Drug delivery in oncology: from basic research to cancer therapy 1
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IMAGE 1
VII
CONTENTS TO VOLUME 1
FOREWORD V PREFACE XVII LIST OF CONTRIBUTORS XIX DRUG DELIVERY IN
ONCOLOGY - CHALLENGE AND PERSPECTIVES LIX
PART I PRINCIPLES OF TUMOR TARGETING 1
1 LIMITS OF CONVENTIONAL CANCER CHEMOTHERAPY 3 KLAUS MROSS AND FELIX
KRATZ 1.1 INTRODUCTION: THE ERA OF CANCER CHEMOTHERAPY 3 1.2 DILEMMA AND
CHALLENGE OF TREATING MALIGNANT DISEASES 14
1.3 ADVERSE EFFECTS 16
1.3.1 COMMON SIDE-EFFECTS 18 1.3.1.1 DEPRESSION OF THE IMMUNE SYSTEM 18
1.3.1.2 FATIGUE 19 1.3.1.3 TENDENCY TO BLEED EASILY 19
1.3.1.4 GASTROINTESTINAL DISTRESS 19 1.3.1.5 HAIR LOSS 20 1.3.2 DAMAGE
TO SPECIFIC ORGANS 20
1.3.2.1 CARDIOTOXICITY 20 1.3.2.2 HEPATOTOXICITY 21 1.3.2.3
NEPHROTOXICITY 22 1.3.2.4 PULMONARY SIDE-EFFECTS 22
1.3.2.5 VASCULAR ADVERSE EFFECTS 23 1.3.2.6 TISSUE DAMAGE
(EXTRAVASATION) 23 1.3.2.7 NEUROLOGICAL SIDE-EFFECTS 24 1.3.2.8
SECONDARY NEOPLASMS 25
1.3.2.9 INFERTILITY 25 1.3.2.10 OTHER SIDE-EFFECTS 25 1.4 SUPPORTIVE
CARE 25
1.5 NEW APPROACHES COMPLEMENTING CURRENT CANCER CHEMOTHERAPY 26 1.6
CONCLUSIONS AND PERSPECTIVES 2% REFERENCES 29
BIBLIOGRAFISCHE INFORMATIONEN HTTP://D-NB.INFO/1011200406
DIGITALISIERT DURCH
IMAGE 2
VIII CONTENTS
2 PATHOPHYSIOLOGICAL AND VASCULAR CHARACTERISTICS OF SOLID TUMORS IN
RELATION TO DRUG DELIVERY 33 PETER VAUPEL 2.1 INTRODUCTION 33
2.2 BASIC PRINCIPLES OF BLOOD VESSEL FORMATION IN SOLID TUMORS 34 2.2.1
ANGIOGENESIS 34
2.2.2 VASCULAR CO-OPTION 36 2.2.3 VASCULOGENESIS 36 2.2.4
INTUSSUSCEPTION 36
2.2.5 VASCULAR MIMICRY 36 2.2.6 MICROVESSEL FORMATION BY MYELOID CELLS
36 2.3 TUMOR LYMPHANGIOGENESIS 37 2.4 TUMOR VASCULARITY AND BLOOD FLOW
37
2.5 ARTERIOVENOUS SHUNT PERFUSION IN TUMORS 38 2.6 VOLUME AND
CHARACTERISTICS OF THE TUMOR INTERSTITIAL SPACE 40 2.7 INTERSTITIAL
FLUID PRESSURE IN TUMORS 42 2.8 ROLE OF THE DISORGANIZED, COMPROMISED
MICROCIRCULATION AS AN
OBSTACLE IN DRUG DELIVERY 43 2.8.1 BLOOD-BORNE DELIVERY 43 2.8.2
EXTRAVASATION OF ANTICANCER AGENTS 45 2.9 INTERSTITIAL BARRIERS TO DRUG
DELIVERY 46 2.10 PATHOPHYSIOLOGICAL TUMOR MICROENVIRONMENT AS AN
OBSTACLE IN TUMOR
THERAPY 47
2.10.1 HYPOXIA AS AN OBSTACLE IN DRUG THERAPY 48 2.10.1.1 DIRECT EFFECTS
48 2.10.1.2 INDIRECT EFFECTS BASED ON CHANGES IN THE TRANSCRIPTOME, IN
DIFFERENTIAL REGULATION OF GENE EXPRESSION, AND IN ALTERATIONS OF THE
PROTEOME 49
2.10.1.3 INDIRECT EFFECTS BASED ON ENHANCED MUTAGENESIS, GENOMIC
INSTABILITY, AND CLONAL SELECTION 51 2.10.1.4 TUMOR HYPOXIA: AN ADVERSE
PARAMETER IN CHEMOTHERAPY 51 2.10.2 TUMOR ACIDOSIS AND DRUG RESISTANCE
53 2.11 CONCLUSIONS 56
ACKNOWLEDGMENTS 56 REFERENCES 56
3 ENHANCED PERMEABILITY AND RETENTION EFFECT IN RELATION TO TUMOR
TARGETING 65 HIROSHI MAEDA
3.1 BACKGROUND AND STATUS QUO 65
3.2 WHAT IS THE EPR EFFECT: MECHANISM, UNIQUENESS, AND FACTORS INVOLVED
66 3.3 HETEROGENEITY OF THE EPR EFFECT: A PROBLEM IN DRUG DELIVERY 72
3.4 OVERCOMING THE HETEROGENEITY OF THE EPR EFFECT FOR DRUG DELIVERY AND
HOW TO ENHANCE THE EPR EFFECT 75 3.4.1 ANGIOTENSIN II-INDUCED HIGH BLOOD
PRESSURE 75
IMAGE 3
CONTENTS IX
3.4.2 USE OF NO-RELEASING AGENTS 78
3.4.3 USE OF OTHER VASCULAR MODULATORS 79 3.5 PEG DILEMMA: STEALTH
EFFECT AND ANTI-PEG IGM ANTIBODY 79 3.6 CONCLUDING REMARKS 80
ACKNOWLEDGMENTS 81 REFERENCES 81
4 PHARMACOKINETICS OF IMMUNOGLOBULIN C AND SERUM ALBUMIN: IMPACT OF THE
NEONATAL FC RECEPTOR ON DRUG DESIGN 85 JAN TERJE ANDERSEN AND JUGER
SANDLIE 4.1 INTRODUCTION 85
4.2 DISCOVERY OF FCRN 87
4.3 FCRN STRUCTURE 88
4.4 FCRN-LIGAND INTERACTIONS 89
4.5 FCRN AS A MULTIPLAYER WITH THERAPEUTIC UTILITIES 90 4.5.1
DIRECTIONAL PLACENTAL TRANSPORT 90 4.5.2 FCRN AT MUCOSAL SURFACES 91
4.5.3 SYSTEMIC FCRN-MEDIATED RECYCLING 92 4.5.4 ROLE OF FCRN IN ANTIGEN
PRESENTATION 93 4.5.5 FCRN AT IMMUNE-PRIVILEGED SITES 94 4.5.6 FCRN IN
THE KIDNEYS 94
4.5.7 FCRN EXPRESSED BY THE LIVER 95 4.6 ENGINEERING IGG FOR ALTERED
FCRN BINDING AND PHARMACOKINETICS 95 4.6.1 IGG FC FUSIONS 95
4.6.2 ENGINEERED IGG VARIANTS 96 4.6.3 BLOCKING FCRN RECYCLING 102 4.7
TARGETING FCRN BY SA 102
4.7.1 SA FUSIONS 102
4.7.2 TARGETING SA 105
4.8 CONSIDERING CROSS-SPECIES BINDING 111 4.9 CONCLUDING REMARKS 113
ACKNOWLEDGMENT 113 REFERENCES 113
5 DEVELOPMENT OF CANCER-TARGETING LIGANDS AND LIGAND-DRUG CONJUGATES 121
RUIWU LIU, KAI XIAO, JUNTAO LUO, AND KIT S. LAM 5.1 INTRODUCTION 121
5.2 OVERVIEW OF CANCER-TARGETING LIGAND-DRUG CONJUGATES 122 5.3
CANCER-TARGETING LIGANDS 125 5.3.1 INTRODUCTION 125
5.3.2 PHAGE-DISPLAY LIBRARY APPROACH 125 5.3.2.1 PHAGE-DISPLAY LIBRARY
SCREENING AND DECODING J27 5.3.2.2 EXAMPLES 127
IMAGE 4
X I CONTENTS
5.3.3 OBOC COMBINATORIAL LIBRARY APPROACH 131
5.3.3.1 OBOC LIBRARY DESIGN 132 5.3.3.2 OBOC LIBRARY CONSTRUCTION 135
5.3.3.3 OBOC LIBRARY SCREENING 137 5.3.3.4 OBOC LIBRARY DECODING 138
5.3.3.5 IIGAND OPTIMIZATION 139 5.3.3.6 EXAMPLES 140 5.4 LINKERS 143
5.4.1 ACID-SENSITIVE LINKERS 143 5.4.2 ENZYMATIC CLEAVAGE 143 5.4.3
SELF-IMMOLATIVE SPACERS 145
5.4.4 REDUCTIVE CLEAVAGE 146 5.4.5 ON-DEMAND CLEAVABLE LINKER 146 5.5
EXAMPLES OF CANCER-TARGETING LIGAND-DRUG CONJUGATES 147 5.5.1 FOLK
ACID-DRUG CONJUGATES 147 5.5.2 PEPTIDE LIGAND-DRUG CONJUGATES 148
5.5.3 PEPTIDE HORMONE-DRUG CONJUGATES 150 5.5.4 ANTIBODY-DRUG CONJUGATES
151 5.5.5 ADEPT 154
5.5.6 POLYMER-DRUG CONJUGATES 156 5.5.7 TARGETING LIPOSOMES AND
NANOPARTIDES 158 5.6 CONCLUSIONS AND PERSPECTIVES 159 ACKNOWLEDGMENTS
160
REFERENCES 160
6 ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY (ADEPT) - BASIC PRINCIPLES
AND ITS PRACTICE SO FAR 169 KENNETH D. BAGSHAWE 6.1 INTRODUCTION 169
6.2 PRINCIPLES AND THE COMPONENTS OF ADEPT 170 6.2.1 TARGET 170
6.2.2 ANTIBODY 171
6.2.3 ENZYME 172
6.2.4 PRODRUG AND DRUG 173
6.3 THIRD ESSENTIAL 173
6.4 ADEPT STUDIES ELSEWHERE 175 6.5 REAGENTS FOR FIRST CLINICAL TRIALS
IN LONDON (1990-1995) 176 6.5.1 FIRST ADEPT CLINICAL TRIAL 1 77 6.5.2
SUBSEQUENT ADEPT CLINICAL STUDIES IN LONDON 178 6.5.3 TWO-PHASE ADEPT
CLINICAL STUDIES IN LONDON 179 6.6 TECHNOLOGY ADVANCES 179
6.7 ADEPT FUTURE 181
REFERENCES 181
IMAGE 5
CONTENTS XI
PART II TUMOR IMAGING 187
7 IMAGING TECHNIQUES IN DRUG DEVELOPMENT AND CLINICAL PRACTICE 189
JOHN C. CHANG, SANJIV S. GAMBHIR, AND JUERGEN K. WILLMANN 7.1
INTRODUCTION 189
7.2 CANCER BIOLOGY 191
7.2.1 TUMOR GENETIC HETEROGENEITY 191 7.2.2 ALTERED TUMOR METABOLISM 191
7.2.3 TUMOR ANGIOGENESIS 192 7.2.4 RECEPTOR PATHOLOGIES 194 7.3 CANCER
BIOMARKERS 194
7.3.1 HISTOLOGICAL BIOMARKERS 194 7.3.2 HEMATOLOGICAL BIOMARKERS 196
7.3.3 IMAGING BIOMARKERS 196 7.4 IMAGING TECHNIQUES 197
7.4.1 SPECT 197
7.4.2 PET/PET-CT 198 7'.4.3 MRI 198
7.4.4 CT 199
7.4.5 ULTRASOUND 199
7.4.6 FLUORESCENCE/BIOLUMINESCENCE 200 7.5 EXAMPLES OF IMAGING
ASSESSMENT OF TUMOR RESPONSE 200 7.5.1 SPECT 200
7.5.2 PET/PET-CT 201 7.5.2.1 MICRODOSING 201 7.5.2.2 CANCER METABOLISM
AND PROLIFERATION 202 7.5.2.3 HYPOXIA 204
7.5.2.4 BIOMARKER IMAGING 205 7.5.2.5 ANGIOGENESIS 207 7.5.2.6 APOPTOSIS
207 7.5.3 MRI 207
7.5.3.1 CELLULAR STRUCTURE 209 7.5.3.2 METABOLIC RESPONSE 209 7.5.3.3
TUMOR PERFUSION 210 7.5.4 CT IMAGING 211
7.5.5 ULTRASOUND 212
7.5.6 FLUORESCENCE/BIOLUMINESCENCE 213 7.6 CHALLENGES OF IMAGING IN DRUG
DEVELOPMENT AND VALIDATION 214 7.7 CONCLUSIONS AND FUTURE PERSPECTIVES
215 REFERENCES 217
8 MAGNETIC NANOPARTICLES IN MAGNETIC RESONANCE IMAGING AND DRUG DELIVERY
225 PATRICK D. SUTPHIN, EFRENJ. FLORES, AND MUKESH HARISINGHANI 8.1
INTRODUCTION 225
IMAGE 6
XIII CONTENTS
8.2 PASSIVE TARGETING OF NANOPARTICLES 227
8.2.1 MECHANISM OF ACTION 229 8.2.2 LYMPHOTROPIC NANOPARTICLE MRI 229
8.3 ACTIVE SPIO NANOPARTICLE TARGETING 232 8.3.1 CREATING THE TARGETED
IMAGING AGENTS 233
8.3.1.1 TRANSFERRIN-USPIO NANOPARTICLES 233 8.3.1.2 FOLATE RECEPTOR 235
8.3.1.3 INTEGRINS 235 8.4 NANOPARTICLES IN TARGETED THERAPY 236
8.4.1 NANOPARTICLES IN GENE THERAPY 237 8.4.2 NANOPARTICLES IN
MOLECULARLY TARGETED DRUG DELIVERY 238 8.4.3 CONVERSION OF THERAPEUTIC
AGENT TO IMAGING AGENT 239 8.4.4 TOXIC PAYLOAD 240
8.5 CONCLUSIONS 240
REFERENCES 242
9 PRECLINICAL AND CLINICAL TUMOR IMAGING WITH SPECT/CT AND PET/CT 247
ANDREAS K. BUCK, FLORIAN GAERTNER, AMBROS BEER, KEN HERRMANN, SIBYLLE
ZIEGLER, AND MARKUS SCHWAIGER 9.1 INTRODUCTION 247
9.2 TECHNICAL ASPECTS OF FUNCTIONAL AND MOLECULAR IMAGING WITH SPECT AND
PET 249 9.2.1 PRINCIPLES OF CLINICAL PET AND HYBRID PET/CT IMAGING 249
9.2.2 BIOMARKERS FOR PET AND PET/CT IMAGING 250 9.2.3 PRINCIPLES OF
CLINICAL SPECT AND HYBRID SPECT CT IMAGING 252
9.2.4 BIOMARKERS FOR SPECT AND SPECT/CT IMAGING 258 9.2.5 PRINCIPLES OF
PRECLINICAL IMAGING WITH SPECT AND PET 258 9.3 PRECLINICAL AND CLINICAL
DEVELOPMENTS 260 9.3.1 IMAGING NEOANGIOGENESIS 260 9.3.1.1 VEGF/VEGFR
IMAGING 261 9.3.1.2 RADIOLABELED INTEGRIN ANTAGONISTS (RGD PEPTIDES) 262
9.3.1.3 MONOMERIC TRACER LABELING STRATEGIES 262 9.3.2 IMAGING THE
PROLIFERATIVE ACTIVITY OF TUMORS 264 9.3.3 IMAGING THE HYPOXIE CELL
FRACTION OF TUMORS 267 9.3.4 IMAGING RECEPTOR EXPRESSION 269 9.4
CLINICAL APPLICATIONS OF SPECT/CT AND PET 272 9.4.1 DIFFERENTIATION OF
BENIGN FROM MALIGNANT TUMORS AND CANCER
DETECTION 272
9.4.2 STAGING OF CANCER: PROGNOSTIC POTENTIAL OF IMAGING BIOMARKERS 273
9.4.3 ASSESSMENT OF RESPONSE TO THERAPY 274 9.4.4 RESTAGINGOF CANCER AND
DETECTION OF RECURRENCE 274 9.4.5 PET FOR RADIATION TREATMENT PLANNING
275 9.4.6 PET FOR CANCER DRUG DEVELOPMENT 275 9.4.7 SPECT/CT FOR MAPPING
OF SLNS 276
IMAGE 7
CONTENTS XIII
9.4.8 SPECT/CT FOR DETECTION OF BONE METASTASES 277
9.4.9 SPECT/CT IN THYROID CANCER 278 9.4.10 SPECT/CT FOR IMAGING OF
ADRENOCORTICAL TUMORS 279 9.4.11 SPECT/CT IN NEUROENDOCRINE TUMORS 281
9.5 CONCLUSIONS AND PERSPECTIVES 281 REFERENCES 282
CONTENTS TO VOLUME 2
PART III MACROMOLECULAR DRUG DELIVERY SYSTEMS 289
ANTIBODY-BASED SYSTEMS 289
10 EMPOWERED ANTIBODIES FOR CANCER THERAPY 291 STEPHEN C. ALLEY, SIMONE
JEGER, ROBERT P. LYON, DJANGO SUSSMAN, AND PETER D. SENTER
11 MAPPING ACCESSIBLE VASCULAR TARGETS TO PENETRATE ORGANS AND SOLID
TUMORS 325 KERRI A. MASSEY AND JAN E. SCHNITZER
12 CONSIDERATIONS OF LINKER TECHNOLOGIES 355 LAURENT DUCRY
13 ANTIBODY-MAYTANSINOID CONJUGATES: FROM THE BENCH TO THE CLINIC 375
HANS ERICKSON
14 CALICHEAMICIN ANTIBODY-DRUG CONJUGATES AND BEYOND 395 PUJA SAPRA,
JOHN DIJOSEPH, AND HANS-PETER GERBER
15 ANTIBODIES FOR THE DELIVERY OF RADIONUCLIDES 411 ANNA M. WU
16 BISPECIFIC ANTIBODIES AND IMMUNE THERAPY TARGETING 441
SERGEJ M. KIPRIJANOV
POLYMER-BASED SYSTEMS 483
17 DESIGN OF POLYMER-DRUG CONJUGATES 485
JINDFICH KOPEIEK AND PAVLA KOPEIKOVA
18 DENDRITIC POLYMERS IN ONCOLOGY: FACTS, FEATURES, AND APPLICATIONS 513
MOHIUDDIN ABDUL QUADIR, MARCELO CALDERON, AND RAINER HAAG
IMAGE 8
XIV CONTENTS
19 SITE-SPECIFIC PRODRUG ACTIVATION AND THE CONCEPT OF
SELF-IMMOLATION 553 ANDRE WARNECKE
20 LIGAND-ASSISTED VASCULAR TARGETING OF POLYMER THERAPEUTICS 591 ANAT
ELDAR-BOOCK, DINA POLYAK, AND RONIT SATCHI-FAINARO
21 DRUG CONJUGATES WITH POLYJETHYLENE CLYCOL) 627 HONG ZHAO, LEE M.
GREENBERGER, AND IVAN D. HORAK
22 THERMO-RESPONSIVE POLYMERS 667 DRAZEN RAUCHER AND SHAMA MOKTAN
23 POLYSACCHARIDE-BASED DRUG CONJUGATES FOR TUMOR TARGETING 701 GURUSAMY
SARAVANAKUMAR, JAE HYUNG PARK, KWANGMEYUNG KIM, AND ICK CHAN KWON
24 SERUM PROTEINS AS DRUG CARRIERS OF ANTICANCER AGENTS 747 FELIX KRATZ,
ANDREAS WUNDER, AND BAKHEET ELSADEK
25 FUTURE TRENDS, CHALLENGES, AND OPPORTUNITIES WITH POLYMER-BASED
COMBINATION THERAPY IN CANCER 805 CORALIE DELADRIERE, RUT LUCAS, AND
MARIA J. VICENT
26 CLINICAL EXPERIENCE WITH DRUG-POLYMER CONJUGATES 839 KHALID ABU AJAJ
AND FELIX KRATZ
PART IV NANO- AND MICROPARTICULATE DRUG DELIVERY SYSTEMS 885
LIPID-BASED SYSTEMS 885
27 OVERVIEW ON NANOCARRIERS AS DELIVERY SYSTEMS 887 HAIFA SHEN, ELVIN
BLANCO, BIANA GODIN, RITA E. SERDA, AGATHE K. STREIFF, AND MAURO FERRARI
28 DEVELOPMENT OF PEGYLATED LIPOSOMES 907 I. CRAIG HENDERSON
29 IMMUNOLIPOSOMES 951
VLADIMIR P. TORCHILIN
30 RESPONSIVE LIPOSOMES (FOR SOLID TUMOR THERAPY) 989 STAVROULA SOFOU
IMAGE 9
CONTENTS XV
31 NANOSCALE DELIVERY SYSTEMS FOR COMBINATION CHEMOTHERAPY 1013
BARRY D. LIBOIRON, PAUL G. TARDI, TROY O. HARASYM, AND LAWRENCE, D.
MAYER
POLYMER-BASED SYSTEMS 1051
32 MICELLAR STRUCTURES AS DRUG DELIVERY SYSTEMS 1053 NOBUHIRO NISHIYAMA,
HORACIO CABRAI, AND KAZUNORI KATAOKA
33 TAILOR-MADE HYDROGELS FOR TUMOR DELIVERY 1071 SUNGWON KIM AND KINAM
PARK
34 PH-TRIGGERED MICELLES FOR TUMOR DELIVERY 1099 HAIQING YIN AND YOU HAN
BAE
35 ALBUMIN-DRUG NANOPARTICLES 1133
NEIL DESAI
36 CARBON NANOTUBES 1163
DAVID A. SCHEINBERG, CARLOS H. VILLA, FREDDY ESCORDA, AND MICHAEL R.
MCDEVITT
CONTENTS TO VOLUME 3
PART V LIGAND-BASED DRUG DELIVERY SYSTEMS 1187
37 CELL-PENETRATING PEPTIDES IN CANCER TARGETING 1189 KAIDO KURRIKOFF,
JULIA SUHORUTSENKO, AND UELO LANGEL
38 TARGETING TO PEPTIDE RECEPTORS 1219 ANDREW V. SCHALLY AND GABOR
HALMOS
39 APTAMER CONJUGATES: EMERGING DELIVERY PLATFORMS FOR TARGETED CANCER
THERAPY 1263 ZEYU XIAO, JULIAN FRIEDER, BENJAMIN A. TEPLY, AND OMID C.
FAROKHZAD
40 DESIGN AND SYNTHESIS OF DRUG CONJUGATES OF VITAMINS AND GROWTH
FACTORS 1283 IONTCHO R. VLAHOV, PAULJ. KLEINDL, AND FEI YOU
41 DRUG CONJUGATES WITH POLYUNSATURATED FATTY ACIDS 1323 JOSHUA SEITZ
AND IWAO OJIMA
IMAGE 10
XVI I CONTENTS
PART VI SPECIAL TOPICS 1359
42 RNA DRUG DELIVERY APPROACHES 1361 YUAN ZHANG AND LEAF HUANG
43 LOCAL GENE DELIVERY FOR THERAPY OF SOLID TUMORS 1391 WOLFGANG
WALTHER, PETER M. SCHLAG, AND ULRIKE STEIN
44 VIRAL VECTORS FOR RNA INTERFERENCE APPLICATIONS IN CANCER RESEARCH
AND THERAPY 1415 HENRY FECHNER AND JENS KURRECK
45 DESIGN OF TARGETED PROTEIN TOXINS 1443 HENDRIK FUCHS AND CHRISTOPHER
BACHRAN
46 DRUG TARGETING TO THE CENTRAL NERVOUS SYSTEM 1489 GERT FRICKER, ANNE
MAHRINGER, MELANIE OTT, AND VALESKA REICHEL
47 LIVER TUMOR TARGETING 1519
KATRIN HOCHDOERFFER, GIUSEPPINA DI STEFANO, HIROSHI MAEDA, AND FELIX
KRATZ
48 PHOTODYNAMIC THERAPY: PHOTOSENSITIZER TARGETING AND DELIVERY 1569
PAWEL MROZ, SULBHA K. SHARMA, TIMUR ZHIYENTAYEV, YING-YING HUANG, AND
MICHAEL R. HAMBLIN
49 TUMOR-TARGETING STRATEGIES WITH ANTICANCER PLATINUM COMPLEXES 1605
MARKUS GALANSKI AND BERNHARD K. KEPPLER
INDEX 1631 |
| any_adam_object | 1 |
| author2 | Kratz, Felix |
| author2_role | edt |
| author2_variant | f k fk |
| author_facet | Kratz, Felix |
| building | Verbundindex |
| bvnumber | BV040416122 |
| ctrlnum | (OCoLC)815892466 (DE-599)DNB1011200406 |
| discipline | Chemie / Pharmazie |
| format | Book |
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| genre | (DE-588)4143413-4 Aufsatzsammlung gnd-content |
| genre_facet | Aufsatzsammlung |
| id | DE-604.BV040416122 |
| illustrated | Illustrated |
| indexdate | 2025-02-09T19:00:41Z |
| institution | BVB |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-025268984 |
| oclc_num | 815892466 |
| open_access_boolean | |
| owner | DE-19 DE-BY-UBM |
| owner_facet | DE-19 DE-BY-UBM |
| physical | LXXXV, 288 S. Ill., graph. Darst. 25 cm |
| publishDate | 2012 |
| publishDateSearch | 2012 |
| publishDateSort | 2012 |
| publisher | Wiley-VCH |
| record_format | marc |
| spelling | Drug delivery in oncology from basic research to cancer therapy 1 ed. by Felix Kratz ... Weinheim Wiley-VCH 2012 LXXXV, 288 S. Ill., graph. Darst. 25 cm txt rdacontent n rdamedia nc rdacarrier Wirkstofffreisetzung (DE-588)4190018-2 gnd rswk-swf Cytostatikum (DE-588)4068347-3 gnd rswk-swf (DE-588)4143413-4 Aufsatzsammlung gnd-content Cytostatikum (DE-588)4068347-3 s Wirkstofffreisetzung (DE-588)4190018-2 s DE-604 Kratz, Felix edt (DE-604)BV040416114 1 X:MVB text/html http://deposit.dnb.de/cgi-bin/dokserv?id=3718078&prov=M&dok_var=1&dok_ext=htm Inhaltstext DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=025268984&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Drug delivery in oncology from basic research to cancer therapy Wirkstofffreisetzung (DE-588)4190018-2 gnd Cytostatikum (DE-588)4068347-3 gnd |
| subject_GND | (DE-588)4190018-2 (DE-588)4068347-3 (DE-588)4143413-4 |
| title | Drug delivery in oncology from basic research to cancer therapy |
| title_auth | Drug delivery in oncology from basic research to cancer therapy |
| title_exact_search | Drug delivery in oncology from basic research to cancer therapy |
| title_full | Drug delivery in oncology from basic research to cancer therapy 1 ed. by Felix Kratz ... |
| title_fullStr | Drug delivery in oncology from basic research to cancer therapy 1 ed. by Felix Kratz ... |
| title_full_unstemmed | Drug delivery in oncology from basic research to cancer therapy 1 ed. by Felix Kratz ... |
| title_short | Drug delivery in oncology |
| title_sort | drug delivery in oncology from basic research to cancer therapy |
| title_sub | from basic research to cancer therapy |
| topic | Wirkstofffreisetzung (DE-588)4190018-2 gnd Cytostatikum (DE-588)4068347-3 gnd |
| topic_facet | Wirkstofffreisetzung Cytostatikum Aufsatzsammlung |
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| volume_link | (DE-604)BV040416114 |
| work_keys_str_mv | AT kratzfelix drugdeliveryinoncologyfrombasicresearchtocancertherapy1 |