Peptide-based targeted therapeutics and apoptosis imaging probes for cancer therapy

  • Sri Murugan Poongkavithai Vadevoo
  • Smriti Gurung
  • Fatima Khan
  • Md. Enamul Haque
  • Gowri Rangaswamy Gunassekaran
  • Lianhua Chi
  • Uttapol Permpoon
  • Byungheon LeeEmail author


Peptides have advantages over antibodies in terms of deep tissue penetration, low immunogenicity, and cost-effective production, but they have short circulation time and poor stability in vivo. Peptides have been extensively used as targeting moieties for the delivery of drug-loaded nanoparticles and function as targeted therapeutics in cancer treatment. Here, we review peptides that are exploited as targeted therapeutics in cancer therapy and apoptosis imaging probes for the monitoring of treatment responses.


Apoptosis CD44v6 Imaging PD-L1 Phage display Pro-apoptotic peptide Targeted therapeutics 



This work was supported by Grants from the National Research Foundation (NRF- 2014R1A5A2009242 and NRF-2018R1A2B200837) and the Bio & Medical Technology Development Program (2017M3A9G8083382).

Compliance with ethical standards

Conflict of interest

The authors confirm that they have no conflict of interest.


  1. Adamczyk M, Kostka G, Palut D (1998) The role of apoptosis in cell physiology and pathology. Rocz Panstw Zakl Hig 49:415–432Google Scholar
  2. Arap W, Haedicke W, Bernasconi M, Kain R, Rajotte D, Krajewski S, Ellerby HM, Bredesen DE, Pasqualini R, Ruoslahti E (2002) Targeting the prostate for destruction through a vascular address. Proc Natl Acad Sci USA 99:1527–1531CrossRefGoogle Scholar
  3. Basakran NS (2015) CD44 as a potential diagnostic tumor marker. Saudi Med J 36:273–279CrossRefGoogle Scholar
  4. Blankenberg FG, Strauss HW (2012) Recent advances in the molecular imaging of programmed cell death: part I-pathophysiology and radiotracers. J Nucl Med 53:1659–1662CrossRefGoogle Scholar
  5. Bullok K, Piwnica-Worms D (2005) Synthesis and characterization of a small, membrane-permeant, caspase-activatable far-red fluorescent peptide for imaging apoptosis. J Med Chem 48:5404–5407CrossRefGoogle Scholar
  6. Bullok KE, Maxwell D, Kesarwala AH, Gammon S, Prior JL, Snow M, Stanley S, Piwnica-Worms D (2007) Biochemical and in vivo characterization of a small, membrane-permeant, caspase-activatable far-red fluorescent peptide for imaging apoptosis. Biochemistry 46:4055–4065CrossRefGoogle Scholar
  7. Burtea C, Laurent S, Lancelot E, Ballet S, Murariu O, Rousseaux O, Port M, Vander Elst L, Corot C, Muller RN (2009) Peptidic targeting of phosphatidylserine for the MRI detection of apoptosis in atherosclerotic plaques. Mol Pharm 6:1903–1919CrossRefGoogle Scholar
  8. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (2007) Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27:111–122CrossRefGoogle Scholar
  9. Chang HN, Liu BY, Qi YK, Zhou Y, Chen YP, Pan KM, Li WW, Zhou XM, Ma WW, Fu CY (2015) Blocking of the PD-1/PD-L1 interaction by ad-peptide antagonist for cancer immunotherapy. Angew Chem 54:11760–11764CrossRefGoogle Scholar
  10. Dine J, Gordon R, Shames Y, Kasler MK, Barton-Burke M (2017) Immune checkpoint inhibitors: an innovation in immunotherapy for the treatment and management of patients with cancer. Asia-Pac J Oncol Nurs 4:127–135CrossRefGoogle Scholar
  11. Dong H, Zhu G, Tamada K, Chen L (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5:1365–1369CrossRefGoogle Scholar
  12. Ellerby HM, Arap W, Ellerby LM, Kain R, Andrusiak R, Del Rio G, Krajewski S, Lombardo CR, Rao R, Ruoslahti E (1999) Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med 5:1032–1038CrossRefGoogle Scholar
  13. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516CrossRefGoogle Scholar
  14. Fantin VR, Berardi MJ, Babbe H, Michelman MV, Manning CM, Leder P (2005) A bifunctional targeted peptide that blocks HER-2 tyrosine kinase and disables mitochondrial function in HER-2-positive carcinoma cells. Cancer Res 65:6891–6900CrossRefGoogle Scholar
  15. Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, Bluestone JA (2009) Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal. Nat Immunol 10:1185–1192CrossRefGoogle Scholar
  16. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206:3015–3029CrossRefGoogle Scholar
  17. Johnson CB, Win SY (2018) Combination therapy with PD-1/PD-L1 blockade: an overview of ongoing clinical trials. Oncoimmunology 7:e1408744CrossRefGoogle Scholar
  18. Jung HK, Wang K, Jung MK, Kim IS, Lee BH (2014) In vivo near-infrared fluorescence imaging of apoptosis using histone H1-targeting peptide probe after anti-cancer treatment with cisplatin and cetuximab for early decision on tumor response. PLoS ONE 9:e100341CrossRefGoogle Scholar
  19. Jung HK, Kim S, Park R-W, Park J-Y, Kim I-S, Lee B (2016) Bladder tumor-targeted delivery of pro-apoptotic peptide for cancer therapy. J Control Release 235:259–267CrossRefGoogle Scholar
  20. Kim ES, Kim JE, Patel MA, Mangraviti A, Ruzevick J, Lim M (2016) Immune checkpoint modulators: an emerging antiglioma armamentarium. J Immunol Res 2016:1–14Google Scholar
  21. Kwak W, Ha YS, Soni N, Lee W, Park SI, Ahn H, An GI, Kim IS, Lee BH, Yoo J (2015) Apoptosis imaging studies in various animal models using radio-iodinated peptide. Apoptosis 20:110–121CrossRefGoogle Scholar
  22. Ladner RC, Sato AK, Gorzelany J, De Souza M (2004) Phage display-derived peptides as therapeutic alternatives to antibodies. Drug Discov Today 9:525–529CrossRefGoogle Scholar
  23. Lanneau D, Brunet M, Frisan E, Solary E, Fontenay M, Garrido C (2008) Heat shock proteins: essential proteins for apoptosis regulation. J Cell Mol Med 12:743–761CrossRefGoogle Scholar
  24. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268CrossRefGoogle Scholar
  25. Laumonier C, Segers J, Laurent S, Michel A, Coppee F, Belayew A, Elst LV, Muller RN (2006) A new peptidic vector for molecular imaging of apoptosis, identified by phage display technology. J Biomol Screen 11:537–545CrossRefGoogle Scholar
  26. Li C, Zhang N, Zhou J, Ding C, Jin Y, Cui X, Pu K, Zhu Y (2018) Peptide blocking of PD-1/PD-L1 interaction for cancer immunotherapy. Cancer Immunol Res 6:178–188CrossRefGoogle Scholar
  27. Mai JC, Mi Z, Kim S-H, Ng B, Robbins PD (2001) A proapoptotic peptide for the treatment of solid tumors. Cancer Res 61:7709–7712Google Scholar
  28. Manish G, Vimukta S (2011) Targeted drug delivery system: a review. Res J Chem Sci 1:135–138Google Scholar
  29. Matzke-Ogi A, Jannasch K, Shatirishvili M, Fuchs B, Chiblak S, Morton J, Tawk B, Lindner T, Sansom O, Alves F, Warth A, Schwager C, Mier W, Kleeff J, Ponta H, Abdollahi A, Orian-Rousseau V (2016) Inhibition of tumor growth and metastasis in pancreatic cancer models by interference with CD44v6 signaling. Gastroenterology 150:513–525CrossRefGoogle Scholar
  30. Mavilio D, Lugli E (2013) Inhibiting the inhibitors: checkpoints blockade in solid tumors. Oncoimmunology 2:e26535CrossRefGoogle Scholar
  31. Mcilwain DR, Berger T, Mak TW (2013) Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 5:a008656CrossRefGoogle Scholar
  32. Michaud NR (2005) Novel peptides targeting the hepatocyte growth factor receptor c-Met for the treatment of cancer. Expert Opin Ther Pat 15:621–625CrossRefGoogle Scholar
  33. Mousavizadeh A, Jabbari A, Akrami M, Bardania H (2017) Cell targeting peptides as smart ligands for targeting of therapeutic or diagnostic agents: a systematic review. Colloids Surf B 158:507–517CrossRefGoogle Scholar
  34. Niu G, Chen X (2010) Apoptosis imaging: beyond annexin V. J Nucl Med 51:1659–1662CrossRefGoogle Scholar
  35. Obiri N, Siegel J, Varricchio F, Puri R (1994) Expression of high-affinity IL-4 receptors on human melanoma, ovarian and breast carcinoma cells. Clin Exp Immunol 95:148–155CrossRefGoogle Scholar
  36. Ohsawa S, Hamada S, Yoshida H, Miura M (2008) Caspase-mediated changes in histone H1 in early apoptosis: prolonged caspase activation in developing olfactory sensory neurons. Cell Death Differ 15:1429–1439CrossRefGoogle Scholar
  37. Olaku V, Matzke A, Mitchell C, Hasenauer S, Sakkaravarthi A, Pace G, Ponta H, Orian-Rousseau V (2011) c-Met recruits ICAM-1 as a coreceptor to compensate for the loss of CD44 in Cd44 null mice. Mol Biol Cell 22:2777–2786CrossRefGoogle Scholar
  38. Orian-Rousseau V (2010) CD44, a therapeutic target for metastasising tumours. Eur J Cancer 46:1271–1277CrossRefGoogle Scholar
  39. Orian-Rousseau V, Ponta H (2015) Perspectives of CD44 targeting therapies. Arch Toxicol 89:3–14CrossRefGoogle Scholar
  40. Orian-Rousseau V, Chen L, Sleeman JP, Herrlich P, Ponta H (2002) CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 16:3074–3086CrossRefGoogle Scholar
  41. Patel SA, Longacre TA, Ladabaum U, Lebensohn A, Lin AY, Haraldsdottir S (2018) Tumor molecular testing guides Anti-PD-1 therapy and provides evidence for pathogenicity ismatch Repair Variants. Oncologist 23:1395–1400CrossRefGoogle Scholar
  42. Pham W, Weissleder R, Tung CH (2002) An azulene dimer as a near-infrared quencher. Angew Chem Int Ed Engl 41:3659–3662CrossRefGoogle Scholar
  43. Pianko MJ, Liu Y, Bagchi S, Lesokhin AM (2017) Immune checkpoint blockade for hematologic malignancies: a review. Stem Cell Investig 4:32–42CrossRefGoogle Scholar
  44. Plati J, Bucur O, Khosravi-Far R (2011) Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb) 3:279–296CrossRefGoogle Scholar
  45. Radermacher KA, Boutry S, Laurent S, Elst LV, Mahieu I, Bouzin C, Magat J, Gregoire V, Feron O, Muller RN, Jordan BF, Gallez B (2010) Iron oxide particles covered with hexapeptides targeted at phosphatidylserine as MR biomarkers of tumor cell death. Contrast Media Mol Imaging 5:258–267CrossRefGoogle Scholar
  46. Rios-Doria J, Durham N, Wetzel L, Rothstein R, Chesebrough J, Holoweckyj N, Zhao W, Leow CC, Hollingsworth R (2015) Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models. Neoplasia 17:661–670CrossRefGoogle Scholar
  47. Ruoslahti E (2012) Peptides as targeting elements and tissue penetration devices for nanoparticles. Adv Mater 24:3747–3756CrossRefGoogle Scholar
  48. Sandomenico A, Caporale A, Doti N, Cross S, Cruciani G, Chambery A, De SF, Ruvo M (2018) Synthetic peptide libraries. From random mixtures to in vivo testing. Curr Med Chem. Google Scholar
  49. Schutters K, Reutelingsperger C (2010) Phosphatidylserine targeting for diagnosis and treatment of human diseases. Apoptosis 15:1072–1082CrossRefGoogle Scholar
  50. Smith BA, Smith BD (2012) Biomarkers and molecular probes for cell death imaging and targeted therapeutics. Bioconjug Chem 23:1989–2006CrossRefGoogle Scholar
  51. Smolarczyk R, Cichoń T, Graja K, Hucz J, Sochanik A, Szala S (2006) Antitumor effect of RGD-4C-GG-D (KLAKLAK) 2 peptide in mouse B16 (F10) melanoma model. Acta Biochim Pol 53:801–805Google Scholar
  52. Solis MA, Chen YH, Wong TY, Bittencourt VZ, Lin YC, Huang LL (2012) Hyaluronan regulates cell behavior: a potential niche matrix for stem cells. Biochem Res Int. Google Scholar
  53. Song S, Xiong C, Lu W, Ku G, Huang G, Li C (2013) Apoptosis imaging probe predicts early chemotherapy response in preclinical models: a comparative study with 18F-FDG PET. J Nucl Med 54:104–110CrossRefGoogle Scholar
  54. Speiser P, Wanner C, Tempfer C, Mittelbock M, Hanzal E, Bancher-Todesca D, Gitsch G, Reinthaller A, Kainz C (1997) CD44 is an independent prognostic factor in early-stage cervical cancer. Int J Cancer 74:185–188CrossRefGoogle Scholar
  55. Stauder R, Eisterer W, Thaler J, Gunthert U (1995) CD44 variant isoforms in non-Hodgkin’s lymphoma: a new independent prognostic factor. Blood 85:2885–2899Google Scholar
  56. Svensen N, Walton JG, Bradley M (2012) Peptides for cell-selective drug delivery. Trends Pharmacol Sci 33:186–192CrossRefGoogle Scholar
  57. Takayama S, Reed JC, Homma S (2003) Heat-shock proteins as regulators of apoptosis. Oncogene 22:9041–9047CrossRefGoogle Scholar
  58. Tam EM, Runyon ST, Santell L, Quan C, Yao X, Kirchhofer D, Skelton NJ, Lazarus RA (2009) Noncompetitive inhibition of hepatocyte growth factor-dependent Met signaling by a phage-derived peptide. J Mol Biol 385:79–90CrossRefGoogle Scholar
  59. Thapa N, Kim S, So IS, Lee BH, Kwon IC, Choi K, Kim IS (2008) Discovery of a phosphatidylserine-recognizing peptide and its utility in molecular imaging of tumour apoptosis. J Cell Mol Med 12:1649–1660CrossRefGoogle Scholar
  60. Tjhay F, Motohara T, Tayama S, Narantuya D, Fujimoto K, Guo J, Sakaguchi I, Honda R, Tashiro H, Katabuchi H (2015) CD44 variant 6 is correlated with peritoneal dissemination and poor prognosis in patients with advanced epithelial ovarian cancer. Cancer Sci 106:1421–1428CrossRefGoogle Scholar
  61. Tremmel M, Matzke A, Albrecht I, Laib AM, Olaku V, Ballmer-Hofer K, Christofori G, Heroult M, Augustin HG, Ponta H, Orian-Rousseau V (2009) A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis. Blood 114:5236–5244CrossRefGoogle Scholar
  62. Vadevoo SMP, Kim J-E, Gunassekaran GR, Jung H-K, Chi L, Kim DE, Lee S-H, Im S-H, Lee B (2017) Interleukin 4 receptor-targeted pro-apoptotic peptide blocks tumor growth and metastasis by enhancing anti-tumor immunity. Mol Cancer Ther 12:2803–2816CrossRefGoogle Scholar
  63. Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M (2010) Synthetic therapeutic peptides: science and market. Drug Discov Today 15:40–56CrossRefGoogle Scholar
  64. Wang K, Purushotham S, Lee JY, Na MH, Park H, Oh SJ, Park RW, Park JY, Lee E, Cho BC, Song MN, Baek MC, Kwak W, Yoo J, Hoffman AS, Oh YK, Kim IS, Lee BH (2010) In vivo imaging of tumor apoptosis using histone H1-targeting peptide. J Control Release 148:283–291CrossRefGoogle Scholar
  65. Wang F, Ma J, Liu J, Jin H, Huang D (2012) Synthetic small peptides acting on B7H1 enhance apoptosis in pancreatic cancer cells. Mol Med Rep 6:553–557CrossRefGoogle Scholar
  66. Wang JL, Su WY, Lin YW, Xiong H, Chen YX, Xu J, Fang JY (2017) CD44v6 overexpression related to metastasis and poor prognosis of colorectal cancer: a meta-analysis. Oncotarget 8:12866–12876Google Scholar
  67. Xiong C, Brewer K, Song S, Zhang R, Lu W, Wen X, Li C (2011) Peptide-based imaging agents targeting phosphatidylserine for the detection of apoptosis. J Med Chem 54:1825–1835CrossRefGoogle Scholar
  68. Yang S, Meng J, Yang Y, Liu H, Wang C, Liu J, Zhang Y, Wang C, Xu H (2016) A HSP60-targeting peptide for cell apoptosis imaging. Oncogenesis 5:e201CrossRefGoogle Scholar
  69. Zeng W, Wang X, Xu P, Liu G, Eden HS, Chen X (2015) Molecular imaging of apoptosis: from micro to macro. Theranostics 5:559–582CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  • Sri Murugan Poongkavithai Vadevoo
    • 1
    • 2
  • Smriti Gurung
    • 1
    • 2
  • Fatima Khan
    • 1
    • 2
  • Md. Enamul Haque
    • 1
    • 2
  • Gowri Rangaswamy Gunassekaran
    • 1
    • 2
  • Lianhua Chi
    • 1
    • 2
  • Uttapol Permpoon
    • 1
    • 2
  • Byungheon Lee
    • 1
    • 2
    Email author
  1. 1.Department of Biochemistry and Cell Biology, School of MedicineKyungpook National UniversityDaeguRepublic of Korea
  2. 2.BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, CMRI, School of MedicineKyungpook National UniversityDaeguRepublic of Korea

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