Paclitaxel-Triazine Dendrimer Constructs: Efficacy, Toxicity, and Characterization

Chapter
Part of the Nanostructure Science and Technology book series (NST)

Abstract

This chapter reviews work from our laboratory over the last 10 years as it pertains to efforts focused on the exploration of triazine dendrimers as vehicles for drug delivery. The discussion is restricted to our efforts in paclitaxel-laden constructs, an area that we have had the most success and have made the greatest investment in time and energy. Areas of emphasis include the evolution of synthetic strategies, characterization, biodistribution, biocompatibility, safety and toxicity, efficacy, and therapeutic advantage. Throughout, limitations and challenges to these efforts are delineated. This chapter is not intended to exhaustively recapitulate the published work. Interested readers are referred to the original research publications and the supporting information provided with each. Instead, the intent is to provide insight into the evolution of the design and to realize this opportunity to share intuitions currently guiding these efforts which, accordingly, are less (or as yet un-) substantiated with experiment.

Keywords

Toxicity Sarcoma Paclitaxel Disulfide Anhydride 

Notes

Acknowledgments

The authors thank Dr. Sonke Svenson for the opportunity to convey the contents of our presentation at the National ACS Meeting in Boston (2010) in this forum. In addition to the long-standing efforts of coworkers identified in the relevant citations, the authors wish to thank Dr. Xiankai Sun and Su-Tang Lo of the University of Texas Southwestern Medical Center for ongoing collaboration in this area. Additionally, individuals of the Nanotechnology Characterization Laboratory who contributed to the collection of data on these dendrimers include Stephan Stern, Jeffrey D. Clogston, Jiwen Zheng, Pavan P. Adiseshaiah, Marina Dobrovolskaia, as led by Anil Patri. This work is supported with funds from Texas Christian University. The work is impacted by partnerships with others in related areas, including Drs. Thomas Kissel and Olivia Merkel in Marburg, Dr. Sunil Shaunak in London, Drs. Pete Choyke and Hisataka Kobayashi in Bethesda, and Giovanni Pavan at SUPSI.

References

  1. 1.
    Duncan R (2003) The dawning era of polymer therapeutics. Nat Rev Drug Discov 2:347–360CrossRefGoogle Scholar
  2. 2.
    Putnam D (2008) Drug delivery: the heart of the matter. Nat Mater 7:836–837CrossRefGoogle Scholar
  3. 3.
    Menjoge AR, Kannan RM, Tomalia DA (2010) Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications. Drug Discov Today 15:171–185CrossRefGoogle Scholar
  4. 4.
    Scripture CD, Figg WD, Sparreboom A (2005) Paclitaxel chemotherapy: from empiricism to a mechanism-based formulation strategy. Ther Clin Risk Manag 1:107–114CrossRefGoogle Scholar
  5. 5.
    Crown J, O’Leary M, Ooi WS (2004) Docetaxel and paclitaxel in the treatment of breast cancer: a review of clinical experience. Oncologist 9:24–32CrossRefGoogle Scholar
  6. 6.
    Blum JL, Savin MA, Edelman G, Pippen JE, Robert NJ, Geister BV, Kirby RL, Clawson A, O’Shaughnessy JA (2007) Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes. Clin Breast Cancer 7:850–856CrossRefGoogle Scholar
  7. 7.
    Hawkins MJ, Soon-Shiong P, Desai N (2008) Protein nanoparticles as drug carriers in clinical medicine. Adv Drug Deliv Rev 60:876–885CrossRefGoogle Scholar
  8. 8.
    Bonomi P (2007) Paclitaxel poliglumex (PPX, CT-2103): macromolecular medicine for advanced non-small-cell lung cancer. Expert Rev Anticancer Ther 7:415–422CrossRefGoogle Scholar
  9. 9.
    Albain KS, Belani CP, Bonomi P, O’Byrne KJ, Schiller JH, Socinski M (2006) PIONEER: a phase III randomized trial of paclitaxel poliglumex versus paclitaxel in chemotherapy-naive women with advanced-stage non-small-cell lung cancer and performance status of 2. Clin Lung Cancer 7:417–419CrossRefGoogle Scholar
  10. 10.
    Beeram M, Rowinsky EK, Hammond LA, Patnaik A, Schwartz GH, de Bono JS, Forero L, Forouzesh B, Berg KE, Rubin EH, Beers S, Killian A, Kwiatek J, McGuire J, Spivey L, Takimoto CH (2002) A phase I pharmacokinetic (PK) study of PEG-paclitaxel in patients with advanced solid tumors (Abstract). Proc Am Soc Clin Oncol 21:405Google Scholar
  11. 11.
    Meerum Terwogt JM, ten Bokkel Huinink WW, Schellens JH, Schot M, Mandjes IA, Zurlo MG, Rocchetti M, Rosing H, Koopman FJ, Beijnen JH (2001) Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel. Anticancer Drugs 12:315–323CrossRefGoogle Scholar
  12. 12.
    Khandare JJ, Jayant S, Singh A, Chandna P, Wang Y, Vorsa N, Minko T (2006) Dendrimer versus linear conjugate: influence of polymeric architecture on the delivery and anticancer effect of paclitaxel. Bioconjug Chem 17:1464–1472CrossRefGoogle Scholar
  13. 13.
    Gao Y, Chen L, Gu W, Xi Y, Lin L, Li Y (2008) Targeted nanoassembly loaded with docetaxel improves intracellular drug delivery and efficacy in murine breast cancer model. Mol Pharm 5:1044–1054CrossRefGoogle Scholar
  14. 14.
    Vrudhula VM, MacMaster JF, Li Z, Kerr DE, Senter PD (2002) Reductively activated disulfide prodrugs of paclitaxel. Bioorg Med Chem Lett 12:3591–3594CrossRefGoogle Scholar
  15. 15.
    Majoros IJ, Myc A, Thomas T, Mehta CB, Baker JR (2006) PAMAM dendrimer-based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality. Biomacromolecules 7:572–579CrossRefGoogle Scholar
  16. 16.
    Papas S, Akoumianaki T, Kalogios C, Hadjiarapolglou L, Theodoropoulous PA, Tsikaris V (2007) Synthesis and antitumor activity of peptide-paclitaxel conjugates. J Pept Sci 13:662–671CrossRefGoogle Scholar
  17. 17.
    El Alaoui A, Saha N, Schmidt F, Monneret C, Florent J-C (2006) New Taxol (paclitaxel) prodrugs designed for ADEPT and PMT strategies in cancer chemotherapy. Bioorg Med Chem Lett 14:5012–5019CrossRefGoogle Scholar
  18. 18.
    Zou Y, Fu H, Ghosh S, Farquhar D, Klostergaard J (2004) Antitumor activity of hydrophilic paclitaxel copolymer prodrug using locoregional delivery in human orthotopic non-small cell lung cancer xenograft models. Clin Cancer Res 10:7382–7391CrossRefGoogle Scholar
  19. 19.
    Guillemard V, Saragovi HU (2001) Taxane-antibody conjugates afford potent cytotoxicity, enhanced solubility, and tumor target selectivity. Cancer Res 61:694–699Google Scholar
  20. 20.
    Simanek EE, Hanan A, Lalwani S, Lim J, Mintzer M, Venditto VJ, Vittur B (2010) The eight year thicket of triazine dendrimers: strategies, targets, and applications. Proc R Soc A 466:1445–1468CrossRefGoogle Scholar
  21. 21.
    Steffensen MB, Simanek EE (2003) Chemoselective building blocks for dendrimers from relative reactivity data. Org Lett 5:2359–2361CrossRefGoogle Scholar
  22. 22.
    Moreno KX, Simanek EE (2008) Identification of diamine linkers with differing reactivity and their application in the synthesis of a melamine dendrimers. Tetrahedron Lett 49:1152–1154CrossRefGoogle Scholar
  23. 23.
    Hollink E, Simanek EE (2006) A divergent route to diversity in macromolecules. Org Lett 8:2293–2295CrossRefGoogle Scholar
  24. 24.
    Crampton H, Hollink E, Perez LM, Simanek EE (2007) A divergent route towards single-chemical entity triazine dendrimers with opportunities for structural diversity. New J Chem 31:1283–1290CrossRefGoogle Scholar
  25. 25.
    Lim J, Mintzer MA, Perez LM, Simanek EE (2010) Synthesis of odd generation triazine dendrimers using a divergent, hypermonomer approach. Org Lett 12:1148–1151CrossRefGoogle Scholar
  26. 26.
    Chen HT, Neerman MF, Parrish AR, Simanek EE (2004) Cytotoxicity, hemolysis, and acute in vivo toxicity of dendrimers based on melamine, candidate vehicles for drug delivery. J Am Chem Soc 126:10044–10048CrossRefGoogle Scholar
  27. 27.
    Venditto VJ, Allred K, Allred CD, Simanek EE (2009) Intercepting triazine dendrimer synthesis with nucleophilic pharmacophores as a general strategy toward drug delivery vehicles. Chem Commun 5541–5542Google Scholar
  28. 28.
    Lim J, Venditto VJ, Simanek EE (2010) Synthesis and characterization of a triazine dendrimer that sequesters iron(III) using 12 desferrioxamine B groups. Bioorg Med Chem 18:5749–5753CrossRefGoogle Scholar
  29. 29.
    Lim J, Simanek EE (2008) Synthesis of water-soluble dendrimers based on melamine bearing 16 paclitaxel groups. Org Lett 10:201–204CrossRefGoogle Scholar
  30. 30.
    Lim J, Chouai A, Lo S-T, Liu W, Sun X, Simanek EE (2009) Design, synthesis, characterization, and biological evaluation of triazine dendrimers bearing paclitaxel using ester and ester/disulfide linkages. Biconjug Chem 20:2154–2161CrossRefGoogle Scholar
  31. 31.
    Chouai A, Simanek EE (2008) Kilogram-scale synthesis of a second-generation dendrimer based on 1,3,5-triazine using green and industrially compatible methods with a single chromatographic step. J Org Chem 73:2357–2366CrossRefGoogle Scholar
  32. 32.
    Chouai A, Venditto VJ, Simanek EE, Vanderplas BC, Ragan JA (2009) Large scale green synthesis of a generation-1 melamine (triazine) dendrimer. Organic Synth 86:151Google Scholar
  33. 33.
    Greish K, Fang J, Inutsuka T, Nagamitsu A, Maeda H (2003) Macromolecular therapeutics: advantages and prospects with special emphasis on solid tumour targeting. Clin Pharmacokinet 42:1089–1105CrossRefGoogle Scholar
  34. 34.
    Lim J, Guo Y, Rostollan CL, Stanfield J, Hsieh J-T, Sun X, Simanek EE (2008) The role of the size and number of polyethylene glycol chains in the biodistribution and tumor localization of triazine dendrimers. Mol Pharm 5:540–547CrossRefGoogle Scholar
  35. 35.
    Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 6:6387–6392Google Scholar
  36. 36.
    Majoros IJ, Myc C, Thomas T, Mehta CB, Baker JR, Jr. (2006) PAMAM dendrimer-based multifunctional conjugate for cancer therapy: Synthesis, characterization, and functionality. Biomacromolecules 7: 572Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of ChemistryTexas Christian UniversityFort WorthUSA

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