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Sugar-Modified Dendrimers Enhancing Anti-Leukemia Drug Delivery

Explore sugar-modified dendrimers as carriers of anti-leukemia drugs, prolonging drug circulation time, protecting against resistance mechanisms, and achieving controlled release and targeting. Discover their advantages and protection against enzymatic degradation. Learn about cytotoxicity testing and internalization into leukemia cells. Presented at BIODENDRIMER 2014.

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Sugar-Modified Dendrimers Enhancing Anti-Leukemia Drug Delivery

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  1. Sugar-modified PPI dendrimers as carriers of anti-leukemia drugs Barbara Klajnert-Maculewicz Department of General Biophysics University of Lodz

  2. Linear polymer 1930s Branched polymer 1960s Dendrimer 1980s

  3. D. Tomalia G. Newcome dendrimer - gr. dendron arborol - lat. arbor cascade molecule F. Vögtle

  4. dendrimer arborol dendrimer - gr. dendron arborol - lat. arbor cascade molecule cascade molecule

  5. globular shape • monodispersity • big dimensions • high reactivity • good solubility

  6. ANTI-MICROBIAL ACTIVITY DRUG DELIVERY GENE CARRIERS ANTI-HIV ACTIVITY ANTI-PRION ACTIVITY

  7. Dendrimers as drug carriers

  8. prolonging the circulation time in blood • protecting unstable drugs from the environment • enhancing solubility of poorly soluble drugs • achieving a controlled release and tissue targeting • one molecule of dendrimer is capable • to carry drugs at high density • slower release than for a free drug

  9. Physiological nucleoside analogues (NAs) Cytarabine is used to treat different forms of leukemia, including acute and chronic myelogenous (AML and CML) and acute lymphocytic leukemia (ALL).

  10. arabinose - cytosine

  11. Drug resistance mechanisms

  12. Conventional therapy with ara-C Drug resistance Dendrimers as carriers of ara-CTP

  13. Maltose-modified PPI dendrimer PPI-OS-Mal G5 (approx. 30% maltose) Dr. Dietmar Appelhans Synthesis: Fischer et al. Biomacromolec. 10 (2009) 1314-1325

  14. Advantages of sugar modification • non-hemolytical 1, 2 • do not cause platelets aggregation 2 • low toxicity in vitro 3 • low toxicity in vivo 4 • retained activity 1, 5, 6 • B. Klajnert et al. Chem. Eur. J. 14 (2008) 7030-7041 • B. Ziemba et al.J. Biomed. Mater. Res. A.100(2012) 2870 • A. Janaszewska et al. New J. Chem. 36 (2012) 428-437 • B. Ziemba et al. J. Biomed. Mater. Res. A 99 (2011) 261-268 • M. Fischer et al. Biomacromolecules 11 (2010) 1314-1325 • M. Ciołkowski et al.Colloid Surface B 95 (2012) 103-108

  15. complexes: + ara-CTP • dendrimer and ara-CTP form complexes (ara-CTP/dendrimer=10) • complexes are stable • ara-CTP is protected against enzymatic degradation

  16. Protection agaist enzymatic degradation – FPLC method dephosphorylation adenosine ATP alkaline phosphatase A. Szulc et al. New J. Chem. 36 (2012) 1610-1615

  17. Protection agaist enzymatic degradation – FPLC method A254 nm retention time = 13 min free ATP bound ATP retention time = 19 min A. Szulc et al. New J. Chem. 36 (2012) 1610-1615

  18. Protection agaist enzymatic degradation – FPLC method adenosine retention time = 29 min free ATP bound ATP A. Szulc et al. New J. Chem. 36 (2012) 1610-1615

  19. Protection agaist enzymatic degradation – FPLC method adenosine retention time = 29 min system PPI-m G5 + adenosine no complex! A. Szulc et al. New J. Chem. 36 (2012) 1610-1615

  20. Protection agaist enzymatic degradation – FPLC method adenosine red line: system PPI-m G5 + ATP + alkaline phosphatase retention time = 29 min bound ATP no free ATP A. Szulc et al. New J. Chem. 36 (2012) 1610-1615

  21. Protection agaist enzymatic degradation – FPLC method red line: system PPI-m G5 + ATP + alkaline phosphatase bound ATP 26% of complexed ATP was degraded. A. Szulc et al. New J. Chem. 36 (2012) 1610-1615

  22. leukemia cell line: control cells: PBMC 1301 peripheral blood mononuclear cells human acute lymphoblastic T cells

  23. Internalization of dendrimers into cells Flow cytometry fluorescein (FITC)

  24. Internalization of dendrimers into 1301 cells Confocal microscopy fluorescein (FITC)

  25. Cytotoxicity Alamar Blue assay Cytotoxicity test with resazurin - in live cells it is reduced to resorufin: lexc=530 nm lem=590 nm

  26. Dendrimer cytotoxicity

  27. Cytotoxicity - 1301 48h

  28. Cytotoxicity - 1301 48h

  29. Cytotoxicity - 1301 48h *

  30. Cytotoxicity - 1301 72h ** * *

  31. Cytotoxicity - PBMC 48h

  32. Cytotoxicity - PBMC 72h

  33. Inhibitor of nucleoside transporters NBMPR - nitrobenzylmercaptopurine

  34. Inhibitors of NT in 1301 48 h 72 h

  35. 1301 1. 2. 3. CONCLUSIONS: Anti-leukemia activity: > > ! >>

  36. BIODENDRIMER 2014 Acknowledgements Aleksandra Szulc, M.Sc. PhD student University of Lodz Poland Dr. Dietmar Appelhans Leibniz-Institute für Polymerforschung Dresden e.V. Germany TEAM project „Biological properties and biomedical applications of dendrimers”

  37. BIODENDRIMER 2014 Thank you. Faculty of Biology and Environmental Protection, Lodz, Poland

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