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University of Maryland Baltimore …

University of Maryland Baltimore
Experimental Therapeutics Symposium 2009

Published in: Education, Health & Medicine
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  • 1. Dr. Marie-Christine Daniel, Chemistry & Biochemistry Department University of Maryland Baltimore County Multifunctional Nanovectors for Cancer Therapy: New Drug Delivery Systems for Pancreatic, Breast and Prostate Cancer Therapies
  • 2. Ideal drug Main Challenge in Chemotherapy: Targeting
  • 3.
    • Multimodal targeting: right size and shape, targeting moiety for binding to cancer cells
    • Overcoming biological barriers, minimizing rapid clearance of drug from body
    • Overcoming multidrug resistance (MDR)
    • Combination therapy
    Needs for an EFFICIENT chemotherapy Goal = Preferential and effective concentration of therapeutic agents and imaging enhancers at tumor sites, by:
  • 4.
    • Enhanced Permeability and Retention effect (EPR)
    • Passive targeting
    Benefits of nanocarriers
  • 5. What are NANOvectors ?
  • 6. Dendronized gold nanoparticles Au + D I Targeting Chemotherapeutic Drug D Imaging Au E D D T E I T T I Chemotherapeutic Drug E STRATEGY OF THE PROJECTS
  • 7. DENDRIMER DENDRON Au GOLD NANOPARTICLE Ligands Generation numbers Core Termini Focal point Comparison Gold nanoparticle/ dendrimer/ dendron
  • 8. Why gold particles?
    • Biocompatible,
    • Tunable in size, coating,
    • Diversity of ligands possible
    • Anti-angiogenic intrinsic properties
    • X-rays enhancing properties
    • Photothermal therapy possible
    Why dendrons on gold particles?
    • Multifunctional
    • Focal point functionalized differently than periphery
    • Branched molecules
        • Dense patches on the GNPs surface
  • 9.
    • 3 projects involving targeted combination therapy for :
    • pancreatic cancer
    • metastatic breast cancer
    • hormone-refractory prostate cancer
    • Common aspects :
    • Backbone dendron
    • imaging agent (MRI contrast agent)
    • Differences :
    • Targeting moieties
    • Drug combinations
    Gd(DOTA) -
  • 10. Common starting dendron
  • 11. Spacer and backbone dendron formation Backbone dendron Spacer :
  • 12. Imaging dendron Gd(DOTA) - Gd 3+
  • 13. Pancreatic Cancer specificities
    • Targeting moiety: Transferrin (Tf)
    • (TFRC expressed on 93% of pancreatic tumour cells, in contrast to normal tissues)
    • Combination therapy: Gemcitabine and anti-RON antibody
    • (Pyrimidine antagonist) (against receptor tyrosine kinase)
    • Blockade of the RON receptor enhanced gemcitabine induced apoptosis by as much as 32% apoptosis compared with gemcitabine alone
  • 14. Pancreatic Cancer: Targeting dendron Transferrin
  • 15. Pancreatic Cancer: Gemcitabine-dendron Gemcitabine: Linkage through imine bond: pH-sensitive Stable in physiological plasma pH (7.4) But cleaved inside lysosomes (pH 4.5) Imine bond
  • 16. Pancreatic Cancer: Anti-RON-dendron HS-CH 2 -CH 2 -NH 2 Pepsin Anti-RON
  • 17. Pancreatic Cancer: Nanovectors Au + T T D I Transferrin Gemcitabine Anti-RON antibody I D T D T I D I D T D T I D I D T T D T T I D T D D I I D T T D I
  • 18. Metastatic Breast Cancer specificities
    • Targeting moiety : Transferrin (Tf)
    • (TFRC overexpressed on 74% of breast tumour cells, in contrast to normal tissues)
    • Combination therapy : Docetaxel and Epirubicin
    • (Taxane) (anthracycline)
    • Synergistic activity against metastatic breast cancer: median survival of 18 months;
    • 42% 2-year survival.
  • 19. Metastatic Breast Cancer: Docetaxel-dendron Docetaxel Docetaxel analog
  • 20. Metastatic Breast Cancer: Epirubicin-dendron Epirubicin:
  • 21. Metastatic Breast Cancer: Nanovectors Au + D I Transferrin Docetaxel MRI contrast agent Au E D D T E I T T I Epirubicin
  • 22. Hormone-Refractory Prostate Cancer specificities
    • Targeting moiety : anti-CD166 antibody (Fab’ fragment)
    • (CD166 antigens overexpressed on 86% of prostate tumors, in contrast to other tissues)
    • Combination therapy : Docetaxel and Prednisone
    • (Taxane) ( corticosteroid )
    • Synergistic activity against hormone-refractory prostate cancer:
    • now, standard treatment;
    • median survival of 19 months
    • .
  • 23. Hormone-Refractory Prostate Cancer: targeting dendron HS-CH 2 -CH 2 -NH 2 Pepsin Anti-CD166 Coupling with maleimide
  • 24. Hormone-Refractory Prostate Cancer: Prednisone-dendron Acyl hydrazone
  • 25. Hormone-Refractory Prostate Cancer: Nanovectors Au + D I Anti-CD166 Docetaxel MRI contrast agent Au P D D T P I T T I Prednisone
  • 26.
    • Pancreatic Cancer: - pancreas carcinoma cell line PANC-1 (which overexpress transferrin receptor),
    • - human umbilical vein endothelial cells (HUVEC),
    • Breast Cancer: - human breast carcinoma cell lines SKBR3 and MDA-MB-231 (which overexpress transferrin receptors),
    • - HMEC and MCF-10A (which do not express transferrin receptors)
    • Prostate Cancer: - metastatic human prostate carcinoma cell lines PC3 and DU-145 (which overexpress CD166 ALCAM antigen),
    • - HBL-100 control cells (that are known to be ALCAM-negative)
    Evaluations: In vitro testing
    • Targeting efficacy.
    • Cytotoxicity/ anti-proliferative activity.
    • Translational Core Laboratory (UMSOM, Greenebaum Cancer Center, Dr. Mariola Sadowska)
    • Dr. Elena Klyushnenkova (UMSOM)
    Cell lines used:
  • 27. Aknowledgements
    • Group: Dr. Hongmu Pan
    • Margaret Grow,
    • Cesar Baeta,
    • Maria Bednarek
    • Collaborations: Dr. Mariola Sadowska
    • Dr. Elena Klyushnenkova
    • Dr. Rao Gullapalli
    • Funding: PanCAN/AACR
    • DoD