Prof. Satchi-Fainaro Ronit

  
Affiliation:Sackler School of Medicine
Sackler School of Medicine building
room 607
Tel:  (972)-3-6407427
(972)-3-6408733
(972)-3-6407427
 
Fax: (972)-3-6409108
 
Email: ronitsf@post.tau.ac.il
 
Personal Website:

 
Postal Address:Sackler School of Medicine
Tel Aviv University
Tel Aviv 69978

Research Interest

Multivalency of polymer therapeutics used for the integration of anti-angiogenic therapy with chemotherapy 
Tumors consist of three general compartments: tumor cells, tumor vasculature and non-endothelial tumor stroma. The ability of cancers to grow is dependent on the formation and maintenance of new blood vessels from pre-existing vasculature in a complex process referred to as Angiogenesis (Figure 1). Tumors may remain small and dormant if unable to elicit functional angiogenesis. Consequently, the microvascular endothelial cell, recruited by a tumor, has become a paramount factor in tumor progression and metastases formation making both the tumor cells and their surrounding stroma a target for combined anticancer and anti-angiogenic therapy.


Figure 1. The angiogenic switch and the use of nanomedicines such as Polymer Therapeutics (A), to treat angiogenic tumors (B-C). The enhanced permeability and retention (EPR) effect allows nanoconjugates to extravasate through the tumor leaky vessels (D-E), accumulate in the tumor bed selectively and internalize into the tumor epithelial and tumor endothelial cells via endocytosis (F).

 

Selective therapy remains a key issue for successful treatment in cancer therapy. Prolonged administration of effective concentrations of chemotherapeutic or anti-angiogenic agents is usually not possible because of dose-limiting systemic toxicities involving non-malignant tissues. Therefore, a constant effort has been the development of new drug delivery systems that mediate drug release selectively at the tumor site. Multimodality targeted nanomedicines offer the potential for improved efficacy and diminished toxicity. One way to achieve such selectivity is to activate a prodrug specifically by a confined enzymatic activity. In this concept, the enzyme is either expressed by the tumor cells or the tumor endothelial cells, or is brought to the tumor by a targeting moiety. The prodrug is converted to an active drug by the local or localized enzyme at the tumor site. Alternatively, the lower pH in the tumor microenvironment can be utilized for selectively activating a prodrug.
Our strategy for advancing the field of vascular biology and the development of vascular targeting nanomedicines is by:
1. Characterization of tumor vasculature for tailored-made therapy. Identifying new molecular markers on tumor endothelial cells in order to develop better drugs and better targeting moieties.
2. Design of novel nanocarriers as strategies to target angiogenesis inhibitors to tumor vasculature. To improve the therapeutic index of chemotherapeutic and antiangiogenic agents by conjugation to polymeric nanocarriers.
3. Investigation of the mechanism of action of angiogenesis inhibitors (endogenous and pharmacological inhibitors).
4. Intravital non-invasive molecular imaging of treated tumor-bearing mice to follow tumor progression, pharmacodynamics and pharmacokinetics of the synthesized nanomedicines.
5. Shedding light on the molecular basis of tumor dormancy using polymer therapeutics.
Our lab has recently designed some novel anti-angiogenic and antitumor polymer-drug nano-conjugates (Figure 2). Our results point at our polymer therapeutics as novel bi-specific nano-conjugates targeting both the tumor epithelial and endothelial compartments warranting their use on a wide spectrum of primary tumors and metastatic ones.


Figure 2.  Intravenous administration of a FITC-labeled polymer-drug nano-conjugate with a diameter size of 100 nm into:  (a) Normal vasculature adjacent to (b) tumor blood vessels in a subcutaneous implanted osteosarcoma. Tumor vessels demonstrate exaggerated size, tortuosity, and permeability. (c) Internalization of a FITC-labeled (green) nano-conjugate (d) into a human umbilical vein endothelial cell (HUVEC).

Selected Publications


  • Eldar-Boock A, Miller K, Sanchis J, Lupu R, Vicent MJ and Satchi-Fainaro R, Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel, Biomaterials, 32, 3862-3874 (2011).
  • Segal E, Pan H, Benayoun L, Kopečková P, Shaked Y, Kopeček J and Satchi-Fainaro R, Enhanced safety profile and antitumor activity of targeted HPMA copolymer-alendronate-TNP-470 nanoconjugate in the treatment of bone malignances, Biomaterials, 32(19), 4450-4463 (2011).
  • Polyak D, Ryppa C, Ofek P, Licha K, Many A, Kratz F and Satchi-Fainaro R, Development of PEGylated doxorubicin-E-[c(RGDfK)2] conjugate for integrin-targeted cancer therapy, Polymers for Advanced Technologies, 22, 103–113 (2011).
  • Miller K, Eldar-Boock A, Polyak D, Segal E, Benayoun L, Shaked Y and Satchi-Fainaro R, Anti-angiogenic antitumor activity of HPMA copolymer paclitaxel-alendronate conjugate on breast cancer bone metastases mouse model, Molecular Pharmaceutics, in press (2011).
  • Clementi C, Miller K, Mero A, Satchi-Fainaro R and Pasut G, Dendritic-PEG bearing paclitaxel and alendronate for targeting bone neoplasms, Molecular Pharmaceutics, in press (2011).
  • Karton-Lifshin N, Segal E, Omer L, Portnoy M, Satchi-Fainaro R*, Shabat D*, Non-Invasive Intravital Optical Imaging of Hydrogen Peroxide, Journal of the American Chemical Society (JACS), in press (2011). *Corresponding authors.
  • Ofek P, Fischer W, Calderon M, Haag R and Satchi-Fainaro R, In vivo delivery of siRNA to tumors and their vasculature by novel dendritic nanocarriers, FASEB Journal, 24(9), 3122-34 (2010).
  • Ofek P, Miller K, Eldar-Boock A, Polyak D, Segal E and Satchi-Fainaro R, Rational design of multifunctional polymer therapeutics for cancer theranostics, Special Theme issue: Polymer Therapeutics as novel nanomedicines, Israel Journal of Chemistry, 50 (2), 185-203 (2010). (Cover feature).
  • Miller K, Erez R, Segal E, Shabat D and Satchi-Fainaro R, A novel bi-specific agent based on a polymer-alendronate-taxane conjugate to target bone metastases, Angew Chem Int Ed Engl 48, 2949 –2954 (2009).
  • Segal E, Pan HZ, Udagawa T, Kopeckova P, Kopecek J and Satchi-Fainaro R, A novel combined targeted anticancer and anti-angiogenic polymer therapeutic, PLoS One, 4(4):e5233 (2009).
  • Stern L, Perry R, Ofek P, Many A, Shabat D and Satchi-Fainaro R, A novel antitumor prodrug designed to be cleaved by the endopeptidase legumain, Bioconjugate Chemistry, 20(3), 500–510 (2009).
  • Satchi-Fainaro R, Mamluk R, Wang L, Short S, Puder M, Nagy J, Feng D, Dvorak AM, Dvorak HF, Mukhopadhyay D and Folkman J, Inhibition of vascular leakiness and angiogenesis by TNP-470 and its polymer conjugate, caplostatin, Cancer Cell, 7(3), 251-261 (2005). (Cover feature).
  • Satchi-Fainaro R, Puder M, Davies J, Tran H, Greene AK, Corfas G and Folkman J, Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470, Nature Medicine, 10 (3), 255-261 (2004).
  • Satchi-Fainaro R, Hailu H, Davies JW, Summerford C and Duncan R, PDEPT: Polymer directed enzyme prodrug therapy. II. HPMA copolymer-β-lactamase and HPMA-Cephalosporin-Doxorubicin as a model combination, Bioconjugate Chemistry, 14 (4), 797-804 (2003).
  • Satchi R, Connors TA and Duncan R, PDEPT: Polymer-directed enzyme prodrug therapy. HPMA copolymer-cathepsin B and PK1 as a model combination, British Journal of Cancer, 85 (7) 1070-1076 (2001).