Dr. Marie-Christine Daniel, Chemistry & Biochemistry Department University of Maryland Baltimore County Multifunctional Na...
Ideal drug Main Challenge in Chemotherapy:  Targeting
<ul><li>Multimodal targeting: right size and shape,  targeting moiety  for binding to cancer cells </li></ul><ul><li>Overc...
<ul><li>Enhanced Permeability and Retention effect (EPR) </li></ul><ul><li>Passive targeting </li></ul>Benefits of nanocar...
What are NANOvectors ?
Dendronized gold nanoparticles  Au + D I Targeting Chemotherapeutic  Drug D Imaging Au E D D T E I T T I Chemotherapeutic ...
DENDRIMER DENDRON Au GOLD  NANOPARTICLE Ligands Generation  numbers Core Termini Focal point Comparison Gold nanoparticle/...
Why gold particles? <ul><li>Biocompatible, </li></ul><ul><li>Tunable in size, coating, </li></ul><ul><li>Diversity of liga...
<ul><li>3 projects involving  targeted combination therapy  for : </li></ul><ul><li>pancreatic  cancer </li></ul><ul><li>m...
Common starting dendron
Spacer and backbone dendron formation Backbone dendron Spacer :
Imaging dendron Gd(DOTA) - Gd 3+
Pancreatic Cancer specificities <ul><li>Targeting moiety:  Transferrin  (Tf) </li></ul><ul><li>(TFRC expressed on 93% of p...
Pancreatic Cancer: Targeting dendron Transferrin
Pancreatic Cancer: Gemcitabine-dendron Gemcitabine:  Linkage  through  imine  bond: pH-sensitive Stable in physiological p...
Pancreatic Cancer: Anti-RON-dendron HS-CH 2 -CH 2 -NH 2 Pepsin Anti-RON
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...
Metastatic Breast Cancer specificities <ul><li>Targeting moiety :  Transferrin  (Tf) </li></ul><ul><li>(TFRC overexpressed...
Metastatic Breast Cancer: Docetaxel-dendron Docetaxel Docetaxel analog
Metastatic Breast Cancer: Epirubicin-dendron Epirubicin:
Metastatic Breast Cancer: Nanovectors Au + D I Transferrin Docetaxel MRI  contrast agent Au E D D T E I T T I Epirubicin
Hormone-Refractory Prostate Cancer specificities  <ul><li>Targeting moiety :  anti-CD166 antibody (Fab’ fragment) </li></u...
Hormone-Refractory Prostate Cancer: targeting dendron HS-CH 2 -CH 2 -NH 2 Pepsin Anti-CD166 Coupling with maleimide
Hormone-Refractory Prostate Cancer: Prednisone-dendron Acyl hydrazone
Hormone-Refractory Prostate Cancer: Nanovectors Au + D I Anti-CD166 Docetaxel MRI  contrast agent Au P D D T P I T T I Pre...
<ul><li>Pancreatic Cancer: -  pancreas carcinoma cell line PANC-1   (which overexpress    transferrin receptor),  </li></u...
Aknowledgements <ul><li>Group:  Dr. Hongmu Pan </li></ul><ul><li>  Margaret Grow, </li></ul><ul><li>  Cesar Baeta, </li></...
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Daniel

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University of Maryland Baltimore
Experimental Therapeutics Symposium 2009

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Daniel

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

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