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A thermally responsive biopolymer conjugated to an acid-sensitive derivative of paclitaxel stabilizes microtubules, arrests cell cycle, and induces apoptosis

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Summary

Poor aqueous solubility limits the therapeutic index of paclitaxel as an anti-cancer drug. Synthesis of soluble prodrugs of paclitaxel, or conjugation of the drug to macromolecular carriers have been reported to increase its water-solubility. Macromolecular drug carriers have an added advantage of targeting the drug to the tumor site due to the abnormal tumor blood and lymphatic vasculature. This study describes a thermally responsive macromolecular carrier, elastin-like polypeptide (ELP) for the delivery of paclitaxel. Paclitaxel was bound to ELP by conjugation with the 6-maleimidocaproyl hydrazone derivative of paclitaxel, an acid-sensitive paclitaxel prodrug, for the potential treatment of breast cancer. Focused hyperthermia above a specific transition temperature at the site of a tumor causes ELP to aggregate and accumulate, thereby increasing the local concentration of the drug cargo. The paclitaxel prodrug described here bears an acid-sensitive linker that is cleavable at the lysosomal/endosomal pH, which allows a controlled intracellular release of the drug. The ELP-delivered paclitaxel in the presence of hyperthermia inhibits MCF-7 cell proliferation by stabilizing the microtubule structures, arresting the cells at the G2/M stage, and inducing apoptosis in a manner similar to conventional paclitaxel. It also inhibits proliferation of a paclitaxel resistant MCF-7 cell line. These data provide an in vitro proof of concept for the use of ELP as a delivery vehicle of paclitaxel.

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References

  1. Maeda H, Seymour LW, Miyamoto Y (1992) Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo. Bioconjug Chem 3:351–362

    Article  PubMed  CAS  Google Scholar 

  2. Yamaoka T, Tabata Y, Ikada Y (1994) Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci 83:601–606

    Article  PubMed  CAS  Google Scholar 

  3. Kratz F (2007) DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trials. Expert Opin Investig Drugs 16:855–866

    Article  PubMed  CAS  Google Scholar 

  4. Schmaljohann D (2006) Thermo- and pH-responsive polymers in drug delivery. Adv Drug Deliv Rev 58:1655–1670

    Article  PubMed  CAS  Google Scholar 

  5. Raucher D, Massodi I, Bidwell GL (2008) Thermally targeted delivery of chemotherapeutics and anti-cancer peptides by elastin-like polypeptide. Expert Opin Drug Deliv 5:353–369

    Article  PubMed  CAS  Google Scholar 

  6. Wu AM, Senter PD (2005) Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol 23:1137–1146

    Article  PubMed  CAS  Google Scholar 

  7. Sudimack J, Lee RJ (2000) Targeted drug delivery via the folate receptor. Adv Drug Deliv Rev 41:147–162

    Article  PubMed  CAS  Google Scholar 

  8. Laakkonen P, Zhang L, Ruoslahti E (2008) Peptide targeting of tumor lymph vessels. Ann NY Acad Sci 1131:37–43

    Article  PubMed  CAS  Google Scholar 

  9. Bidwell GL 3rd, Raucher D (2005) Application of thermally responsive polypeptides directed against c-Myc transcriptional function for cancer therapy. Mol Cancer Ther 4:1076–1085

    Article  PubMed  CAS  Google Scholar 

  10. Urry DW (1988) Entropic elastic processes in protein mechanisms. I. Elastic structure due to an inverse temperature transition and elasticity due to internal chain dynamics. J Protein Chem 7:1–34

    Article  PubMed  CAS  Google Scholar 

  11. MacEwan SR, Chilkoti A (2010) Elastin-like polypeptides: biomedical applications of tunable biopolymers. Biopolymers 94:60–77

    Article  PubMed  CAS  Google Scholar 

  12. Liu W et al (2006) Tumor accumulation, degradation and pharmacokinetics of elastin-like polypeptides in nude mice. J Control Release 116:170–178

    Article  PubMed  CAS  Google Scholar 

  13. Bidwell GL 3rd et al (2010) A thermally targeted peptide inhibitor of symmetrical dimethylation inhibits cancer-cell proliferation. Peptides 31:834–841

    Article  PubMed  CAS  Google Scholar 

  14. Massodi I, et al. (2009) Inhibition of ovarian cancer cell proliferation by a cell cycle inhibitory peptide fused to a thermally responsive polypeptide carrier. Int J Cancer 126(2):533–544. doi:10.1002/ijc.24725

    Article  Google Scholar 

  15. Massodi I, Thomas E, Raucher D (2009) Application of thermally responsive elastin-like polypeptide fused to a lactoferrin-derived peptide for treatment of pancreatic cancer. Molecules 14:1999–2015

    Article  PubMed  CAS  Google Scholar 

  16. Liu W, et al. (2006) Tumor accumulation, degradation and pharmacokinetics of elastin-like polypeptides in nude mice. J Control Release 116(2):170–178

    Article  PubMed  CAS  Google Scholar 

  17. Weiss RB et al (1990) Hypersensitivity reactions from taxol. J Clin Oncol 8:1263–1268

    PubMed  CAS  Google Scholar 

  18. Gradishar WJ (2006) Albumin-bound paclitaxel: a next-generation taxane. Expert Opin Pharmacother 7:1041–1053

    Article  PubMed  CAS  Google Scholar 

  19. Rodrigues P et al (2003) Synthesis and in vitro efficacy of acid-sensitive poly(ethylene glycol) paclitaxel conjugates. Bioorg Med Chem Lett 13:355–360

    Article  PubMed  CAS  Google Scholar 

  20. Ajaj KA, Biniossek ML, Kratz F (2009) Development of protein-binding bifunctional linkers for a new generation of dual-acting prodrugs. Bioconjug Chem 20:390–396

    Article  PubMed  CAS  Google Scholar 

  21. Rousselle C et al (2001) Enhanced delivery of doxorubicin into the brain via a peptide-vector-mediated strategy: saturation kinetics and specificity. J Pharmacol Exp Ther 296:124–131

    PubMed  CAS  Google Scholar 

  22. Meyer DE, Chilkoti A (2002) Genetically encoded synthesis of protein-based polymers with precisely specified molecular weight and sequence by recursive directional ligation: examples from the elastin-like polypeptide system. Biomacromolecules 3:357–367

    Article  PubMed  CAS  Google Scholar 

  23. Daniell H et al (1997) Hyperexpression of a synthetic protein-based polymer gene. Methods Mol Biol 63:359–371

    PubMed  CAS  Google Scholar 

  24. Bidwell GL 3rd et al (2007) Development of elastin-like polypeptide for thermally targeted delivery of doxorubicin. Biochem Pharmacol 73:620–631

    Article  PubMed  CAS  Google Scholar 

  25. Dreher MR et al (2003) Evaluation of an elastin-like polypeptide-doxorubicin conjugate for cancer therapy. J Control Release 91:31–43

    Article  PubMed  CAS  Google Scholar 

  26. Massodi I, Bidwell GL 3rd, Raucher D (2005) Evaluation of cell penetrating peptides fused to elastin-like polypeptide for drug delivery. J Control Release 108:396–408

    Article  PubMed  CAS  Google Scholar 

  27. Wang TH, Wang HS, Soong YK (2000) Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer 88:2619–2628

    Article  PubMed  CAS  Google Scholar 

  28. Villeneuve DJ et al (2006) cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat 96:17–39

    Article  PubMed  CAS  Google Scholar 

  29. Bidwell GL 3rd et al (2007) A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance. Invest New Drugs 25:313–326

    Article  PubMed  CAS  Google Scholar 

  30. Griset AP et al (2009) Expansile nanoparticles: synthesis, characterization, and in vivo efficacy of an acid-responsive polymeric drug delivery system. J Am Chem Soc 131:2469–2471

    Article  PubMed  CAS  Google Scholar 

  31. Li Y et al (2009) Novel thermo-sensitive core-shell nanoparticles for targeted paclitaxel delivery. Nanotechnology 20:065104

    Article  PubMed  Google Scholar 

  32. Torres K, Horwitz SB (1998) Mechanisms of taxol-induced cell death are concentration dependent. Cancer Res 58:3620–3626

    PubMed  CAS  Google Scholar 

  33. Mansilla S, Bataller M, Portugal J (2006) Mitotic catastrophe as a consequence of chemotherapy. Anticancer Agents Med Chem 6:589–602

    Article  PubMed  CAS  Google Scholar 

  34. Massodi I et al (2010) Inhibition of ovarian cancer cell proliferation by a cell cycle inhibitory peptide fused to a thermally responsive polypeptide carrier. Int J Cancer 126:533–544

    Article  PubMed  CAS  Google Scholar 

  35. Brigger I, Dubernet C, Couvreur P (2002) Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev 54:631–651

    Article  PubMed  CAS  Google Scholar 

  36. Guo B et al (2003) Potent killing of paclitaxel- and doxorubicin-resistant breast cancer cells by calphostin C accompanied by cytoplasmic vacuolization. Breast Cancer Res Treat 82:125–141

    Article  PubMed  CAS  Google Scholar 

  37. Orr GA et al (2003) Mechanisms of taxol resistance related to microtubules. Oncogene 22:7280–7295

    Article  PubMed  CAS  Google Scholar 

  38. Ambudkar SV et al (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39:361–398

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This research was supported by grants from the National Science Foundation (CBET-0931041) and the National Institute of Health (R43 CA135799-01A2). We thank Ms. Rowshan Begum for purification of the proteins used in the study, and Dr. Gene L. Bidwell III and Ms. Emily H. Thomas for helpful discussion.

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Authors and Affiliations

  1. University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA

    Shama Moktan & Drazen Raucher

  2. Division of Macromoleuclar Prodrugs, Breisacher Strasse 117, 79106, Freiburg, Germany

    Claudia Ryppa & Felix Kratz

  3. 2500 North State Street, Jackson, MS, 39216, USA

    Drazen Raucher

Authors
  1. Shama Moktan
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  2. Claudia Ryppa
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  3. Felix Kratz
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  4. Drazen Raucher
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Correspondence to Drazen Raucher.

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Moktan, S., Ryppa, C., Kratz, F. et al. A thermally responsive biopolymer conjugated to an acid-sensitive derivative of paclitaxel stabilizes microtubules, arrests cell cycle, and induces apoptosis. Invest New Drugs 30, 236–248 (2012). https://doi.org/10.1007/s10637-010-9560-x

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  • DOI: https://doi.org/10.1007/s10637-010-9560-x

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