Small targeted cytotoxics: current state and promises from DNA-encoded chemical libraries.

The targeted delivery of potent cytotoxic agents has emerged as a promising strategy for the treatment of cancer and other serious conditions. Traditionally, antibodies against markers of disease have been used as drug-delivery vehicles. More recently, lower molecular weight ligands have been proposed for the generation of a novel class of targeted cytotoxics with improved properties. Advances in this field crucially rely on efficient methods for the identification and optimization of organic molecules capable of high-affinity binding and selective recognition of target proteins. The advent of DNA-encoded chemical libraries allows the construction and screening of compound collections of unprecedented size. In this Review, we survey developments in the field of small ligand-based targeted cytotoxics and show how innovative library technologies will help develop the drugs of the future.

[1]  Takuya Ueda,et al.  Cell-free translation reconstituted with purified components , 2001, Nature Biotechnology.

[2]  R. Jensen,et al.  In Vitro and in Vivo Antitumor Effects of Cytotoxic Camptothecin-Bombesin Conjugates Are Mediated by Specific Interaction with Cellular Bombesin Receptors , 2006, Journal of Pharmacology and Experimental Therapeutics.

[3]  F. Bootz,et al.  The antibody-mediated targeted delivery of interleukin-10 inhibits endometriosis in a syngeneic mouse model. , 2011, Human Reproduction.

[4]  U. Kompella,et al.  Luteinizing hormone-releasing hormone receptor–targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy , 2009, Molecular Cancer Therapeutics.

[5]  R. Doyle,et al.  Vitamin B12 in drug delivery: breaking through the barriers to a B12 bioconjugate pharmaceutical , 2011, Expert opinion on drug delivery.

[6]  D. Coy,et al.  Somatostatin receptor-targeted anti-cancer therapy. , 2011, Current drug delivery.

[7]  P. Harbury,et al.  Synthetic ligands discovered by in vitro selection. , 2007, Journal of the American Chemical Society.

[8]  E. Sausville,et al.  Mining the National Cancer Institute's tumor-screening database: identification of compounds with similar cellular activities. , 2002, Journal of medicinal chemistry.

[9]  A. Schally,et al.  Use of analogs of peptide hormones conjugated to cytotoxic radicals for chemotherapy targeted to receptors on tumors. , 2011, Current drug delivery.

[10]  Baoguang Zhao,et al.  Design, synthesis and selection of DNA-encoded small-molecule libraries. , 2009, Nature chemical biology.

[11]  D. McDonald,et al.  Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. , 2003, The American journal of pathology.

[12]  J. Reddy,et al.  Synthesis and biological evaluation of EC72: a new folate-targeted chemotherapeutic. , 2005, Bioconjugate chemistry.

[13]  K. Heider,et al.  Effective Immunoconjugate Therapy in Cancer Models Targeting a Serine Protease of Tumor Fibroblasts , 2008, Clinical Cancer Research.

[14]  P. Low,et al.  Synthesis of [(99m)Tc]DTPA-folate and its evaluation as a folate-receptor-targeted radiopharmaceutical. , 2000, Bioconjugate chemistry.

[15]  L. Dinkelborg,et al.  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY A High-Affinity Human Antibody That Targets Tumoral Blood Vessels , 1999 .

[16]  G. Adams,et al.  Influence of affinity and antigen internalization on the uptake and penetration of Anti-HER2 antibodies in solid tumors. , 2011, Cancer research.

[17]  S. Q. Xie,et al.  Proteomic Analysis of Mitotic RNA Polymerase II Reveals Novel Interactors and Association With Proteins Dysfunctional in Disease* , 2011, Molecular & Cellular Proteomics.

[18]  Moorthy P Ponnusamy,et al.  Targeting the EGFR signaling pathway in cancer therapy , 2012, Expert opinion on therapeutic targets.

[19]  Dario Neri,et al.  Site-specific traceless coupling of potent cytotoxic drugs to recombinant antibodies for pharmacodelivery. , 2012, Journal of the American Chemical Society.

[20]  Christoph E. Dumelin,et al.  Selection of streptavidin binders from a DNA-encoded chemical library. , 2006, Bioconjugate chemistry.

[21]  Damon L. Meyer,et al.  Lysosomal Trafficking and Cysteine Protease Metabolism Confer Target-specific Cytotoxicity by Peptide-linked Anti-CD30-Auristatin Conjugates* , 2006, Journal of Biological Chemistry.

[22]  Roy Bicknell,et al.  Tumour vascular targeting , 2005, Nature Reviews Cancer.

[23]  Michael A. Stravs,et al.  Discovery of small-molecule interleukin-2 inhibitors from a DNA-encoded chemical library. , 2012, Chemistry.

[24]  M. Graham,et al.  Radiopeptide Imaging and Therapy in the United States , 2011, The Journal of Nuclear Medicine.

[25]  John M Lambert,et al.  Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. , 2008, Cancer research.

[26]  Philip S Low,et al.  Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases. , 2008, Accounts of chemical research.

[27]  J. Schneider-Mergener,et al.  A novel class of small functional peptides that bind and inhibit human alpha-thrombin isolated by mRNA display. , 2003, Chemistry & biology.

[28]  N. Neamati,et al.  Evaluation of biodistribution and anti-tumor effect of a dimeric RGD peptide–paclitaxel conjugate in mice with breast cancer , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[29]  S. Deutscher,et al.  Peptides specific to the galectin-3 carbohydrate recognition domain inhibit metastasis-associated cancer cell adhesion. , 2004, Carcinogenesis.

[30]  Damon L. Meyer,et al.  cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. , 2003, Blood.

[31]  B. Teicher,et al.  Antibody Conjugate Therapeutics: Challenges and Potential , 2011, Clinical Cancer Research.

[32]  A. Bajo,et al.  Targeted doxorubicin-containing luteinizing hormone-releasing hormone analogue AN-152 inhibits the growth of doxorubicin-resistant MX-1 human breast cancers. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  P. Low,et al.  Synthesis and activity of folate conjugated didemnin B for potential treatment of inflammatory diseases. , 2012, Bioorganic & medicinal chemistry letters.

[34]  P. Low,et al.  Synthesis and biological analysis of prostate-specific membrane antigen-targeted anticancer prodrugs. , 2010, Journal of Medicinal Chemistry.

[35]  A. Schally,et al.  Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[36]  H. Hogenkamp,et al.  Tumor imaging via indium 111-labeled DTPA-adenosylcobalamin. , 1999, Mayo Clinic proceedings.

[37]  S. Ross,et al.  Imaging tumors with an albumin-binding Fab, a novel tumor-targeting agent. , 2007, Cancer research.

[38]  Triantafyllos Stylianopoulos,et al.  Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. , 2011, Annual review of chemical and biomolecular engineering.

[39]  T. Katoh,et al.  Natural product-like macrocyclic N-methyl-peptide inhibitors against a ubiquitin ligase uncovered from a ribosome-expressed de novo library. , 2011, Chemistry & biology.

[40]  Dario Neri,et al.  Tumor-Targeting Properties of Novel Antibodies Specific to the Large Isoform of Tenascin-C , 2006, Clinical Cancer Research.

[41]  M. Port,et al.  In vivo imaging of folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugates. , 2012, Molecular pharmaceutics.

[42]  C. Allaart,et al.  A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. , 2007, Arthritis and rheumatism.

[43]  Christoph E. Dumelin,et al.  Isolation of potent and specific trypsin inhibitors from a DNA-encoded chemical library. , 2010, Bioconjugate chemistry.

[44]  S. Iacobelli,et al.  Oxaliplatin activity against metastatic colorectal cancer. A phase II study of 5-day continuous venous infusion at circadian rhythm modulated rate. , 1993, European journal of cancer.

[45]  L. Zardi,et al.  Fibronectin as target for tumor therapy , 2006, International journal of cancer.

[46]  M. Lee,et al.  Calicheamicins: Discovery, Structure, Chemistry, and Interaction with DNA , 1991 .

[47]  C. Cordon-Cardo,et al.  Prostate-specific membrane antigen expression in normal and malignant human tissues. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[48]  A. Schally,et al.  Targeted cytotoxic bombesin analog AN-215 effectively inhibits experimental human breast cancers with a low induction of multi-drug resistance proteins. , 2005, Endocrine-related cancer.

[49]  M. Jordan,et al.  Microtubules as a target for anticancer drugs , 2004, Nature Reviews Cancer.

[50]  Md Nazrul Islam,et al.  Efficacy and safety of methotrexate in articular and cutaneous manifestations of systemic lupus erythematosus , 2012, International journal of rheumatic diseases.

[51]  G. P. Smith,et al.  Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. , 1985, Science.

[52]  P. Low,et al.  Synthesis and evaluation of taxol-folic acid conjugates as targeted antineoplastics. , 2002, Bioorganic & medicinal chemistry.

[53]  J. Daguer,et al.  DNA-templated combinatorial assembly of small molecule fragments amenable to selection/amplification cycles , 2011 .

[54]  R. Ladner,et al.  M13 bacteriophage displaying disulfide-constrained microproteins. , 1993, Gene.

[55]  P. Low,et al.  Characterization of the pH of Folate Receptor-Containing Endosomes and the Rate of Hydrolysis of Internalized Acid-Labile Folate-Drug Conjugates , 2007, Journal of Pharmacology and Experimental Therapeutics.

[56]  R. Lerner,et al.  Encoded combinatorial chemistry. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[57]  P. Schultz,et al.  A chemically induced vaccine strategy for prostate cancer. , 2011, ACS chemical biology.

[58]  V. Ambrosini,et al.  Radiopeptide Imaging and Therapy in Europe , 2011, The Journal of Nuclear Medicine.

[59]  Ralph Weissleder,et al.  Detection of early prostate cancer using a hepsin-targeted imaging agent. , 2008, Cancer research.

[60]  I. Ojima.  Use of Fluorine in the Medicinal Chemistry and Chemical Biology of Bioactive Compounds—A Case Study on Fluorinated Taxane Anticancer Agents , 2004, Chembiochem : a European journal of chemical biology.

[61]  H. Sindermann,et al.  Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors. , 2010, Gynecologic oncology.

[62]  N. Adey,et al.  An M13 phage library displaying random 38-amino-acid peptides as a source of novel sequences with affinity to selected targets. , 1993, Gene.

[63]  Samu Melkko,et al.  On the magnitude of the chelate effect for the recognition of proteins by pharmacophores scaffolded by self-assembling oligonucleotides. , 2006, Chemistry & biology.

[64]  Philip S Low,et al.  Design, synthesis, and preclinical evaluation of prostate-specific membrane antigen targeted (99m)Tc-radioimaging agents. , 2009, Molecular pharmaceutics.

[65]  A. Schally,et al.  Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors. , 1999, European journal of endocrinology.

[66]  P. Lambin,et al.  Imaging of CA IX with fluorescent labelled sulfonamides distinguishes hypoxic and (re)-oxygenated cells in a xenograft tumour model. , 2009, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[67]  M. Marmion,et al.  Synthesis and evaluation of 99mTc(CO)(3)-DTPA-folate as a folate-receptor-targeted radiopharmaceutical. , 2002, Nuclear medicine and biology.

[68]  D. Cane,et al.  Chemical evolution as a tool for molecular discovery. , 2007, Annual review of biochemistry.

[69]  Joo Chuan Tong,et al.  In silico design of small molecules. , 2012, Methods in molecular biology.

[70]  Yuuki Hayashi,et al.  In vitro selection of anti-Akt2 thioether-macrocyclic peptides leading to isoform-selective inhibitors. , 2012, ACS chemical biology.

[71]  M. Green,et al.  Targeting the tumor-associated folate receptor with an 111In-DTPA conjugate of pteroic acid. , 2005, Journal of the American Chemical Society.

[72]  J. Scheuermann,et al.  A traceless vascular-targeting antibody-drug conjugate for cancer therapy. , 2012, Angewandte Chemie.

[73]  Tiancheng Liu,et al.  A targeted low molecular weight near-infrared fluorescent probe for prostate cancer. , 2010, Bioorganic & medicinal chemistry letters.

[74]  Dario Neri,et al.  Immunoscintigraphic detection of the ED-B domain of fibronectin, a marker of angiogenesis, in patients with cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[75]  Donald M. O'Rourke,et al.  Rationally designed anti-HER2/neu peptide mimetic disables P185HER2/neu tyrosine kinases in vitro and in vivo , 2000, Nature Biotechnology.

[76]  Rakesh K Jain,et al.  Mosaic tumor vessels: cellular basis and ultrastructure of focal regions lacking endothelial cell markers. , 2005, Cancer research.

[77]  A. Bajo,et al.  Preclinical evaluation of therapeutic effects of targeted cytotoxic analogs of somatostatin and bombesin on human gastric carcinomas , 2003, Cancer.

[78]  S. Deutscher.  Phage display in molecular imaging and diagnosis of cancer. , 2010, Chemical reviews.

[79]  R L Sokoloff,et al.  A dual‐monoclonal sandwich assay for prostate‐specific membrane antigen: Levels in tissues, seminal fluid and urine , 2000, The Prostate.

[80]  P. Marcato,et al.  Aldehyde dehydrogenase: Its role as a cancer stem cell marker comes down to the specific isoform , 2011, Cell cycle.

[81]  H. Maecke,et al.  Radiopharmaceutical development of radiolabelled peptides , 2012, European Journal of Nuclear Medicine and Molecular Imaging.

[82]  P. Low,et al.  Ligand Binding and Kinetics of Folate Receptor Recycling in Vivo: Impact on Receptor-Mediated Drug Delivery , 2004, Molecular Pharmacology.

[83]  J. Wong,et al.  A pretherapy biodistribution and dosimetry study of indium-111-radiolabeled trastuzumab in patients with human epidermal growth factor receptor 2-overexpressing breast cancer. , 2010, Cancer biotherapy & radiopharmaceuticals.

[84]  J. Reddy,et al.  Folate receptor-specific antitumor activity of EC131, a folate-maytansinoid conjugate. , 2007, Cancer research.

[85]  J. Reddy,et al.  Preclinical antitumor activity of a novel folate-targeted dual drug conjugate. , 2007, Molecular pharmaceutics.

[86]  A. Schally,et al.  Inhibition of growth of MX‐1, MCF‐7‐MIII and MDA‐MB‐231 human breast cancer xenografts after administration of a targeted cytotoxic analog of somatostatin, AN‐238 , 1999, International journal of cancer.

[87]  David E Reichert,et al.  Preparation of 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate as potential folate-receptor-targeted PET radiopharmaceuticals. , 2003, Nuclear medicine and biology.

[88]  W. Oyen,et al.  Optimization of radioimmunotherapy of renal cell carcinoma: labeling of monoclonal antibody cG250 with 131I, 90Y, 177Lu, or 186Re. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[89]  G. Adams,et al.  High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. , 2001, Cancer research.

[90]  S. Rosenberg,et al.  High-affinity urokinase receptor antagonists identified with bacteriophage peptide display. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[91]  J. Reddy,et al.  Comparative preclinical activity of the folate‐targeted Vinca alkaloid conjugates EC140 and EC145 , 2007, International journal of cancer.

[92]  G. Winter,et al.  Making antibodies by phage display technology. , 1994, Annual review of immunology.

[93]  A. Schally,et al.  Targeted cytotoxic analog of luteinizing hormone‐releasing hormone AN‐207 inhibits the growth of PC‐82 human prostate cancer in nude mice , 1999 .

[94]  Markus Kalisch,et al.  Selection of Carbonic Anhydrase IX Inhibitors from One Million DNA-Encoded Compounds. , 2011, ACS chemical biology.

[95]  Michelle R. Arkin,et al.  Small-molecule inhibitors of protein–protein interactions: progressing towards the dream , 2004, Nature Reviews Drug Discovery.

[96]  M Kovacs,et al.  Cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin or 2-pyrrolinodoxorubicin, a derivative 500-1000 times more potent. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[97]  D. Boger,et al.  Induction of endonucleolytic DNA fragmentation and apoptosis by the duocarmycins , 1994 .

[98]  D. Nowotnik,et al.  Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumours. , 2004, Journal of inorganic biochemistry.

[99]  Christopher P Leamon,et al.  Engineering folate-drug conjugates to target cancer: from chemistry to clinic. , 2012, Bioconjugate chemistry.

[100]  A. Epenetos,et al.  Monoclonal Antibody Targeting of Ovarian Carcinoma , 1998, Oncology.

[101]  Erkki Ruoslahti,et al.  Phage Libraries Displaying Cyclic Peptides with Different Ring Sizes: Ligand Specificities of the RGD-Directed Integrins , 1995, Bio/Technology.

[102]  S. Gambhir,et al.  Optimizing radiolabeled engineered anti-p185HER2 antibody fragments for in vivo imaging. , 2005, Cancer research.

[103]  Ki Young Choi,et al.  Protease-Activated Drug Development , 2012, Theranostics.

[104]  P. Low,et al.  Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acid-aminopterin conjugate , 2011, Arthritis research & therapy.

[105]  A. Schally,et al.  Targeted therapy with a cytotoxic somatostatin analog, AN‐238, inhibits growth of human experimental endometrial carcinomas expressing multidrug resistance protein MDR‐1 , 2005, Cancer.

[106]  David R. Liu,et al.  DNA-Templated Organic Synthesis and Selection of a Library of Macrocycles , 2004, Science.

[107]  Rajeeva Singh,et al.  Design of antibody-maytansinoid conjugates allows for efficient detoxification via liver metabolism. , 2011, Bioconjugate chemistry.

[108]  H. Suga,et al.  Ribosomal production and in vitro selection of natural product-like peptidomimetics: the FIT and RaPID systems. , 2012, Current opinion in chemical biology.

[109]  P. Low,et al.  Synthesis and activity of a folate peptide camptothecin prodrug. , 2006, Bioorganic & medicinal chemistry letters.

[110]  Philip S Low,et al.  Real time, noninvasive imaging and quantitation of the accumulation of ligand-targeted drugs into receptor-expressing solid tumors. , 2009, Molecular pharmaceutics.

[111]  Dario Neri,et al.  Targeting by affinity–matured recombinant antibody fragments of an angiogenesis associated fibronectin isoform , 1997, Nature Biotechnology.

[112]  A. Gualberto.  Brentuximab Vedotin (SGN-35), an antibody–drug conjugate for the treatment of CD30-positive malignancies , 2012, Expert opinion on investigational drugs.

[113]  R. Cass,et al.  Screening of cyclic peptide phage libraries identifies ligands that bind streptavidin with high affinities. , 1995, Biochemistry.

[114]  M. Rusckowski,et al.  Evidence of specificity of radiolabeled phage display peptides for the TAG-72 antigen. , 2007, Cancer biotherapy & radiopharmaceuticals.

[115]  Grietje Molema,et al.  Tumor Infarction in Mice by Antibody-Directed Targeting of Tissue Factor to Tumor Vasculature , 1997, Science.

[116]  R. W. Baldwin,et al.  Biodistribution and tumour localization of a methotrexate‐monoclonal‐antibody 791T/36 conjugate in nude mice with human tumour xenografts , 2006, International journal of cancer.

[117]  Christoph E. Dumelin,et al.  Encoded self-assembling chemical libraries , 2004, Nature Biotechnology.

[118]  C. Grissom,et al.  Synthesis and characterization of a cobalamin-colchicine conjugate as a novel tumor-targeted cytotoxin. , 2004, The Journal of organic chemistry.

[119]  D. Neri,et al.  Antibody-drug conjugates: basic concepts, examples and future perspectives. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[120]  P. Low,et al.  Imaging sites of infection using a 99mTc-labeled folate conjugate targeted to folate receptor positive macrophages. , 2012, Molecular pharmaceutics.

[121]  Philip S Low,et al.  Folate receptor-mediated targeting of therapeutic and imaging agents to activated macrophages in rheumatoid arthritis. , 2004, Advanced drug delivery reviews.

[122]  T. Tsukamoto,et al.  Progress in the discovery and development of glutamate carboxypeptidase II inhibitors. , 2007, Drug discovery today.

[123]  P. Low,et al.  Diplasmenylcholine−Folate Liposomes: An Efficient Vehicle for Intracellular Drug Delivery† , 1998 .

[124]  L. Zardi,et al.  Selective targeting of tumoral vasculature: Comparison of different formats of an antibody (L19) to the ED‐B domain of fibronectin , 2002, International journal of cancer.

[125]  P. Low,et al.  Design and synthesis of [111In]DTPA-folate for use as a tumor-targeted radiopharmaceutical. , 1997, Bioconjugate chemistry.

[126]  J. Reddy,et al.  Preclinical evaluation of EC145, a folate-vinca alkaloid conjugate. , 2007, Cancer research.

[127]  Andreas Plückthun,et al.  Ribosome display: a perspective. , 2012, Methods in molecular biology.

[128]  I. Ojima.  Guided molecular missiles for tumor-targeting chemotherapy--case studies using the second-generation taxoids as warheads. , 2008, Accounts of chemical research.

[129]  A. Schally,et al.  Design, synthesis, and in vitro evaluation of cytotoxic analogs of bombesin-like peptides containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[130]  P. Low,et al.  Cytotoxicity of folate-Pseudomonas exotoxin conjugates toward tumor cells. Contribution of translocation domain. , 1993, The Journal of biological chemistry.

[131]  Richard W Roberts,et al.  Design of cyclic peptides that bind protein surfaces with antibody-like affinity. , 2007, ACS chemical biology.

[132]  P. Erba,et al.  Expression of the oncofetal ED-B-containing fibronectin isoform in hematologic tumors enables ED-B-targeted 131I-L19SIP radioimmunotherapy in Hodgkin lymphoma patients. , 2009, Blood.

[133]  David R. Liu,et al.  Translation of DNA into a library of 13,000 synthetic small-molecule macrocycles suitable for in vitro selection. , 2008, Journal of the American Chemical Society.

[134]  Christof Baltes,et al.  A portable albumin binder from a DNA-encoded chemical library. , 2008, Angewandte Chemie.

[135]  Laurent Ducry,et al.  Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. , 2010, Bioconjugate chemistry.

[136]  J. Reubi.  Peptide receptors as molecular targets for cancer diagnosis and therapy. , 2003, Endocrine reviews.

[137]  M. Sliwkowski,et al.  Trastuzumab emtansine (T-DM1): a novel agent for targeting HER2+ breast cancer. , 2011, Clinical breast cancer.

[138]  Giuseppe Zanotti,et al.  Bicyclic peptide inhibitor reveals large contact interface with a protease target. , 2012, ACS chemical biology.

[139]  R. Scheller,et al.  Oxidizing potential of endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody-drug conjugates. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[140]  Christoph E. Dumelin,et al.  Isolation of high-affinity trypsin inhibitors from a DNA-encoded chemical library. , 2007, Angewandte Chemie.

[141]  Philip S Low,et al.  Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging , 2006, Proceedings of the National Academy of Sciences.

[142]  P. Low,et al.  Folate-targeted therapies for cancer. , 2010, Journal of medicinal chemistry.

[143]  P. Hajduk,et al.  A decade of fragment-based drug design: strategic advances and lessons learned , 2007, Nature Reviews Drug Discovery.

[144]  Erkki Ruoslahti,et al.  A tumor-homing peptide with a targeting specificity related to lymphatic vessels , 2002, Nature Medicine.

[145]  P. Low,et al.  Prostate-specific membrane antigen targeted imaging and therapy of prostate cancer using a PSMA inhibitor as a homing ligand. , 2009, Molecular pharmaceutics.

[146]  G. Winter,et al.  Bicyclic Peptides with Optimized Ring Size Inhibit Human Plasma Kallikrein and its Orthologues While Sparing Paralogous Proteases , 2012, ChemMedChem.

[147]  J W Szostak,et al.  RNA-peptide fusions for the in vitro selection of peptides and proteins. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[148]  H. Kroemer,et al.  Elucidation of the mechanism enabling tumor selective prodrug monotherapy. , 1998, Cancer research.

[149]  P. Lambin,et al.  Synthesis and biological evaluation of a 99mTc-labelled sulfonamide conjugate for in vivo visualization of carbonic anhydrase IX expression in tumor hypoxia. , 2010, Nuclear medicine and biology.

[150]  B. Schäfer,et al.  Identification of a rhabdomyosarcoma targeting peptide by phage display with sequence similarities to the tumour lymphatic‐homing peptide LyP‐1 , 2009, International journal of cancer.

[151]  V. Reuter,et al.  Prostate-specific membrane antigen is produced in tumor-associated neovasculature. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[152]  Samu Melkko,et al.  DNA-encoded chemical libraries for the discovery of MMP-3 inhibitors. , 2008, Bioconjugate chemistry.

[153]  Jeffrey T. Lau,et al.  Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. , 2009, Blood.

[154]  D. Neri,et al.  Isolation and characterization of human monoclonal antibodies specific to MMP-1A, MMP-2 and MMP-3. , 2010, Experimental cell research.

[155]  G. Winter,et al.  Phage-encoded combinatorial chemical libraries based on bicyclic peptides. , 2009, Nature chemical biology.

[156]  P. Low,et al.  Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro. , 1995, Biochimica et biophysica acta.

[157]  J. Reddy,et al.  Folate receptor specific anti-tumor activity of folate–mitomycin conjugates , 2006, Cancer Chemotherapy and Pharmacology.

[158]  J. Fuselier,et al.  Effects of Camptothecin Conjugated to a Somatostatin Analog Vector on Growth of Tumor Cell Lines in Culture and Related Tumors in Rodents , 2004, Drug delivery.

[159]  J. Reddy,et al.  Folate targeting enables durable and specific antitumor responses from a therapeutically null tubulysin B analogue. , 2008, Cancer research.

[160]  Y. Sohn,et al.  Synthesis, biodistribution and antitumor activity of hematoporphyrin-platinum(II) conjugates. , 2003, Bioorganic & medicinal chemistry.

[161]  T. Katoh,et al.  Flexizymes for genetic code reprogramming , 2011, Nature Protocols.

[162]  Damon L. Meyer,et al.  Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. , 2006, Bioconjugate chemistry.

[163]  H. Moch,et al.  New derivatives of vitamin B12 show preferential targeting of tumors. , 2008, Cancer research.

[164]  A. Ricart.  Antibody-Drug Conjugates of Calicheamicin Derivative: Gemtuzumab Ozogamicin and Inotuzumab Ozogamicin , 2011, Clinical Cancer Research.

[165]  P. Senter,et al.  Novel peptide linkers for highly potent antibody-auristatin conjugate. , 2008, Bioconjugate chemistry.

[166]  S. Sieber,et al.  Duocarmycin analogues target aldehyde dehydrogenase 1 in lung cancer cells. , 2012, Angewandte Chemie.

[167]  Michael E Phelps,et al.  Estimation of paclitaxel biodistribution and uptake in human-derived xenografts in vivo with (18)F-fluoropaclitaxel. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[168]  D. Neri,et al.  Tumour-targeting properties of antibodies specific to MMP-1A, MMP-2 and MMP-3 , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[169]  Hiroshi Murakami,et al.  A highly flexible tRNA acylation method for non-natural polypeptide synthesis , 2006, Nature Methods.

[170]  E. Gautherot,et al.  Two-step targeting of xenografted colon carcinoma using a bispecific antibody and 188Re-labeled bivalent hapten: biodistribution and dosimetry studies. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[171]  L. Kèlland,et al.  Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity. , 2001, Journal of medicinal chemistry.

[172]  P. Low,et al.  Indium-111-DTPA-folate as a potential folate-receptor-targeted radiopharmaceutical. , 1998, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[173]  David R. Liu,et al.  In Vitro Selection of a DNA-Templated Small-Molecule Library Reveals a Class of Macrocyclic Kinase Inhibitors , 2010, Journal of the American Chemical Society.

[174]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[175]  A. Schally,et al.  Targeting cytotoxic conjugates of somatostatin, luteinizing hormone-releasing hormone and bombesin to cancers expressing their receptors: a "smarter" chemotherapy. , 2005, Current pharmaceutical design.

[176]  Z. Gartner,et al.  The generality of DNA-templated synthesis as a basis for evolving non-natural small molecules. , 2001, Journal of the American Chemical Society.

[177]  E. Ruoslahti,et al.  Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. , 1998, Science.

[178]  P. T. Jones,et al.  Isolation of high affinity human antibodies directly from large synthetic repertoires. , 1994, The EMBO journal.

[179]  A. Ryan,et al.  The effects of vandetanib on paclitaxel tumor distribution and antitumor activity in a xenograft model of human ovarian carcinoma. , 2009, Neoplasia.

[180]  K. Aldape,et al.  A model of molecular interactions on short oligonucleotide microarrays , 2003, Nature Biotechnology.

[181]  X. Wu,et al.  Tumor specific novel taxoid-monoclonal antibody conjugates. , 2002, Current medicinal chemistry.

[182]  B. Spingler,et al.  Picolylamine-methylphosphonic acid esters as tridentate ligands for the labeling of alcohols with the fac-[M(CO)3]+ core (M = 99mTc, Re): synthesis and biodistribution of model compounds and of a 99mTc-labeled cobinamide. , 2005, Nuclear medicine and biology.

[183]  J N Weinstein,et al.  Targeting cancer micrometastases with monoclonal antibodies: a binding-site barrier. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[184]  M. Pellecchia,et al.  Novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells. , 2012, Journal of medicinal chemistry.

[185]  J. Szostak,et al.  In Vitro Selection of Highly Modified Cyclic Peptides That Act as Tight Binding Inhibitors , 2012, Journal of the American Chemical Society.

[186]  P. Low,et al.  Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis. , 1994, The Journal of biological chemistry.

[187]  Christian Beisel,et al.  High-throughput sequencing for the identification of binding molecules from DNA-encoded chemical libraries. , 2010, Bioorganic & medicinal chemistry letters.

[188]  D. Benjamin,et al.  Intracellular Activation of SGN-35, a Potent Anti-CD30 Antibody-Drug Conjugate , 2010, Clinical Cancer Research.

[189]  Peter Bühlmann,et al.  Discovery of TNF inhibitors from a DNA-encoded chemical library based on diels-alder cycloaddition. , 2009, Chemistry & biology.

[190]  Steven A. Carr,et al.  The Matrisome: In Silico Definition and In Vivo Characterization by Proteomics of Normal and Tumor Extracellular Matrices , 2011, Molecular & Cellular Proteomics.

[191]  A. Kozikowski,et al.  Design and Synthesis of a PSMA Inhibitor–Doxorubicin Conjugate for Targeted Prostate Cancer Therapy , 2006, ChemMedChem.

[192]  B. Kieseier,et al.  Chemotherapeutics in the treatment of multiple sclerosis , 2010, Therapeutic advances in neurological disorders.

[193]  Stephen C Alley,et al.  Antibody-drug conjugates: targeted drug delivery for cancer. , 2010, Current opinion in chemical biology.

[194]  R. O'connor,et al.  The pharmacology of cancer resistance. , 2007, Anticancer research.

[195]  O. Chaloin,et al.  Selection of a synthetic glycan oligomer from a library of DNA-templated fragments against DC-SIGN and inhibition of HIV gp120 binding to dendritic cells. , 2011, Chemical communications.

[196]  H. Hogenkamp,et al.  Transcobalamin II receptor imaging via radiolabeled diethylene-triaminepentaacetate cobalamin analogs. , 1997, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[197]  P. L. Jager,et al.  Biodistribution of 89Zr‐trastuzumab and PET Imaging of HER2‐Positive Lesions in Patients With Metastatic Breast Cancer , 2010, Clinical pharmacology and therapeutics.

[198]  Xianrui Zhao,et al.  Mechanism-based tumor-targeting drug delivery system. Validation of efficient vitamin receptor-mediated endocytosis and drug release. , 2010, Bioconjugate chemistry.

[199]  W. Oyen,et al.  Pretargeting with bispecific anti-renal cell carcinoma x anti-DTPA(In) antibody in 3 RCC models. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[200]  J. Visvader,et al.  Cancer stem cells in solid tumours: accumulating evidence and unresolved questions , 2008, Nature Reviews Cancer.

[201]  Hiroshi Fukuda,et al.  Studies on 18F-labeled pyrimidines. Tumor uptakes of 18F-5-fluorouracil, 18F-5-fluorouridine, and 18F-5-fluorodeoxyuridine in animals , 2004, European Journal of Nuclear Medicine.

[202]  A. Schally,et al.  Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[203]  P. Low,et al.  Folate targeting of haptens to cancer cell surfaces mediates immunotherapy of syngeneic murine tumors , 2002, Cancer Immunology, Immunotherapy.

[204]  P. Low,et al.  Folate receptor-targeted drugs for cancer and inflammatory diseases. , 2004, Advanced drug delivery reviews.

[205]  P. Laakkonen,et al.  Homing peptides as targeted delivery vehicles. , 2010, Integrative biology : quantitative biosciences from nano to macro.

[206]  C. Supuran,et al.  Targeting tumor-associated carbonic anhydrase IX in cancer therapy. , 2006, Trends in pharmacological sciences.

[207]  F. Bootz,et al.  Antibody-mediated delivery of IL-10 inhibits the progression of established collagen-induced arthritis , 2007, Arthritis research & therapy.

[208]  Xiaoyuan Chen,et al.  Imaging of Urokinase-Type Plasminogen Activator Receptor Expression Using a 64Cu-Labeled Linear Peptide Antagonist by microPET , 2008, Clinical Cancer Research.

[209]  Lars Kolster Petersen,et al.  A yoctoliter-scale DNA reactor for small-molecule evolution. , 2009, Journal of the American Chemical Society.

[210]  J. Reddy,et al.  Synthesis and biological evaluation of EC20: a new folate-derived, (99m)Tc-based radiopharmaceutical. , 2002, Bioconjugate chemistry.

[211]  G. Mariani,et al.  Clinical validation of the avidin/indium-111 biotin approach for imaging infection/inflammation in orthopaedic patients , 1999, European Journal of Nuclear Medicine.

[212]  A. Schally,et al.  Targeted chemotherapy with cytotoxic bombesin analogue AN‐215 can overcome chemoresistance in experimental renal cell carcinomas , 2005, Cancer.

[213]  Claudiu T. Supuran,et al.  Interfering with pH regulation in tumours as a therapeutic strategy , 2011, Nature Reviews Drug Discovery.

[214]  Dario Neri,et al.  20 years of DNA-encoded chemical libraries. , 2011, Chemical communications.

[215]  B. Kay,et al.  Filamentous phage display in the new millennium. , 2005, Chemical reviews.

[216]  E. Sausville,et al.  Clinical Pharmacokinetics and Exposure‐Toxicity Relationship of a Folate‐Vinca Alkaloid Conjugate EC145 in Cancer Patients , 2009, Journal of clinical pharmacology.

[217]  B. Spingler,et al.  Cyanide-bridged vitamin B12-cisplatin conjugates. , 2005, Chemistry.

[218]  H. Morita,et al.  Synthesis and biological evaluation of tubulysin D analogs related to stereoisomers of tubuvaline. , 2011, Bioorganic & medicinal chemistry letters.

[219]  P. Low,et al.  Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results , 2011, Nature Medicine.

[220]  J. Reddy,et al.  Synthesis and biological evaluation of EC140: a novel folate-targeted vinca alkaloid conjugate. , 2006, Bioconjugate chemistry.

[221]  L. Aarden,et al.  A novel method for the detection of antibodies to adalimumab in the presence of drug reveals "hidden" immunogenicity in rheumatoid arthritis patients. , 2010, Journal of immunological methods.

[222]  P. Kaufmann,et al.  Comparative in vivo analysis of the atherosclerotic plaque targeting properties of eight human monoclonal antibodies. , 2011, Atherosclerosis.

[223]  P. Low,et al.  Folate-targeted immunotherapy effectively treats established adjuvant and collagen-induced arthritis , 2006, Arthritis research & therapy.

[224]  P. Thorpe.  Vascular Targeting Agents as Cancer Therapeutics , 2004, Clinical Cancer Research.

[225]  J. Reddy,et al.  In vivo structural activity and optimization studies of folate-tubulysin conjugates. , 2009, Molecular pharmaceutics.

[226]  Lorenz M Mayr,et al.  Novel trends in high-throughput screening. , 2009, Current opinion in pharmacology.