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

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Abstract

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.

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References

  • Adamczyk M, Kostka G, Palut D (1998) The role of apoptosis in cell physiology and pathology. Rocz Panstw Zakl Hig 49:415–432

    CAS  PubMed  Google Scholar 

  • 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 99:1527–1531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Basakran NS (2015) CD44 as a potential diagnostic tumor marker. Saudi Med J 36:273–279

    Article  PubMed  PubMed Central  Google Scholar 

  • Blankenberg FG, Strauss HW (2012) Recent advances in the molecular imaging of programmed cell death: part I-pathophysiology and radiotracers. J Nucl Med 53:1659–1662

    Article  CAS  PubMed  Google Scholar 

  • 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 48:5404–5407

    Article  CAS  PubMed  Google Scholar 

  • 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 46:4055–4065

    Article  CAS  PubMed  Google Scholar 

  • 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 6:1903–1919

    Article  CAS  PubMed  Google Scholar 

  • 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 27:111–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 54:11760–11764

    Article  CAS  Google Scholar 

  • 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 4:127–135

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 5:1365–1369

    Article  CAS  PubMed  Google Scholar 

  • 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 5:1032–1038

    Article  CAS  PubMed  Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 65:6891–6900

    Article  CAS  PubMed  Google Scholar 

  • 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 10:1185–1192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 206:3015–3029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson CB, Win SY (2018) Combination therapy with PD-1/PD-L1 blockade: an overview of ongoing clinical trials. Oncoimmunology 7:e1408744

    Article  PubMed  PubMed Central  Google Scholar 

  • 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:e100341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 235:259–267

    Article  CAS  PubMed  Google Scholar 

  • Kim ES, Kim JE, Patel MA, Mangraviti A, Ruzevick J, Lim M (2016) Immune checkpoint modulators: an emerging antiglioma armamentarium. J Immunol Res 2016:1–14

    Google Scholar 

  • 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 20:110–121

    Article  CAS  PubMed  Google Scholar 

  • Ladner RC, Sato AK, Gorzelany J, De Souza M (2004) Phage display-derived peptides as therapeutic alternatives to antibodies. Drug Discov Today 9:525–529

    Article  CAS  PubMed  Google Scholar 

  • 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 12:743–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 2:261–268

    Article  CAS  PubMed  Google Scholar 

  • 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 11:537–545

    Article  CAS  PubMed  Google Scholar 

  • 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 6:178–188

    Article  CAS  PubMed  Google Scholar 

  • Mai JC, Mi Z, Kim S-H, Ng B, Robbins PD (2001) A proapoptotic peptide for the treatment of solid tumors. Cancer Res 61:7709–7712

    CAS  PubMed  Google Scholar 

  • Manish G, Vimukta S (2011) Targeted drug delivery system: a review. Res J Chem Sci 1:135–138

    Google Scholar 

  • 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 150:513–525

    Article  PubMed  Google Scholar 

  • Mavilio D, Lugli E (2013) Inhibiting the inhibitors: checkpoints blockade in solid tumors. Oncoimmunology 2:e26535

    Article  PubMed  PubMed Central  Google Scholar 

  • Mcilwain DR, Berger T, Mak TW (2013) Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 5:a008656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michaud NR (2005) Novel peptides targeting the hepatocyte growth factor receptor c-Met for the treatment of cancer. Expert Opin Ther Pat 15:621–625

    Article  CAS  Google Scholar 

  • 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 158:507–517

    Article  CAS  Google Scholar 

  • Niu G, Chen X (2010) Apoptosis imaging: beyond annexin V. J Nucl Med 51:1659–1662

    Article  CAS  PubMed  Google Scholar 

  • 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 95:148–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 15:1429–1439

    Article  CAS  PubMed  Google Scholar 

  • 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 22:2777–2786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orian-Rousseau V (2010) CD44, a therapeutic target for metastasising tumours. Eur J Cancer 46:1271–1277

    Article  CAS  PubMed  Google Scholar 

  • Orian-Rousseau V, Ponta H (2015) Perspectives of CD44 targeting therapies. Arch Toxicol 89:3–14

    Article  CAS  PubMed  Google Scholar 

  • 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 16:3074–3086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 23:1395–1400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pham W, Weissleder R, Tung CH (2002) An azulene dimer as a near-infrared quencher. Angew Chem Int Ed Engl 41:3659–3662

    Article  CAS  PubMed  Google Scholar 

  • Pianko MJ, Liu Y, Bagchi S, Lesokhin AM (2017) Immune checkpoint blockade for hematologic malignancies: a review. Stem Cell Investig 4:32–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plati J, Bucur O, Khosravi-Far R (2011) Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb) 3:279–296

    Article  CAS  Google Scholar 

  • 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 5:258–267

    Article  CAS  PubMed  Google Scholar 

  • 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 17:661–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruoslahti E (2012) Peptides as targeting elements and tissue penetration devices for nanoparticles. Adv Mater 24:3747–3756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. https://doi.org/10.2174/0929867325666180716110833

    Article  Google Scholar 

  • Schutters K, Reutelingsperger C (2010) Phosphatidylserine targeting for diagnosis and treatment of human diseases. Apoptosis 15:1072–1082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith BA, Smith BD (2012) Biomarkers and molecular probes for cell death imaging and targeted therapeutics. Bioconjug Chem 23:1989–2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 53:801–805

    CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1155/2012/346972

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 54:104–110

    Article  CAS  PubMed  Google Scholar 

  • 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 74:185–188

    Article  CAS  PubMed  Google Scholar 

  • Stauder R, Eisterer W, Thaler J, Gunthert U (1995) CD44 variant isoforms in non-Hodgkin’s lymphoma: a new independent prognostic factor. Blood 85:2885–2899

    CAS  PubMed  Google Scholar 

  • Svensen N, Walton JG, Bradley M (2012) Peptides for cell-selective drug delivery. Trends Pharmacol Sci 33:186–192

    Article  CAS  PubMed  Google Scholar 

  • Takayama S, Reed JC, Homma S (2003) Heat-shock proteins as regulators of apoptosis. Oncogene 22:9041–9047

    Article  CAS  PubMed  Google Scholar 

  • 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 385:79–90

    Article  CAS  PubMed  Google Scholar 

  • 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 12:1649–1660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 106:1421–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 114:5236–5244

    Article  CAS  PubMed  Google Scholar 

  • 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 12:2803–2816

    Article  CAS  Google Scholar 

  • Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M (2010) Synthetic therapeutic peptides: science and market. Drug Discov Today 15:40–56

    Article  CAS  PubMed  Google Scholar 

  • 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 148:283–291

    Article  CAS  PubMed  Google Scholar 

  • 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 6:553–557

    Article  CAS  PubMed  Google Scholar 

  • 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 8:12866–12876

    PubMed  Google Scholar 

  • 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 54:1825–1835

    Article  CAS  PubMed  Google Scholar 

  • 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:e201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeng W, Wang X, Xu P, Liu G, Eden HS, Chen X (2015) Molecular imaging of apoptosis: from micro to macro. Theranostics 5:559–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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

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Vadevoo, S.M.P., Gurung, S., Khan, F. et al. Peptide-based targeted therapeutics and apoptosis imaging probes for cancer therapy. Arch. Pharm. Res. 42, 150–158 (2019). https://doi.org/10.1007/s12272-019-01125-0

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