Abstract
There is a growing interest for the discovery of new cancer-targeted delivery systems for drug delivery and diagnosis. A synopsis of the bibliographic data will be presented on bombesin, neurotensin, octreotide, Arg-Gly-Asp, luteinizing hormone-releasing hormone and other peptides. Many of them have reached the clinics for therapeutic or diagnostic purposes, and have been utilized as carriers of known cytotoxic agents such as doxorubicin, paclitaxel, cisplatin, methotrexate or dyes and radioisotopes. In our article, recent advances in the development of peptides as carriers of cytotoxic drugs or radiometals will be analyzed.
Graphical abstract
- bombesin receptor-targeted delivery systems
- cancer-targeted drug delivery
- ErbB receptor-targeted delivery systems
- integrin receptor-targeted delivery systems
- LHRH receptor-targeted delivery systems
- neurotensin receptor-targeted delivery systems
- peptide
- peptide-drug conjugates
- somatostatin receptor-targeted delivery systems
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 Global cancer transitions according to the Human Development Index (2008-2030): a population-based study. Lancet Oncol. 13(8), 790–801 (2012).
- 2 . Endocytic mechanisms for targeted drug delivery. Adv. Drug Deliv. Rev. 59(8), 748–758 (2007).
- 3 Endosomal escape pathways for delivery of biologicals. J. Control. Rel. 151(3), 220–228 (2011).
- 4 . Mechanisms of drug release in nanotherapeutic delivery systems. Chem. Rev. 115(9), 3388–3432 (2015). • Provides an overview of the different linkers employed in targeted drug delivery.
- 5 . Antibody-drug conjugates as novel anti-cancer chemotherapeutics. Biosci. Rep. 35, e00225 (2015).
- 6 . Fate of antibody-drug conjugates in cancer cells. J. Exp. Clin. Cancer Res. 37(1), 20 (2018). •• Provides an overview of antibody-drug conjugates in cancer cells.
- 7 . Targeted drug delivery for cancer therapy: the other side of antibodies. J. Hematol. Oncol. 5(1), 70 (2012).
- 8 . Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell 55(6), 1179–1188 (1988).
- 9 . Therapeutic peptides: historical perspectives current development trends, and future directions. Bioorg. Med. Chem. 26(10), 2700–2707 (2018).
- 10 . Peptide-based radiopharmaceuticals: future tools for diagnostic imaging of cancers and other diseases. Med. Res. Rev. 24(3), 357–397 (2004).
- 11 . Peptides for therapy and diagnosis of Alzheimer's disease. Curr. Pharm. Des. 18(6), 755–767 (2012).
- 12 Peptide-based treatment: a promising cancer therapy. J. Immunol. Res. 2015, 1–13 (2015).
- 13 The potential therapeutic application of peptides and peptidomimetics in cardiovascular disease. Front. Pharmacol. 7, 526 (2016).
- 14 . Strategic approaches to optimizing peptide ADME Properties. AAPS J. 17(1), 134–143 (2015).
- 15 . Integrins: bidirectional allosteric signaling machines. Cell 110(6), 673–687 (2002).
- 16 . Structural basis of transmembrane domain interactions in integrin signaling. Cell Adh. Migr. 4(2), 243–248 (2010).
- 17 The role of integrins in the development and homeostasis of the epidermis and skin appendages. Acta Naturae 5(4), 22–33 (2013).
- 18 Integrin activation controls metastasis in human breast cancer. Proc. Natl Acad. Sci. USA 98(4), 1853–1858 (2001).
- 19 External validation suggests integrin beta 3 as prognostic biomarker in serous ovarian adenocarcinomas. BMC Cancer 9, 336 (2009).
- 20 Correlation between the tumoral expression of beta3-integrin and outcome in cervical cancer patients who had undergone radiotherapy. Br. J. Cancer 92(1), 41–46 (2005).
- 21 Association between integrin expression and prognosis in localized prostate cancer. Prostate 70(11), 1189–1195 (2010).
- 22 Perspective of αvβ6-integrin imaging for clinical management of pancreatic carcinoma and its precursor lesions. Mol. Imaging
doi: 10.1177/1536012117709384 (2017) (Epub ahead of print). - 23 Expression of α3β1 integrin receptor and its ligands in human lung tumors, Lung Cancer 14(1), 156 (1996).
- 24 Integrin expression in colon cancer cells is regulated by the cytoplasmic domain of the beta6 integrin subunit. Int. J. Cancer 99(4), 529–537 (2002).
- 25 Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6(5), 421–432 (2010).
- 26 In vivo therapy of malignant melanoma by means of antagonists of alphav integrins, Int. J. Cancer 87(5), 716–723 (2000).
- 27 . New perspectives in cell adhesion: RGD and integrins. Science 238(4826), 491–497 (1987). • Breakthrough paper about the role of Arg-Gly-Asp (RGD) tripeptide in cell adhesion.
- 28 N-methylated cyclic RGD peptides as highly active and selective avb3 integrin antagonists. J. Med. Chem. 42(16), 3033–3040 (1999).
- 29 RGD-mediated delivery of small-molecule drugs. Future Med. Chem. 9(6), 579–604 (2017). •• A comprehensive review about RGD-mediated delivery of small-molecule drugs.
- 30 Novel c(RGDyK)-based conjugates of POPAM and 5-fluorouracil for integrin-targeted cancer therapy. Future Med. Chem. 9(18), 2181–2196 (2017).
- 31 Synthesis and biological evaluation of a platinum(II)-c(RGDyK) conjugate for integrin-targeted photodynamic therapy. Eur. J. Med. Chem. 141, 221–231 (2017).
- 32 . Recent progress in the development of near-infrared organic photothermal and photodynamic nanotherapeutics. Biomater. Sci. 6(4), 746–765 (2018).
- 33 Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome. Oncotarget 7(12), 15018–15032 (2016).
- 34 Synthesis of novel c(AmpRGD)-sunitinib dual conjugates as molecular tools targeting the αvβ3 integrin/VEGFR2 couple and impairing tumor-associated angiogenesis. J. Med. Chem. 60(1), 248–262 (2017).
- 35 Toward the development of a novel non-RGD cyclic peptide drug conjugate for treatment of human metastatic melanoma. Oncotarget 8(1), 757–768 (2017).
- 36 Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat. Med. 15(4), 392–400 (2009).
- 37 . Advancement in integrin facilitated drug delivery. Adv. Drug Deliv. Rev. 97, 111–143 (2016). • A comprehensive review about RGD-mediated delivery of cytotoxic drugs.
- 38 Modulating angiogenesis with integrin-targeted nanomedicines, Adv. Drug Deliv. Rev. 119, 101–119 (2017).
- 39 Dimeric camptothecin-loaded RGD-modified targeted cationic polypeptide-based micelles with high drug loading capacity and redox-responsive drug release capability. Biomater. Sci. 5(12), 2501–2510 (2017).
- 40 Improved pharmacokinetic profile of lipophilic anti-cancer drugs using ανβ3-targeted polyurethane-polyurea nanoparticles. Nanomedicine 14(2), 257–267 (2018).
- 41 Chemodrug delivery using integrin-targeted PLGA-chitosan nanoparticle for lung cancer therapy. Sci. Rep. 7(1), 14674. (2017).
- 42 Dual-targeted and pH-sensitive doxorubicin prodrug-microbubble complex with ultrasound for tumor treatment. Theranostics 7(2), 452–465 (2017).
- 43 . Radiolabeled Cyclic RGD peptide bioconjugates as radiotracers targeting multiple integrins, Bioconjug. Chem. 26(8), 1413–1438 (2015).
- 44 Clinical study of 99mTc-3P-RGD2 peptide imaging in osteolytic bone metastasis. Oncotarget 8(43), 75587–75596 (2017).
- 45 Clinical translation of a dual integrin αvβ3- and gastrin-releasing peptide receptor-targeting PET radiotracer, 68Ga-BBN-RGD. J. Nucl. Med. F58(2), 228–234 (2017).
- 46 . PET radiopharmaceuticals for imaging integrin expression: tracers in clinical studies and recent developments. Biomed. Res. Int. 2014, 871609 (2014).
- 47 Synthesis and biological evaluation of dimeric RGD peptide-paclitaxel conjugate as a model for integrin-targeted drug delivery. J. Med. Chem. 48(4), 1098–1106 (2005).
- 48 Evaluation of biodistribution and anti-tumor effect of a dimeric RGD peptide-paclitaxel conjugate in mice with breast cancer. Eur. J. Nucl. Med. Mol. Imaging 35(8), 1489–1498 (2008).
- 49 Synthesis and biological evaluation (in vitro and in vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin αVβ3. J. Med. Chem. 55(23), 10460–10474 (2012).
- 50 Design, synthesis, and biological evaluation of novel cRGD-paclitaxel conjugates for integrin-assisted drug delivery. Bioconjug. Chem. 23(8), 1610–1622 (2012).
- 51 Synthesis and biological evaluation of RGD peptidomimetic-paclitaxel conjugates bearing lysosomally cleavable linkers. Chemistry 21(18), 6921–6929 (2015).
- 52 Design, synthesis, and biological evaluation of a dual tumor-specific motive containing integrin-targeted plasmin-cleavable doxorubicin prodrug. Mol. Cancer Ther. 1(11), 901–911 (2002).
- 53 . Tumor targeting by doxorubicin-RGD-4C peptide conjugate in an orthotopic mouse hepatoma model. Int. J. Mol. Med. 14(4), 529–535 (2004).
- 54 In vitro and in vivo evaluation of doxorubicin conjugates with the divalent peptide E-[c (RGDfK) 2] that targets integrin αvβ3, Bioconjug. Chem. 19(7), 1414–1422 (2008).
- 55 Doxorubicin-formaldehyde conjugates targeting alphavbeta3 integrin. Mol. Cancer Ther. 3, 1593–1604 (2004).
- 56 Conjugated platinum (IV)-peptide complexes for targeting angiogenic tumor vasculature. Bioconjug. Chem. 19, 39–49 (2008).
- 57 An integrin-targeted photoactivatable Pt(iv) complex as a selective anticancer pro-drug: synthesis and photoactivation studies. Chem. Commun. 51(44), 9169–9172 (2015).
- 58 Integrin-targeted delivery into cancer cells of a Pt(iv) pro-drug through conjugation to RGD-containing peptides. Dalt. Trans. 44(1), 202–212 (2015).
- 59 . A platinum prodrug conjugated with a photosensitizer with aggregation-induced emission (AIE) characteristics for drug activation monitoring and combinatorial photodynamic–chemotherapy against cisplatin resistant cancer cells. Chem. Commun. 51(41), 8626–8629 (2015).
- 60 Targeted theranostic prodrugs based on an aggregation-induced emission (AIE) luminogen for real-time dual-drug tracking. Chem. Commun. 50(78), 11465–11468 (2014).
- 61 The synthesis of a c(RGDyK) targeted SN38 prodrug with an indolequinone structure for bioreductive drug release. Org. Lett. 12(7), 1384–1387 (2010).
- 62 Conjugates of a novel 7-substituted camptothecin with RGD-peptides as αvβ3 integrin ligands: an approach to tumor-targeted therapy. Bioconjug. Chem. 21(11), 1956–1967 (2010).
- 63 Novel tumor-targeted RGD peptide-camptothecin conjugates: synthesis and biological evaluation. Bioorg. Med. Chem. 18(1), 64–72 (2010).
- 64 Synthesis, biological studies and molecular dynamics of new anticancer RGD-based peptide conjugates for targeted drug delivery. Bioorg. Med Chem. 24(2), 294–303 (2016).
- 65 Dual-drug RGD conjugates provide enhanced cytotoxicity to melanoma and non-small lung cancer cells. Biopolymers 106(2), 160–171 (2015).
- 66 . Direct fluorescence monitoring of the delivery and cellular uptake of a cancer-targeted RGD peptide-appended naphthalimide theragnostic prodrug. J. Am. Chem. Soc. 134(30), 12668–12674 (2012).
- 67 Synthesis and biological evaluation of dual action cyclo-RGD/SMAC mimetic conjugates targeting α(v)β(3)/α(v)β(5) integrins and IAP proteins. Org. Biomol. Chem. 12(20), 3288–3302 (2014).
- 68 Synthesis, characterization, and biological evaluation of a dual-action ligand targeting αvβ3 integrin and VEGF receptors. ChemistryOpen 4(5), 633–641 (2015).
- 69 Synthesis and biological evaluation of RGD-conjugated MEK1/2 kinase inhibitors for integrin-targeted cancer therapy. Molecules 18(11), 13957–13978 (2013).
- 70 RGD peptide conjugation results in enhanced antitumor activity of PD0325901 against glioblastoma by both tumor-targeting delivery and combination therapy. Int. J. Pharm. 505(1-2), 329–340 (2016).
- 71 Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis. J. Med. Chem. 56(5), 1853–1864 (2013).
- 72 Dual targeting of integrin αvβ3 and matrix metalloproteinase-2 for optical imaging of tumors and chemotherapeutic delivery. Mol. Cancer Ther. 13(6), 1514–1525 (2014).
- 73 Synthesis of novel c(AmpRGD)-sunitinib dual conjugates as molecular tools targeting the αvβ3 Integrin/VEGFR2 couple and impairing tumor-associated angiogenesis. J. Med. Chem. 60(1), 248–262 (2017).
- 74 . Cyclic RGD-modified chitosan/graphene oxide polymers for drug delivery and cellular imaging. Colloids Surf. B Biointerfaces 122, 332–340 (2014).
- 75 Hyaluronic acid and Arg-Gly-Asp peptide modified graphene oxide with dual receptor-targeting function for cancer therapy. J. Biomater. Appl. 32(1), 54–65 (2017).
- 76 Application of graphene quantum dots for simultaneous fluorescence imaging and tumor-targeted drug delivery. Sens. Actuators B Chem. 256, 616–623 (2018).
- 77 MSN-mediated sequential vascular-to-cell nuclear-targeted drug delivery for efficient tumor regression. Adv. Mater. 26(39), 6742–6748 (2014).
- 78 Label-free luminescent mesoporous silica nanoparticles for imaging and drug delivery. Theranostics 3(9), 650–657 (2013).
- 79 . Synthesis of mesoporous silica nanoparticle-encapsulated alginate microparticles for sustained release and targeting therapy. J. Biomed. Mater. Res. Part B Appl. Biomater. 102(2), 293–302 (2014).
- 80 Liver cancer cells: targeting and prolonged-release drug carriers consisting of mesoporous silica nanoparticles and alginate microspheres. Int. J. Nanomedicine 9(1), 2767–2778 (2014).
- 81 Synthesis of biomolecule-modified mesoporous silica nanoparticles for targeted hydrophobic drug delivery to cancer cells. Small 7(13), 1816–1826 (2011).
- 82 Nanoscale coordination polymers for platinum-based anticancer drug delivery. J. Am. Chem. Soc. 130(35), 11584–11585 (2008).
- 83 Postsynthetic modifications of iron-carboxylate nanoscale metal−organic frameworks for imaging and drug delivery. J. Am. Chem. Soc. 131(40), 14261–14263 (2009).
- 84 Targeted delivery of insoluble cargo (paclitaxel) by PEGylated chitosan nanoparticles grafted with Arg-Gly-Asp (RGD). Mol. Pharm. 9(6), 1736–1747 (2012).
- 85 Screening of novel RGD peptides to modify nanoparticles for targeted cancer therapy. Biomater. Sci. 6(1), 125–135 (2018).
- 86 RGD peptide-mediated chitosan-based polymeric micelles targeting delivery for integrin-overexpressing tumor cells. Int. J. Nanomedicine 6, 3499–3508 (2011).
- 87 . Traceable multifunctional micellar nanocarriers for cancer-targeted co-delivery of MDR-1 siRNA and doxorubicin. ACS Nano 5(6), 5202–5213 (2011).
- 88 Novel tumor-targeting, self-assembling peptide nanofiber as a carrier for effective curcumin delivery. Int. J. Nanomedicine 9(1), 197–214 (2014).
- 89 An effective peptide cargo carrier for the delivery of cisplatin in ovarian cancer cells. Dye Pigment. 143, 342–347 (2017).
- 90 cRGD-functionalized, DOX-conjugated, and 64Cu-labeled superparamagnetic iron oxide nanoparticles for targeted anticancer drug delivery and PET/MR imaging. Biomaterials 32(17), 4151–4160 (2011).
- 91 RGD-modified albumin nanoconjugates for targeted delivery of a porphyrin photosensitizer. Mol. Pharm. 14(8), 2793–2804 (2017).
- 92 Cyclic RGD peptide-modified liposomal drug delivery system for targeted oral apatinib administration: enhanced cellular uptake and improved therapeutic effects. Int. J. Nanomedicine 12, 1941–1958 (2017).
- 93 Curcumin-loaded nanoliposomes linked to homing peptides for integrin targeting and neuropilin-1- mediated internalization. Pharm. Biol. 55(1), 277–285 (2017).
- 94 Design of Y-shaped targeting material for liposome-based multifunctional glioblastoma-targeted drug delivery. J. Control. Rel. 255, 132–141 (2017).
- 95 Self-assembly hydrogels as multifunctional drug delivery of paclitaxel for synergistic tumour-targeting and biocompatibility in vitro and in vivo. J. Pharm. Pharmacol. 69(8), 967–977 (2017).
- 96 Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179(4068), 77–79 (1973).
- 97 . Molecular biology of somatostatin receptors. Endocr. Rev. 16(4), 427–442 (1995).
- 98 Somatostatin receptors in human cancer: incidence, characteristics, functional correlates and clinical implications. J. Steroid Biochem. Mol. Biol. 43(1-3), 27–35 (1992).
- 99 . Therapeutic uses of somatostatin and its analogues: current view and potential applications. Pharmacol. Ther. 152, 98–110 (2015).
- 100 Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol. Ther. 31(2), 169–188 (2010).
- 101 . Somatostatin receptor-targeted anti-cancer therapy. Curr. Drug Deliv. 8(1), 2–10 (2011).
- 102 . Targeting delivery of paclitaxel into tumor cells via somatostatin receptor endocytosis. Chem. Biol. 7(7), 453–461 (2000).
- 103 Paclitaxel-octreotide conjugates in tumor growth inhibition of A549 human non-small cell lung cancer xenografted into nude mice. Eur. J. Pharmacol. 601(1-3), 23–29 (2008).
- 104 Somatostatin receptor-mediated specific delivery of paclitaxel prodrugs for efficient cancer therapy. J. Pharm. Sci. 104(6), 2018–2028 (2015).
- 105 Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin. Proc. Natl Acad. Sci. USA 95, 1794–1799 (1998). • Breakthrough paper about doxorubicin-RC121 conjugate.
- 106 Targeting triple-negative breast cancer through the somatostatin receptor with the new cytotoxic somatostatin analogue AN-162 [AEZS-124]. Anticancer Drugs 24(2), 150–157 (2013).
- 107 Regression of U-87 MG human glioblastomas in nude mice after treatment with a cytotoxic somatostatin analog AN-238. Clin. Cancer Res. 6(2), 709–717 (2000).
- 108 Octreotide-mediated tumor-targeted drug delivery via a cleavable doxorubicin-peptide conjugate. Mol. Pharm. 12(12), 4290–300 (2015).
- 109 An adjustable release rate linking strategy for cytotoxin-peptide conjugates. Bioorg. Med. Chem. Lett. 13(5), 799–803 (2003).
- 110 Targeted chemotherapy using a cytotoxic somatostatin conjugate to inhibit tumor growth and metastasis in nude mice. Clin. Med. Oncol. 2, 491–499 (2008).
- 111 Octreotide-periplocymarin conjugate prodrug for improving targetability and anti-tumor efficiency: synthesis, in vitro and in vivo evaluation. Oncotarget 7(52), 86326–86338 (2016).
- 112 Tumor targeted delivery of octreotide-periplogenin conjugate: synthesis, in vitro and in vivo evaluation. Int. J. Pharm. 502(1-2), 98–106 (2016).
- 113 Synthetic paclitaxel-octreotide conjugate reversing the resistance of A2780/Taxol to paclitaxel in xenografted tumor in nude mice. Oncotarget 7(50), 83451–83461 (2016).
- 114 Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet 333, 242–244 (1989).
- 115 . Somatostatin receptor imaging of non-small cell lung cancer with 99mTc depreotide. Semin. Nucl. Med. 32(2), 92–96 (2002). • Breakthrough paper about 99mTc depreotide radiotracer.
- 116 . Use of radioactive substances in diagnosis and treatment of neuroendocrine tumors. Scand. J. Gastroenterol. 50(6), 740–747 (2015). •• A comprehensive review about radioactive substances in diagnosis and treatment of neuroendocrine tumors.
- 117 Octreotide-conjugated PAMAM for targeted delivery to somatostatin receptors over-expressed tumor cells. J. Drug Target. 22(5), 428–438 (2014).
- 118 Octreotide-modified polymeric micelles as potential carriers for targeted docetaxel delivery to somatostatin receptor overexpressing tumor cells. Pharm. Res. 28(5), 1167–1178 (2011).
- 119 The eradication of breast cancer and cancer stem cells using octreotide modified paclitaxel active targeting micelles and salinomycin passive targeting micelles. Biomaterials 33(2), 679–691 (2012).
- 120 A novel octreotide modified lipid vesicle improved the anticancer efficacy of doxorubicin in somatostatin receptor 2 positive tumor models. Mol. Pharm. 7(4), 1159–1168 (2010).
- 121 Somatostatin receptor-mediated tumor-targeting nanocarriers based on octreotide-PEG conjugated nanographene oxide for combined chemo and photothermal therapy. Small 12(26), 3578–3590 (2016).
- 122 Octreotide-modification enhances the delivery and targeting of doxorubicin-loaded liposomes to somatostatin receptors expressing tumor in vitro and in vivo. Nanotechnology 21(47), 475101 (2010).
- 123 Thailandepsin A-loaded and octreotide-functionalized unimolecular micelles for targeted neuroendocrine cancer therapy. Biomaterials 91, 1–10 (2016).
- 124 International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol. Rev. 60(1), 1–42 (2008).
- 125 The human gastrin-releasing peptide receptor gene structure, its tissue expression and promoter. Gene 264(1), 95–103 (2001).
- 126 Effective inhibition of experimental human ovarian cancers with a targeted cytotoxic bombesin analogue AN-215. Clin. Cancer Res. 11(6), 2408–2415 (2005).
- 127 Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin. Proc. Natl Acad. Sci. USA 95(4), 1794–1799 (1998).
- 128 In vitro and in vivo antitumor effects of cytotoxic camptothecin-bombesin conjugates are mediated by specific interaction with cellular bombesin receptors. J. Pharmacol. Exp. Ther. 318(3), 1265–1272 (2006).
- 129 Development of high affinity camptothecin-bombesin conjugates that have targeted cytotoxicity for bombesin receptor-containing tumor cells. J. Biol. Chem. 279(22), 23580–23589 (2004).
- 130 Single-drug multiligand conjugates: synthesis and preliminary cytotoxicity evaluation of a paclitaxel-dipeptide “scorpion” molecule. Bioconjug. Chem. 17(3), 565–570 (2006).
- 131 Enhancement of cytotoxicity of antimicrobial peptide magainin II in tumor cells by bombesin-targeted delivery. Acta Pharmacol. Sin. 32(1), 79–88 (2011).
- 132 . From bench to bed: new gastrin-releasing peptide receptor-directed radioligands and their use in prostate cancer. PET Clin. 12(2), 205–217 (2017). •• A comprehensive review about radioactive substances in diagnosis and treatment of prostate cancer.
- 133 Radiolabeled bombesin derivatives for preclinical oncological imaging. Biomed. Pharmacother. 87, 58–72 (2017).
- 134 Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment. Expert Opin. Ther. Targets 20(9), 1055–1073 (2016).
- 135 . Review of epidermal growth factor receptor biology. Int. J. Radiat. Oncol. Biol. Phys. 59(2 Suppl.), 21–26 (2004).
- 136 The nuclear epidermal growth factor receptor signaling network and its role in cancer. Discov. Med. 12(66), 419–432 (2011).
- 137 . EGFR and cancer prognosis. Eur. J. Cancer 37, S9–S15 (2001).
- 138 . Molecular-targeted therapies for epidermal growth factor receptor and its resistance mechanisms. Int. J. Mol. Sci. 18(11), pii: E2420 (2017).
- 139 Design and biological activity of epidermal growth factor receptor-targeted peptide doxorubicin conjugate. Biomed. Pharmacother. 70, 268–273 (2015).
- 140 GE11 peptide-conjugated nanoliposomes to enhance the combinational therapeutic efficacy of docetaxel and siRNA in laryngeal cancers. Int. J. Nanomedicine 12, 6461–6470 (2017).
- 141 Co-delivery of docetaxel and curcumin prodrug via dual-targeted nanoparticles with synergistic antitumor activity against prostate cancer. Biomed. Pharmacother. 88, 374–383 (2017).
- 142 EGFR-targeting PLGA-PEG nanoparticles as a curcumin delivery system for breast cancer therapy. Nanoscale 9(42), 16365–16374 (2017).
- 143 EGFR-targeted poly(ethylene glycol)-distearoylphosphatidylethanolamine micelle loaded with paclitaxel for laryngeal cancer: preparation, characterization and in vitro evaluation. Drug Deliv. 22(6), 785–794 (2015).
- 144 GE11 peptide conjugated selenium nanoparticles for EGFR targeted oridonin delivery to achieve enhanced anticancer efficacy by inhibiting EGFR-mediated PI3K/AKT and Ras/Raf/MEK/ERK pathways. Drug Deliv. 24(1), 1549–1564 (2017).
- 145 Synthesis and characterization of cisplatin-loaded, EGFR-targeted biopolymer and in vitro evaluation for targeted delivery. J. Biomed. Mater. Res. A 100(10), 2839–2848 (2012).
- 146 In vitro and in vivo evaluation of 64Cu-radiolabeled KCCYSL peptides for targeting epidermal growth factor receptor-2 in breast carcinomas. Cancer Biother. Radiopharm. 25(6), 693–703 (2010).
- 147 . 111In-labeled KCCYSL peptide as an imaging probe for ErbB-2-expressing ovarian carcinomas. J. Labelled Comp. Radiopharm. 52(14), 583–590 (2009).
- 148 . Emerging strategies for EphA2 receptor targeting for cancer therapeutics. Expert Opin. Ther. Targets 15(1), 31–51 (2011).
- 149 Targeting Eph/ephrin system in cancer therapy. Eur. J. Med. Chem. 142, 152–162 (2017).
- 150 . An ephrin mimetic peptide that selectively targets the EphA2 receptor. J. Biol. Chem. 277(49), 46974–46979 (2002). • Breakthrough paper about ephrin mimetic peptides.
- 151 Targeted delivery of paclitaxel to EphA2-expressing cancer cells. Clin. Cancer Res. 19(1), 128–137 (2013).
- 152 Novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells. J. Med. Chem. 55(5), 2427–2436 (2012).
- 153 Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine. Oncotarget 7(13), 17103–17110 (2016).
- 154 . Design and characterization of novel EphA2 agonists for targeted delivery of chemotherapy to cancer cells. Chem. Biol. 22(7), 876–887 (2015).
- 155 . EphA2 targeting pegylated nanocarrier drug delivery system for treatment of lung cancer. Pharm. Res. 31(10), 2796–2809 (2014).
- 156 Combination approach of YSA peptide anchored docetaxel stealth liposomes with oral antifibrotic agent for the treatment of lung cancer. Mol. Pharm. 13(6), 2049–2058 (2016).
- 157 EphA2 targeted doxorubicin-nanoliposomes for osteosarcoma treatment. Pharm. Res. 34(12), 2891–2900 (2017).
- 158 Effective photothermal chemotherapy using doxorubicin-loaded gold nanospheres that target EphB4 receptors in tumors. Cancer Res. 72(18), 4777–4786 (2012).
- 159 . Targeting the Eph system with peptides and peptide conjugates. Curr. Drug Targets 16(10), 1031–1047 (2015). •• A comprehensive review about erythropoietin-producing human hepatocellular receptor targeting with peptides and peptide conjugates.
- 160 . Structure of the porcine LH- and FSH-releasing hormone. II. Confirmation of the proposed structure by conventional sequential analyses. Biochem. Biophys. Res. Commun. 44(2), 459–463 (1971).
- 161 Receptors for luteinizing hormone releasing hormone (LHRH) expressed in human non-Hodgkin's lymphomas can be targeted for therapy with the cytotoxic LHRH analogue AN-207. Eur. J. Cancer 41(14), 2196–2202 (2005).
- 162 Effective targeted chemotherapy using AEZS-108 (AN-152) for LHRH receptor-positive pancreatic cancers. Oncol. Rep. 26(3), 629–635 (2011).
- 163 High incidence of receptors for luteinizing hormone-releasing hormone (LHRH) and LHRH receptor gene expression in human prostate cancers. J. Urol. 63(2), 623–629 (2000).
- 164 Photodynamic oncotherapy mediated by gonadotropin-releasing hormone receptors. J. Med. Chem. 60(20), 8667–8672 (2017).
- 165 GnRH-Gemcitabine conjugates for the treatment of androgen-independent prostate cancer: pharmacokinetic enhancements combined with targeted drug delivery. Bioconjug. Chem. 25(4), 813–823 (2014).
- 166 Gemcitabine based peptide conjugate with improved metabolic properties and dual mode of efficacy. Mol. Pharm. 14(3), 674–685 (2017).
- 167 . Highly stable PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles for the effective delivery of docetaxel in prostate cancers. Nanoscale Res. Lett. 11(1), 305 (2016).
- 168 Luteinizing hormone-releasing hormone peptide tethered nanoparticulate system for enhanced antitumoral efficacy of paclitaxel. Nanomedicine 11(7), 797–816 (2016).
- 169 Targeted hydroxyethyl starch prodrug for inhibiting the growth and metastasis of prostate cancer. Biomaterials 116, 82–94 (2017).
- 170 Formulation and evaluation of targeted nanoparticles for breast cancer theranostic system. Eur. J. Pharm. Sci. 97, 47–54 (2017).
- 171 Molecular targeting of drug delivery systems to ovarian cancer by BH3 and LHRH peptides. J. Control. Rel. 91(1-2), 61–73 (2003).
- 172 Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide. Proc. Natl Acad. Sci. USA 102(36), 12962–12967 (2005).
- 173 Effective treatment of experimental human endometrial cancers with targeted cytotoxic luteinizing hormone-releasing hormone analogues AN-152 and AN-207. Fertil Steril. 83, 1125–1133 (2005).
- 174 Internalization of cytotoxic analog AN-152 of luteinizing hormone-releasing hormone induces apoptosis in human endometrial and ovarian cancer cell lines independent of multidrug resistance-1 (MDR-1) system. Am. J. Obstet. Gynecol. 191(4), 1164–1172 (2004).
- 175 Effective treatment of experimental ES-2 human ovarian cancers with a cytotoxic analog of luteinizing hormone-releasing hormone AN-207. Anticancer Drugs 13(9), 949–956 (2002).
- 176 Targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 inhibits growth of OV-1063 human epithelial ovarian cancers in nude mice. Am. J. Obstet. Gynecol. 180(5), 1095–1103 (1999).
- 177 Inhibition of human experimental prostate cancers by a targeted cytotoxic luteinizing hormone-releasing hormone analog AN-207. Prostate. 66(2), 200–210 (2006).
- 178 Inhibition of in vivo proliferation of MDA-PCa-2b human prostate cancer by a targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207. Cancer Lett. 176(1), 57–63 (2002). • Breakthrough paper about a luteinizing hormone-releasing hormone-based drug delivery system.
- 179 A conjugate of doxorubicin and an analog of luteinizing hormone-releasing hormone shows increased efficacy against oral and laryngeal cancers. Oral Oncol. 38(7), 657–663 (2002).
- 180 Inhibition of U-87 MG glioblastoma by AN-152 (AEZS-108), a targeted cytotoxic analog of luteinizing hormone-releasing hormone. Oncotarget 4(3), 422–432 (2013).
- 181 Targeted cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AEZS-108 (AN-152), inhibits the growth of DU-145 human castration-resistant prostate cancer in vivo and in vitro through elevating p21 and ROS levels. Oncotarget 5(12), 4567–4578 (2014).
- 182 Receptor-mediated targeting of a photosensitizer by its conjugation to gonadotropin-releasing hormone analogues. J. Med. Chem. 46(19), 3965–3974 (2003).
- 183 Development of an oxime bond containing daunorubicin-gonadotropin-releasing hormone-III conjugate as a potential anticancer drug. Bioconjug. Chem. 20(4), 656–665 (2009).
- 184 In-vivo antitumour effect of daunorubicin-GnRH-III derivative conjugates on colon carcinoma-bearing mice. Anticancer Drugs 23(1), 90–97 (2012).
- 185 [DLys(6)]-luteinizing hormone releasing hormone-curcumin conjugate inhibits pancreatic cancer cell growth in vitro and in vivo. Int. J. Cancer 129(7), 1611–1623 (2011).
- 186 Luteinizing hormone-releasing hormone receptor-targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy. Mol. Cancer Ther. 8(6), 1655–1665 (2009).
- 187 A conjugate of methotrexate and an analog of luteinizing hormone releasing hormone shows increased efficacy against prostate cancer. Sci. Rep. 6, 33894 (2016).
- 188 Peptide-drug conjugate GnRH-sunitinib targets angiogenesis selectively at the site of action to inhibit tumor growth. Cancer Res. 76(5), 1181–1192 (2016).
- 189 Paclitaxel conjugation with the analog of the gonadotropin-releasing hormone as a targeting moiety. Int. J. Pharm. 415(1-2), 175–180 (2011).
- 190 Gonadotropin-releasing hormone receptor-targeted paclitaxel-degarelix conjugate: synthesis and in vitro evaluation. J. Pept. Sci. 21(7), 569–576 (2015).
- 191 Receptor targeted polymers, dendrimers, liposomes: which nanocarrier is the most efficient for tumor-specific treatment and imaging? J. Control. Rel. 130(2), 107–114 (2008).
- 192 Targeted drug and gene delivery systems for lung cancer therapy. Clin. Cancer Res. 15(23), 7299–7308 (2009).
- 193 Integrated self-assembling drug delivery system possessing dual responsive and active targeting for orthotopic ovarian cancer theranostics. Biomaterials 90, 12–26 (2016).
- 194 The in vivo antitumor activity of LHRH targeted methotrexate-human serum albumin nanoparticles in 4T1 tumor-bearing Balb/c mice. Int. J. Pharm. 431(1-2), 183–189 (2012).
- 195 . Highly stable PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles for the effective delivery of docetaxel in prostate cancers. Nanoscale Res. Lett. 11(1), 305 (2016).
- 196 Targeted delivery of doxorubicin to breast cancer cells by magnetic LHRH chitosan bioconjugated nanoparticles. Int. J. Biol. Macromol. 93(Pt A), 1192–1205 (2016).
- 197 Targeted delivery of cisplatin by LHRH-peptide conjugated dextran nanoparticles suppresses breast cancer growth and metastasis. Acta Biomater. 18, 132–143 (2015).
- 198 . Neurotensin and neurotensin receptors. Trends Pharmacol. Sci. 20(7), 302–309 (1999).
- 199 . The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J. Biol. Chem. 248(19), 6854–6861 (1973).
- 200 Neurotensin and its high affinity receptor 1 as a potential pharmacological target in cancer therapy. Front. Endocrinol. 3, 184 (2013).
- 201 Modular branched neurotensin peptides for tumor target tracing and receptor-mediated therapy: a proof-of-concept. Curr. Cancer Drug Targets 10(7), 695–704 (2010). •• Breakthrough paper about branched neurotensin peptides.
- 202 Tumor-selective peptide-carrier delivery of paclitaxel increases in vivo activity of the drug. Sci. Rep. 5, 17736 (2015).
- 203 Target-selective drug delivery through liposomes labeled with oligobranched neurotensin peptides. ChemMedChem. 6(4), 678–685 (2011).
- 204 Nanoparticles exposing neurotensin tumor-specific drivers. J. Pept. Sci. 19(4), 198–204 (2013).
- 205 . Radiopharmaceuticals for imaging and endoradiotherapy of neurotensin receptor-positive tumors. J. Labelled Comp. Radiopharm. 61(3), 309–325 (2018). •• A comprehensive review about radiopharmaceuticals for imaging and endoradiotherapy of neurotensin receptor-positive tumors.
- 206 . Peptide-targeted radionuclide therapy for melanoma. Crit. Rev. Oncol. Hematol. 67, 213–228 (2008).
- 207 Camptothecin-loaded liposomes with α-melanocyte-stimulating hormone enhance cytotoxicity toward and cellular uptake by melanomas: an application of nanomedicine on natural product. J. Tradit. Complement. Med. 3(2), 102–109 (2013).
- 208 Functionalized diterpene parvifloron D-loaded hybrid nanoparticles for targeted delivery in melanoma therapy. Ther. Deliv. 7(8), 521–544 (2016).
- 209 . Development of a ligand-targeted therapeutic agent for neurokinin-1 receptor expressing cancers. Mol. Pharm. 14(11), 3859–3865 (2017).
- 210 . Vip-grafted sterically stabilized phospholipid nanomicellar 17-allylamino-17-demethoxy geldanamycin: a novel targeted nanomedicine for breast cancer. Int. J. Pharm. 365(1-2), 157–161 (2009).
- 211 Proapoptotic peptide-mediated cancer therapy targeted to cell surface p32. Mol. Ther. 21(12), 2195–2204 (2013).
- 212 pH-sensitive polymeric micelles for the co-delivery of proapoptotic peptide and anticancer drug for synergistic cancer therapy. RSC Adv. 7, 12886–12896 (2017).
- 213 Design and in vitro evaluation of bispecific complexes and drug conjugates of anticancer peptide, LyP-1 in human breast cancer. Pharm. Res. 34(2), 352–364 (2017).
- 214 Glioma-targeted drug delivery enabled by a multifunctional peptide. Bioconjug. Chem. 28(3), 775–781 (2017).
- 215 Photodynamic therapy targeting VCAM-1- expressing human umbilical vein endothelial cells using a PpIX-VCAM-1 binding peptide–quantum dot conjugate. RSC Adv. 7, 50562–50570 (2017).
- 216 Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy. Nat. Med. 14(4), 454–458 (2008).
- 217 . Increasing the affinity of cationized polyacrylamide-paclitaxel nanoparticles towards colon cancer cells by a surface recognition peptide. Int. J. Pharm. 531(1), 281–291 (2017).
- 218 Targeting NCAM-expressing neuroblastoma with polymeric precision nanomedicine. J. Control. Rel. 249, 162–172 (2017).