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Tumor homing peptides

Tumor homing peptides. Lixia Wei. How do USPS people deal with tons of letters and packages and send them to different locations efficiently?. Zip Code General Location

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Tumor homing peptides

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  1. Tumor homing peptides Lixia Wei

  2. How do USPS people deal with tons of letters and packages and send them to different locations efficiently?

  3. Zip Code General Location Address Specific Location Zip Code and Address

  4. Cancer and its microenvironment Blood supply is very important for cancer growth and metastasis

  5. Can we target cancer cell or its microenvironment by • any zip code and address in cancer like our home? • Activated endothelial cells and pericytes in the neovasculature express molecules (tumor maker) that are not expressed or are expressed at much lower levels in normal vessels • Lots of biological markers are overexpressed in cancer • VEGF ( Vascular Endothelial Growth Factor) and other growth factors • Integrins: ανβ3 ,ανβ5 • Peptidases/proteases : Aminopeptidase N, MMP family • Membrane proteins with unknown functions • Do we have any carrier to deliver drug or image particles to cancer addresses?

  6. Phage Display • Phage display is a system in which a protein is displayed on the surface • of a phage as a fusion with one of the phage coated proteins. • Phage display technique is a test to screen for protein interaction by • integrating multiple genes from a gene bank into phages

  7. Advantages of selection of tumor target peptide in vivo by phage display technique • peptides displayed on the phage particles can be identified and tested functionally and must overcome natural mechanisms of degradation • peptides recognizing unspecific molecules are depleted from circulation • in vivo selection is able to identify receptors expressed selectively on tumor endothelium These peptides can serve as molecular targets for the development of diagnostic techniques and targeted therapies. Tumor Homing peptide

  8. 1. Homing peptides target to tumor vasculature Endothelial cells in the angiogenic vessels express several proteins that are absent or barely detectable in established blood vessel • The first motif is NGR (Asn-Gly-Arg) • Phage displayed peptide CNGRCVSGCAGRC • was injected into the tail vein of mice bearing • MDA-MB-435 derived tumors and recovered C) NGR binds aminopeptidase N Mice bearing breast cancer( MDA-MB-435) Wadih Arap et al. Science 1998 ,Vol (279) Renata et al. Cancer Research 2000, Vol (60)

  9. The second motif is GSL (Gly-Ser-Leu) • Recovery of CGSLVRC phage and • inhibition of tumor homing by the • soluble peptide CGSLVRC • The third motif is RGD (Arg-Gly-Asp) • Phage displayed peptide CDCRGDCFC • (RGD-4C) was injected into the tail vein • of tumor bearing mice and recovered • RGD motif binds selectively to integrins • which are overexpressed on endothelial • cell surface in the cancer and facilitate • cancer cell migration Wadih Arap et al. Science 1998 ,Vol (279) Renata et al. Cancer Research 2000, Vol (60)

  10. NGR motif peptide targets to the tumor vasculature 5 mins after injection 24 hours after injection control Wadih Arap et al. Science 1998 ,Vol (279)

  11. A fragment of the HMGN2 protein (F3 peptide) • High mobility group protein 2 is highly conserved nucleosomal protein • HMGN2 involves in unfolding higher-order chromatin structure and facilitating the transcriptional • activation of mammalian genes Tumor Brain Mice bearing myeloid leukemia tumor (HL-60) Kimmo porkka et al. PNAS 2002, Vol 99

  12. Nuclear localization of F3 peptide HL-60 with F3 HL-60 with control peptide F3 peptide colocalized with tumor vascular and tumor cells Kimmo porkka et al. PNAS 2002, Vol 99

  13. Peptide CGKRK and CDTRL Mice bearing epidermal squamous cell cancer(K14-HPV-16) Peptide CGKRK and CDTRL colocalized with vascular marker (MECA32) in tumor Jason A. Hoffman et al. Cancer Cell 2003, Vol 4

  14. 2. Homing peptide targets to tumor lymphatic vessels Tumor lymphatics also carry specific markers Peptide LyP-1(CCGNKRTRGC) home to tumor lymphatics and tumor cells Mice bearing MDA-MB-435 breast cancer Peptide LyP-1 was mostly recovered from tumor sites and internalized by tumor cells

  15. LyP-1 (green) Blood vessel (red) LyP-1 (green) Lymphatic vessel (red presents three different markers) Peptide LyP-1 binds to tumor lymphatics and tumor cells in MDA-MB-435 Pirjo Lakkonen et al. Nature Medicine 2002, Vol 8

  16. 3. Homing peptide targets to tumor cells Affibody (Z HER 2:4, 58aa) targets to epidermal growth factor receptor 2 (HER2/neu) Affibody binds to SKBR-3 breast cancer cells with non-competitive manner to Trastuzumab M.Wilkman et al Protein Engineering, Design& Selection 2004, Vol 17

  17. Mice bearing SKOV-3 (breast cancer) tumor Affibody labeled with 125I was imaged by gamma camera after injection 6 hours and 8 hours Ann-Charlott steffen et al. Eur J Nucl Med Mol Imaging 2006, Vol 33

  18. Summary of tumor homing peptides Affibody 31 aa 58aa HER2 Tumor cells Cell surface/ cytoplasmic Erkki Ruoslahti Druge Discoery Today 2002, Vol 7

  19. Application of tumor homing peptides 1. Diagnose cancer F3 peptide LyP-1 peptide Nanoparticle coated homing peptides can target tumor sites Maria E.Akerman et al. PNAS 2002, Vol.99

  20. 2. Deliver drugs to treat cancer • Doxorubicin (Dox) is one of the most frequently used anticancer drugs and • one of a few chemotherapeutic agents known to have antiangiogenic activity • Dox was conjugated with RGD-4C and NGR motifs to treat mice bearing with • MDA-MB-435 Dox-RGD treated mice bearing tumor (MDA-MB-435) Wadih Arap et al. Science 1998 ,Vol (279)

  21. Dox-CNGRC treated mice bearing tumor (MDA-MB-435)

  22. Conclusions: • Phage display is very powerful technique which can be used to identify • homing peptide to target tumor specific markers. • Tumor cell, vasculature and lymphatics have their own zip codes and • addresses. • Homing peptide can be widely used in diagnostic and therapeutic cancers • by conjugating them with anticancer drugs or imaging particles. • In the future, homing peptide drugs may be the most promising methods • to treat kinds of human diseases, not only cancers.

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