Skip to main content

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

  • Chapter
  • First Online:
  • 2098 Accesses

Part of the book series: Nanostructure Science and Technology ((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.

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

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Notes

  1. 1.

     Examples of this strategy are pervasive in our early literature up through 2007. As an alternative, using diamines like piperazine often leads to addition at both amines and the production of a side product that can be difficult to separate and sometimes to detect.

References

  1. Duncan R (2003) The dawning era of polymer therapeutics. Nat Rev Drug Discov 2:347–360

    Article  Google Scholar 

  2. Putnam D (2008) Drug delivery: the heart of the matter. Nat Mater 7:836–837

    Article  Google Scholar 

  3. Menjoge AR, Kannan RM, Tomalia DA (2010) Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications. Drug Discov Today 15:171–185

    Article  Google Scholar 

  4. Scripture CD, Figg WD, Sparreboom A (2005) Paclitaxel chemotherapy: from empiricism to a mechanism-based formulation strategy. Ther Clin Risk Manag 1:107–114

    Article  Google Scholar 

  5. Crown J, O’Leary M, Ooi WS (2004) Docetaxel and paclitaxel in the treatment of breast cancer: a review of clinical experience. Oncologist 9:24–32

    Article  Google Scholar 

  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 7:850–856

    Article  Google Scholar 

  7. Hawkins MJ, Soon-Shiong P, Desai N (2008) Protein nanoparticles as drug carriers in clinical medicine. Adv Drug Deliv Rev 60:876–885

    Article  Google Scholar 

  8. Bonomi P (2007) Paclitaxel poliglumex (PPX, CT-2103): macromolecular medicine for advanced non-small-cell lung cancer. Expert Rev Anticancer Ther 7:415–422

    Article  Google Scholar 

  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 7:417–419

    Article  Google Scholar 

  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 21:405

    Google Scholar 

  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 12:315–323

    Article  Google Scholar 

  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 17:1464–1472

    Article  Google Scholar 

  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 5:1044–1054

    Article  Google Scholar 

  14. Vrudhula VM, MacMaster JF, Li Z, Kerr DE, Senter PD (2002) Reductively activated disulfide prodrugs of paclitaxel. Bioorg Med Chem Lett 12:3591–3594

    Article  Google Scholar 

  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 7:572–579

    Article  Google Scholar 

  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 13:662–671

    Article  Google Scholar 

  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 14:5012–5019

    Article  Google Scholar 

  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 10:7382–7391

    Article  Google Scholar 

  19. Guillemard V, Saragovi HU (2001) Taxane-antibody conjugates afford potent cytotoxicity, enhanced solubility, and tumor target selectivity. Cancer Res 61:694–699

    Google Scholar 

  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 466:1445–1468

    Article  Google Scholar 

  21. Steffensen MB, Simanek EE (2003) Chemoselective building blocks for dendrimers from relative reactivity data. Org Lett 5:2359–2361

    Article  Google Scholar 

  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 49:1152–1154

    Article  Google Scholar 

  23. Hollink E, Simanek EE (2006) A divergent route to diversity in macromolecules. Org Lett 8:2293–2295

    Article  Google Scholar 

  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 31:1283–1290

    Article  Google Scholar 

  25. Lim J, Mintzer MA, Perez LM, Simanek EE (2010) Synthesis of odd generation triazine dendrimers using a divergent, hypermonomer approach. Org Lett 12:1148–1151

    Article  Google Scholar 

  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 126:10044–10048

    Article  Google Scholar 

  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 5541–5542

    Google Scholar 

  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 18:5749–5753

    Article  Google Scholar 

  29. Lim J, Simanek EE (2008) Synthesis of water-soluble dendrimers based on melamine bearing 16 paclitaxel groups. Org Lett 10:201–204

    Article  Google Scholar 

  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 20:2154–2161

    Article  Google Scholar 

  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 73:2357–2366

    Article  Google Scholar 

  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 86:151

    Google Scholar 

  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 42:1089–1105

    Article  Google Scholar 

  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 5:540–547

    Article  Google Scholar 

  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 6:6387–6392

    Google Scholar 

  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: 572

    Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eric E. Simanek .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Simanek, E.E., Lim, J. (2012). Paclitaxel-Triazine Dendrimer Constructs: Efficacy, Toxicity, and Characterization. In: Svenson, S., Prud'homme, R. (eds) Multifunctional Nanoparticles for Drug Delivery Applications. Nanostructure Science and Technology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-2305-8_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-2305-8_5

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4614-2304-1

  • Online ISBN: 978-1-4614-2305-8

  • eBook Packages: EngineeringEngineering (R0)

Publish with us

Policies and ethics