Skip to main content
Book cover

Polymer Therapeutics I pp 59–94Cite as

Domino Dendrimers

Part of the Advances in Polymer Science book series (POLYMER,volume 192)

Abstract

Domino dendrimers have recently been developed and introduced as a potential platform for a single triggered multi-prodrug. Surprisingly, three independent groups reported similar concepts almost simultaneously. These unique structural dendrimers can release all of their tail units, through a domino-like chain fragmentation, which is initiated by a single cleavage at the dendrimer's core. This chapter reviews the recent efforts to design domino-like dendrimers with emphasis on the application of drug delivery. Incorporation of drug molecules as the tail units and an enzyme substrate as the trigger, can generate a multi-prodrug unit that is activated with a single enzymatic cleavage. Dendritic prodrugs, activated through a single catalytic reaction by a specific enzyme, could present significant advantages in the inhibition of tumor growth, especially if the targeted or secreted enzyme exists at relatively low levels in the malignant tissue. Domino dendrimers may also be applied as a general platform for biosensor molecules, used to detect enzymatic activity.

  • Biosensor
  • Cancer
  • Dendrimer
  • Prodrug
  • Self-immolative

This is a preview of subscription content, access via your institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/12_021
  • Chapter length: 36 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   309.00
Price excludes VAT (USA)
  • ISBN: 978-3-540-32945-9
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   399.00
Price excludes VAT (USA)
Hardcover Book
USD   379.99
Price excludes VAT (USA)
Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Abbreviations

AB2:

three arm star dendritic subunit

AB3:

four arm star dendritic subunit

ALL:

acute lymphoblastic leukemia

AML:

acute myeloid leukemia

Boc:

t-butoxycarbonyl

CPT:

campthotecin

DOX:

doxorubicin

HEL:

human erythroleukemia cell line

HL-60:

human acute myeloid leukemia cell line

IC50 :

inhibition concentration (at 50%)

MOLT-3:

human T-lineage acute lymphoblastic leukemia cell line

PBS:

phosphate buffered saline

PGA:

penicillin G amidase

mCPT:

monomeric CPT dendritic prodrug

tCPT:

trimeric CPT dendritic prodrug

TFA:

trifluoroacetic acid

References

  1. Tomalia DA, Frechet JMJ (2002) Journal of Polymer Science: Polymer Chemistry 40:2719–2728

    CAS  CrossRef  Google Scholar 

  2. Grinstaff MW (2002) Biodendrimers: new polymeric biomaterials for tissue engineering. Chemistry 8:2839–2846

    Google Scholar 

  3. Stiriba S-E, Frey H, Haag R (2002) Angew Chem Int Ed 41:1329–1334

    CrossRef  CAS  Google Scholar 

  4. Patri AK, Majoros IJ, Baker JR (2002) Dendritic polymer macromolecular carriers for drug delivery. Curr Opin Chem Biol 6:466–471

    CrossRef  CAS  Google Scholar 

  5. Kim Y, Zimmerman SC (1998) Applications of dendrimers in bio-organic chemistry. Curr Opin Chem Biol 2:733–742

    CrossRef  CAS  Google Scholar 

  6. Tomalia DA (2004) Birth of a new macromolecular architecture: Dendrimers as quantized building blocks for nanoscale synthetic organic chemistry. Aldrichimica Acta 37:39–57

    CAS  Google Scholar 

  7. Aulenta F, Hayes W, Rannard S (2003) Dendrimers: a new class of nanoscopic containers and delivery devices. Eur Poly J 39:1741–1771

    CAS  CrossRef  Google Scholar 

  8. Boas U, Heegaard PMH (2004) Dendrimers in drug research. Chem Soc Rev 33:43–63

    CrossRef  CAS  Google Scholar 

  9. Bosman AW, Janssen HM, Meijer EW (1999) About dendrimers: structure, physical properties, applications. Chem Revs (Washington, DC) 99:1665–1688

    CrossRef  CAS  Google Scholar 

  10. Kobayashi H, Brechbiel MW (2003) Dendrimer-based macromolecular MRI contrast agents: characteristics and application. Mol Imag 2:1–10

    CAS  CrossRef  Google Scholar 

  11. D'Emanuele A, Jevprasesphant R, Penny J, Attwood D (2004) The use of a dendrimer-propranolol prodrug to bypass efflux transporters and enhance oral bioavailability. J Contr Rel 95:447–453

    CrossRef  Google Scholar 

  12. Radu DR, Lai C-Y, Jeftinija K, Rowe EW, Jeftinija S, Lin VSY (2004) A polyamidoamine dendrimer-capped mesoporous silica nanosphere-based gene transfection reagent. J Am Chem Soc 126:13216–13217

    CrossRef  CAS  Google Scholar 

  13. Kim T-I, Seo HJ, Choi JS, Jang H-S, Baek J, Kim K, Park J-S (2004) PAMAM-PEG-PAMAM: novel triblock copolymer as a biocompatible and efficient gene delivery carrier. Biomacromolecules 5:2487–2492

    CAS  CrossRef  Google Scholar 

  14. Kukowska-Latallo JF, Bielinska AU, Johnson J, Spindler R, Tomalia DA, Baker JR Jr (1996) Efficient transfer of genetic material into mammalian cells using Starburst polyamidoamine dendrimers. Proceedings of the National Academy of Sciences of the United States of America 93:4897–4902

    CrossRef  CAS  Google Scholar 

  15. Patri AK, Myc A, Beals J, Thomas TP, Bander NH, Baker JR Jr (2004) Synthesis and in vitro testing of J591 antibody-dendrimer conjugates for targeted prostate cancer therapy. Biocon Chem 15:1174–1181

    CAS  CrossRef  Google Scholar 

  16. Thomas TP, Patri AK, Myc A, Myaing MT, Ye JY, Norris TB, Baker JR Jr (2004) In vitro targeting of synthesized antibody-conjugated dendrimer nanoparticles. Biomacromolecules 5:2269–2274

    CrossRef  CAS  Google Scholar 

  17. Fuchs S, Kapp T, Otto H, Schoeneberg T, Franke P, Gust R, Schlueter AD (2004) A surface-modified dendrimer set for potential application as drug delivery vehicles: synthesis, in vitro toxicity, and intracellular localization. Chemistry–-A European Journal 10:1167–1192

    CAS  CrossRef  Google Scholar 

  18. Ooya T, Lee J, Park K (2004) Hydrotropic dendrimers of generations 4 and 5: synthesis, characterization, and hydrotropic solubilization of paclitaxel. Bioconjugate Chemistry 15:1221–1229

    CrossRef  CAS  Google Scholar 

  19. Kawano T, Okuda T, Aoyagi H, Niidome T (2004) Long circulation of intravenously administered plasmid DNA delivered with dendritic poly(-lysine) in the blood flow. Journal of Controlled Release 99:329–337

    CAS  CrossRef  Google Scholar 

  20. Paleos CM, Tsiourvas D, Sideratou Z, Tziveleka L (2004) Acid- and salt-triggered multifunctional poly(propylene imine) dendrimer as a prospective drug delivery system. Biomacromolecules 5:524–529

    CrossRef  CAS  Google Scholar 

  21. Mammen M, Chio S-K, Whitesides GM (1998) Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew Chem Int Ed 37:2755–2794

    CrossRef  CAS  Google Scholar 

  22. Shaunak S, Thomas S, Gianasi E, Godwin A, Jones E, Teo I, Mireskandari K, Luthert P, Duncan R, Patterson S, Khaw P, Brocchini S (2004) Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation. Nat Biotech 22:977–984

    CrossRef  CAS  Google Scholar 

  23. Benito JM, Gomez-Garcia M, Ortiz Mellet C, Baussanne I, Defaye J, Fernandez JMG (2004) Optimizing saccharide-directed molecular delivery to biological receptors: design, synthesis, and biological evaluation of glycodendrimer-cyclodextrin conjugates. J Am Chem Soc 126:10355–10363

    CrossRef  CAS  Google Scholar 

  24. Ihre HR, Padilla De Jesus OL, Szoka FC Jr, Frechet JMJ (2002) Polyester dendritic systems for drug delivery applications: design, synthesis, and characterization. Biocon Chem 13:443–452

    CAS  CrossRef  Google Scholar 

  25. Amir RJ, Pessah N, Shamis M, Shabat D (2003) Self-immolative dendrimers. Angew Chem Int Ed 42:4494–9

    CrossRef  CAS  Google Scholar 

  26. Shabat D, List B, Amir RJ, Shamis M, Pessah N (2004) In: PCT Int Appl p 153 (Ramot at Tel Aviv University Ltd., Israel; The Scripps Research Institute) Wo

    Google Scholar 

  27. de Groot FM, Albrecht C, Koekkoek R, Beusker PH, Scheeren HW (2003) “Cascade-release dendrimers” liberate all end groups upon a single triggering event in the dendritic core. Angew Chem Int Ed 42:4490–4494

    CrossRef  Google Scholar 

  28. Szalai ML, Kevwitch RM, McGrath DV (2003) Geometric disassembly of dendrimers: dendritic amplification. J Am Chem Soc 125:15688–15689

    CrossRef  CAS  Google Scholar 

  29. Szalai ML, McGrath DV (2004) Phototriggering of geometric dendrimer disassembly: an improved synthesis of 2,4-bis(hydroxymethyl)phenol based dendrimers. Tetrahedron 60:7261–7266

    CrossRef  CAS  Google Scholar 

  30. Firestone R (1998) In: PCT Int Appl p 63 (Bristol-Myers Squibb Co, USA). Wo

    Google Scholar 

  31. Flomenbom O, Amir RJ, Shabat D, Klafter J (2005) Some new aspects of dendrimer applications. J of Luminescence 111:315–325

    CAS  CrossRef  Google Scholar 

  32. de Groot FM, Damen EW, Scheeren HW (2001) Anticancer prodrugs for application in monotherapy: targeting hypoxia, tumor-associated enzymes, and receptors. Curr Med Chem 8:1093–1122

    Google Scholar 

  33. Bagshawe KD, Springer CJ, Searle F, Antoniw P, Sharma SK, Melton RG, Sherwood RF (1988) A cytotoxic agent can be generated selectively at cancer sites. Br J Cancer 58:700–703

    CAS  CrossRef  Google Scholar 

  34. Shamis M, Lode HN, Shabat D (2004) Bioactivation of self-immolative dendritic prodrugs by catalytic antibody 38C2. J Am Chem Soc 126:1726–1731

    CAS  CrossRef  Google Scholar 

  35. Wagner J, Lerner RA, Barbas CF III (1995) Efficient aldolase catalytic antibodies that use the enamine mechanism of natural enzymes. Science (Washington, DC) 270:1797–1800

    CAS  CrossRef  Google Scholar 

  36. Shabat D, Rader C, List B, Lerner RA, Barbas CF III (1999) Multiple event activation of a generic prodrug trigger by antibody catalysis. Proc Natl Acad Sci USA 96:6925–6930

    CrossRef  CAS  Google Scholar 

  37. Rader C, Turner JM, Heine A, Shabat D, Sinha SC, Wilson IA, Lerner RA, Barbas CF (2003) A humanized aldolase antibody for selective chemotherapy and adaptor immunotherapy. J Mol Biol 332:889–899

    CrossRef  CAS  Google Scholar 

  38. Shabat D, Lode H, Pertl U, Reisfeld RA, Rader C, Lerner RA, Barbas CF III (2001) In vivo activity in a catalyic antibody-prodrug system: Antibody catalyzed etoposide prodrug activation for selective chemotherapy. Proc Natl Acad Sci USA 98:7528–7533

    CrossRef  CAS  Google Scholar 

  39. Haba K, Popkov M, Shamis M, Lerner RA, Barbas CF III, Shabat D (2005) Single-triggered trimeric prodrugs. Angew Chem Int Ed 44:716–720

    CrossRef  CAS  Google Scholar 

  40. Li S, Szalai ML, Kevwitch RM, McGrath DV (2003) Dendrimer disassembly by benzyl ether depolymerization. J Am Chem Soc 125:10516–10517

    CAS  CrossRef  Google Scholar 

  41. Amir RJ, Shabat D (2004) Self-immolative dendrimer biodegradability by multi-enzymatic triggering. Chem Commun (Camb) 14:1614–1615

    CrossRef  Google Scholar 

  42. Gopin A, Pessah N, Shamis M, Rader C, Shabat D (2003) A chemical adaptor system designed to link a tumor-targeting device with a prodrug and an enzymatic trigger. Angew Chem Int Ed 42:327–332

    CrossRef  CAS  Google Scholar 

  43. Meijer EW, van Genderen MHP (2003) Chemistry: Dendrimers set to self-destruct. Nature (London, United Kingdom) 426:128–129

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, 69978, Tel Aviv, Israel

    Roey J. Amir & Doron Shabat

Authors
  1. Roey J. Amir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Doron Shabat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Doron Shabat .

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and Permissions

    About this chapter

    Cite this chapter

    Amir, R.J., Shabat, D. Domino Dendrimers. In: Satchi-Fainaro, R., Duncan, R. (eds) Polymer Therapeutics I. Advances in Polymer Science, vol 192. Springer, Berlin, Heidelberg. https://doi.org/10.1007/12_021

    Download citation