011;389(1–3):299–303.

    Article  CAS  Google Scholar 

  34. Gupta PK, Hung CT, Perrier DG. Quantitation of the release of Doxorubicin from colloidal dosage forms using dynamic dialysis. J Pharm Sci. 1987;76(2):141–5.

    Article  CAS  PubMed  Google Scholar 

  35. Washington C. Evaluation of non-sink dialysis methods for the measurement of drug release from colloids: effects of drug partition. Int J Pharm. 1989;56(1):71–4.

    Article  CAS  Google Scholar 

  36. Washington C. Drug release from microdisperse systems: a critical review. Int J Pharm. 1990;58(1):1–12.

    Article  CAS  Google Scholar 

  37. Sturgeon RJ, Schulman SG. Electronic absorption spectra and protolytic equilibria of doxorubicin: direct spectrophotometric determination of microconstants. J Pharm Sci. 1977;66(7):958–61.

    Article  CAS  PubMed  Google Scholar 

  38. Joguparthi V, Xiang T-X, Anderson BD. Liposome transport of hydrophobic drugs: Gel phase lipid bilayer permeability and partitioning of the lactone form of a hydrophobic camptothecin, DB-67. J Pharm Sci. 2008;97(1):400–20.

    Article  CAS  PubMed  Google Scholar 

  39. Li F, Danquah M, Mahato RI. Synthesis and characterization of amphiphilic lipopolymers for micellar drug delivery. Biomacromolecules. 2010;11(10):2610–20.

    Article  CAS  PubMed  Google Scholar 

  40. Sutton D, Wang SH, Nasongkla N, Gao JM, Dormidontova EE. Doxorubicin and beta-lapachone release and interaction with micellar core materials: experiment and modeling. Exp Biol Med. 2007;232(8):1090–9.

    Article  CAS  Google Scholar 

  41. Kwon G, Naito M, Yokoyama M, Okano T, Sakurai Y, Kataoka K. Block copolymer micelles for drug delivery: loading and release of doxorubicin. J Control Release. 1997;48(2–3):195–201.

    Article  CAS  Google Scholar 

  42. Guo X, Shi C, Wang J, Di S, Zhou S. pH-triggered intracellular release from actively targeting polymer micelles. Biomaterials. 2013;34(18):4544–54.

    Article  CAS  PubMed  Google Scholar 

  43. Lee SJ, Bae Y, Kataoka K, Kim D, Lee DS, Kim SC. In vitro release and in vivo anti-tumor efficacy of doxorubicin from biodegradable temperature-sensitive star-shaped PLGA-PEG block copolymer hydrogel. Polym J. 2008;40(2):171–6.

    Article  CAS  Google Scholar 

  44. La SB, 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. 1996;85(1):85–90.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

This work is partially supported by the Kentucky Lung Cancer Research Program and the University of Kentucky Cancer Nanotechnology Training Center (UK-CNTC), grant R25CA153954 from the National Cancer Institute. The content herein is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky, 40536-0596, USA

    Andrei Ponta, Kyle D. Fugit, Bradley D. Anderson & Younsoo Bae

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  1. Andrei Ponta
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  2. Kyle D. Fugit
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  3. Bradley D. Anderson
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  4. Younsoo Bae
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Correspondence to Younsoo Bae.

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Ponta, A., Fugit, K.D., Anderson, B.D. et al. Release, Partitioning, and Conjugation Stability of Doxorubicin in Polymer Micelles Determined by Mechanistic Modeling. Pharm Res 32, 1752–1763 (2015). https://doi.org/10.1007/s11095-014-1573-2

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