Edited by Felix Kratz, Peter Senter, and Henning Steinhagen

Drug Delivery in Oncology

From Basic Research to Cancer Therapy

Volume 3

VCH

Verlag GmbH & Co. KGaA

VII

Contents to Volume 1

Part Principles of Tumor Targeting 3

Limits of Conventional Cancer Chemotherapy 3 Klaus Mross and Felix Kratz

Pathophysiological and Vascular Characteristics of Solid Tumors in Relation to Drug Delivery 33 Peter Vaupel

Enhanced Permeability and Retention Effect in Relation to Tumor Targeting 65 Hiroshi Maeda

Pharmacokinetics of Immunoglobulin G and Serum Albumin: Impact of the Neonatal Fc Receptor on Drug Design 85 Jan Terje Andersen and Sandlie

Development of Cancer-Targeting Ligands and Ligand-Drug Conjugates 121 Ruiwu Liu, Kai Xiao, Juntao Luo, and Kit S. Lam

Antibody-Directed Enzyme Prodrug Therapy (ADEPT) - Basic Principles and its Practice So Far 169 Kenneth D. Bagshawe

Part II Tumor Imaging 187

Imaging Techniques in Drug Development and Clinical Practice 189 John C. Chang, Sanjiv S. Gambhir, K. Willmann

Contents

8 Magnetic in Magnetic Resonance Imaging and Drug Delivery 225 Patrick D. Sutphin, J. Flores, and Mukesh Harisinghani

9 Preclinical and Clinical Tumor Imaging with SPECT/CT and PET/CT 247 Andreas K. Buck, Florian Gartner, Beer, Ken Herrmann, Sibylle

Ziegler, and Markus Schwaiger

Contents to Volume 2

Part Drug Delivery Systems 289

Antibody-Based Systems 289

Empowered Antibodies for Cancer Therapy 291 Stephen C. Alley, Jeger, Robert P. Lyon, Django Sussman, and Peter D. Senter

Mapping Accessible Vascular Targets to Penetrate Organs and Solid Tumors 325 Kerri A. Massey Jan E. Schnitzer

12 Considerations of Linker Technologies 355 Laurent Ducry

13 Conjugates: From the Bench the Clinic 375 Hans Erickson

14 Calicheamicin Conjugates and Beyond 395 Puja Sapra, John and Hans-Peter Gerber

Antibodies for the Delivery of Radionuclides Anna M. Wu

16 Bispecific Antibodies and Immune Therapy Targeting 443

Sergej M. Kiprijanov

Polymer-Based Systems 483

Design of Conjugates 485

and

Contents \ IX

Dendritic Polymers in Oncology: Facts, Features, and Applications 513 Mohiuddin Abdul Quadir, Marcelo Calderon, and Rainer Haag

Site-Specific Prodrug Activation and the Concept of Self-immolation 553 Andre Warnecke

20 Ligand-Assisted Vascular Targeting of Polymer Therapeutics 591 Anat Dina Polyak, and Ronit Satchi-Fainaro

Drug Conjugates with Glycol) 627 Hong Zhao, Lee M. Greenberger, and Ivan D. Horak

22 Thermo-Responsive Polymers 667 Drazen Raucher and Moktan

23 Drug Conjugates for Tumor Targeting 701 Gurusamy Saravanakumar, Jae Hyung Park, Kim, and Chan

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 Conjugates 839 Khalid Abu and Felix Kratz

Part IV Nano- and Drug Delivery Systems 885

Lipid-Based Systems 885

27 Overview on Nanocarriers as Delivery Systems 887 Haifa Blanco, Biana Godin, Rita E. Serda,

Agathe K Streijf, and Mauro Ferrari

28 Development of PEGylated Liposomes 907

I. Craig Henderson

29 951 Vladimir P. Torchilin

X Contents

30 Responsive Liposomes (for Solid Tumor Therapy) 989 Stavroula Sofou

31 Nanoscale Combination Chemotherapy 1013 Barry D. Liboiron, Paul G. Tardi, Troy Harasym, and Lawrence, D. Mayer

Polymer-Based Systems 1051

32 Micellar Structures as Drug Delivery Systems 1053 Nobuhiro Nishiyama, Horacio Cabral, and Kazunori Kataoka

33 Tailor-Made Hydrogels for Tumor Delivery 1071 Sungwon Kim and 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 Escorcia, and Michael R. McDevitt

Contents to Volume 3 Foreword V Preface XXI

Ligand-Based Drug Delivery Systems 1187

37 Cell-Penetrating Peptides in Cancer Targeting 1189 Kaido Kurrikojf, Julia Suhorutsenko, and Langel

37.1 Introduction 1189 37.2 Applications CPPs 1190 37.2.1 Modifying Classical Anticancer Drugs 1191 37.2.2 Inherent Antineoplastic Activity of CPPs 1195 37.2.3 Oligonucleotides 1195 37.2.4 CPP Application in Oncogenic Signaling and Cell Cycle Modulation in

Tumors 1198 37.2.4.1 Oncoproteins 1199 37.2.4.2 Tumor 1200 37.2.4.3 Tumor Suppressor 1201

Contents XI

37.2.4.4 Tumor Suppressors p2l and p27 1202 37.3 Tumor Targeting CPPs 1202 37.3.1 Passive Targeting CPPs 1203 37.3.1.1 EPR Effect 1203 37.3.1.2 Matrix Metalloproteases 1204 37.3.1.3 CPP Systems 1204 37.3.2 Active Targeting CPPs 37.3.2.1 Antibodies as a Targeting Moiety 1205 37.3.2.2 Radioimmunotherapy 1206 37.3.2.3 Homing Peptides 1207 37.4 Advantages and Considerations of CPPs as Delivery Vectors 1208 37.5 Conclusions 1209

Acknowledgments 1210 References 1210

38 Targeting to Peptide Receptors 1219 Andrew V. and Gabor

38.1 Introduction 1219 38.2 Rationale for the Concept of Delivery to Peptide Receptors 1220 38.3 Example 1: Cytotoxic Analogs of LHRHl 1221 38.3.1 Preclinical Considerations Development 1221 38.3.1.1 LHRHl its Receptors l22l 38.3.1.2 Design and Synthesis of Targeted Cytotoxic Analogs of LHRHl 1223 38.3.1.3 Mechanism of Action of Cytotoxic LHRHl Analogs: Targeting to

LHRHl Receptors on 1225 38.3.1.4 Responses of Human Experimental Cancers Expressing Receptors for

RH 1 to Targeted Cytotoxic Analogs of RH 1 3 228 38.3.1.5 of Cytotoxic Analogs 1234 38.3.2 Clinical Development 1235 38.3.2.1 Clinical Phase I and Phase Trials of Cytotoxic LHRHl Analog

in with Ovarian and Endometrial Cancers 1235

38.4 Example 2: Targeted Cytotoxic Somatostatin Analogs 3236 38.4.1 Preclinical Considerations and Development 3236 38.4.1.1 Somatostatin and its Receptors 1236 38.4.1.2 Synthesis of Somatostatin 1238 38.4.1.3 Side-Effects of Cytotoxic Somatostatin Analogs 1243 38.4.2 Clinical Development 1244 38.5 Example 3: Cytotoxic Analogs of Bombesin/Gastrin-Releasing

Peptide 1244 38.5.1 Preclinical Considerations and Development 1244 38.5.1.1 Bombesin/Gastrin-Releasing Peptide and their Receptors 1244 38.5.1.2 Radiolabeled and Cytotoxic Analogs 1245 38.5.2 Clinical Development 38.6 Example 4: Antagonists GHRH 1247

XII Contents

38.6.1 Preclinical Considerations and Development 1247 38.6.1.1 GHRH and GHRH Receptors in Tumors 1247 38.6.1.2 Antagonistic Analogs GHRH 1249 38.6.2 Clinical Developments 1251 38.7 Conclusions and Perspectives 1251

Acknowledgments References 1252

39 Aptamer Conjugates: Emerging Delivery Platforms for Targeted Cancer Therapy 3263 Zeyu Xiao, Jillian Frieder, Benjamin A. and C. Farokhzad

39.1 Introduction 1263 39.2 Isolating Aptamers for Targeted Delivery 1265 39.2.1 Against Purified Proteins 1265 39.2.2 SELEX Against Living Cells 3265 39.3 Applications of Aptamer Conjugates for Targeted Cancer

Therapy 1269 39.3.1 Small-Molecule Delivery via Aptamer Conjugates 1270 39.3.2 Nanoparticle Delivery via Aptamer Conjugate 1271 39.3.3 siRNA Delivery via Aptamer Conjugates 1273 39.4 Considerations of Aptamer Characteristics for In Vivo

Applications 1275 39.4.1 Nuclease Resistance 1275 39.4.2 Optimal Circulating 1275 39.4.3 Rapid Penetration and Longer Retention Time in Target Tissue 1276 39.4.4 Toxicology 1276 39.5 Conclusions and Perspectives 1277

Acknowledgments 1278 References 1278

40 Design and Synthesis of Drug Conjugates of Vitamins and Growth Factors 1283 Iontcho R. Vlahov, J. Kleindl, and Fei You

40.1 Introduction 1283 40.2 Chemical Aspects of FA-Drug Conjugate Design 1284 40.2.1 Folate Receptor-Mediated Endocytosis for Targeted Drug

Delivery 1284 40.2.2 General Criteria for the Design of FA-Drug Conjugates and their

Intracellular Release Mechanisms 1286 40.2.3 Synthesis of FA-Cancer Drug Conjugates Containing

Linker Systems 1288 40.2.3.1 Exploiting Peptide-Based Spacers 1288 40.2.3.2 Exploiting Carbohydrate-Based Spacers 1293 40.2.3.3 Introduction of a Second Unsymmetrical Disulfide Bond: Synthesis of

Releasable Dual-Drug Conjugates 1295

Contents XIII

40.2.4 Application of pH-Responsive Linker Systems for the Synthesis of FA-Drug Conjugates 1298

40.2.5 FR-Targeted Immunotherapy 3298 40.3 Chemical Aspects Vitamin Conjugate Design 1300 40.3.1 Vitamin Proteins and Cellular Transport 1300 40.3.2 Structural Considerations in Vitamin Conjugate Design 1301 40.3.3 Synthesis of Vitamin Conjugates 3303 40.3.3.1 Releasable Conjugates 1301 40.3.3.2 Other Vitamin Conjugates 1303 40.4 Chemical Aspects of Biotin-Drug Conjugate Design 1304 40.4.1 Biotin and Biotin Conjugate Targeting in Cancer Therapy 1304 40.4.2 Synthesis of Biotin-Drug Conjugates 1305 40.5 Other Conjugates 1307 40.5.1 Conjugates of Vitamin E 1307 40.5.2 Conjugates of Vitamin 1307 40.6 Concluding Remarks on Vitamin Targeting 1308 40.7 Growth Factor Conjugates for Tumor Targeting 1308 40.7.1 Growth Factors and Growth Factor Receptors 1308 40.7.2 Growth Factor Targeted Delivery of Protein Toxin 1310 40.7.3 Growth Factor Targeted Delivery of Chemotherapeutics 1311 40.7.4 Growth Factor Targeted Delivery in Radiotherapy and Photodynamic

Therapy 1311 40.7.5 Peptides Targeting Growth Factor Receptor 1312 40.7.6 Concluding Remarks on Growth Factor Targeting 1313

Acknowledgments References 1313

Drug Conjugates with Polyunsaturated Fatty Acids 1323 Joshua Seitz and

41.1 Introduction 1323 41.2 Rationale for the Potential Benefits of PUFA Conjugation to

Chemotherapeutic Drugs 1323 41.2.1 PUFAs in Cancer Progression and Control 1324 41.2.2 Effects of PUFA Internalization on Membrane Composition and

Signaling 1325 41.2.3 Suppression of Tumor-Promoting Biosynthesis by

PUFAs 3326 41.2.4 Influences of PUFAs on Signal Transduction Pathways and Gene

Expression 1328 41.2.5 PUFA Peroxidation and ROS 1331 41.2.6 Synergy of Cytotoxic Drugs and PUFAs for the Treatment of Cancer

Cell Lines 1331 41.3 Drug Conjugates with PUFAs 1332 41.3.1 and PUFA-Second-Generation Taxoid

Conjugates (1) 1332

XIV Contents

41.3.2 (2) 1334 41.3.3 DHA/LNA-DOX (3/4) 1334 41.3.4 (5a/b) 1335 41.3.5 M (6) 1336 41.3.6 (7) 1336 41.3.7 C (8) 1336 41.3.8 (9) and PUFA-Tegafur

11) 1337 41.3.9 DHA-Methotrexate (11) 1338 41.4 Case TXP 1338 41.4.1 Preclinical Evaluations 1338 41.4.2 Pharmacokinetics 1339 41.4.3 Phase I Trials 1342 41.4.4 Phase Trials 3343 41.5 PUFA Conjugates of Second-Generation Taxoids 1345 41.5.1 Preclinical Study of Taxoid

Conjugates 1345 41.5.1.1 Tumor Xenograft 1346 41.5.1.2 Tumor Xenograft 1348 41.5.1.3 (Pancreatic) Tumor Xenograft 1348 41.5.1.4 (Pancreatic) Tumor Xenograft 1348 41.5.1.5 H460 (NSCLC) Tumor Xenograft 1349 41.5.1.6 LNA- and Taxoids 1349 41.5.2 Cytochrome P450 Screening for Assessment of Potential Drug-Drug

Interaction 1349 41.6 Conclusions and Perspectives 1350

Acknowledgments 3350 References 1350

VI Special Topics 1359

42 RNA Drug Delivery Approaches 3363 Yuan Zhang and Leaf Huang

42.1 Introduction 1361 42.2 RNA Molecules with Potential for Cancer Treatment 1361 42.3 Chemical Modification Strategies 1362 42.3.1 Sugar Modification 1364 42.3.2 Nucleobase Modification 1364 42.3.3 Terminal Modification 3365 42.4 Challenges in RNA Delivery 1365 42.4.1 Chemical Stability and Structure Modification 1365 42.4.2 Extracellular Delivery Stage 1366 42.4.3 Target Cell Specificity and Uptake via Targeting Ligands 1366 42.4.4 Endosomal Release 1367 42.5 Potential Adverse Effects RNA Therapy 3367

Contents XV

42.5.1 Induction of Immune Responses 1367 42.5.2 Off-Target Effect 1368 42.5.3 Saturation of Endogenous Silencing Pathway 1368 42.6 RNA Delivery 1368 42.6.1 Physical Methods 3369 42.6.1.1 Hydrodynamic Injection 1369 42.6.1.2 Electroporation 1370 42.6.1.3 Particle Bombardment 1371 42.6.2 Chemical Vectors for RNA Delivery 1371 42.6.2.1 Cationic Lipids/Liposomes and Cationic Lipid Nanoparticles

(Lipoplexes) 1371 42.6.2.2 Lipids 1372 42.6.2.3 Lipid-Like Delivery Molecules (Lipidoids) 1373 42.6.2.4 Cationic Polymers (Polyplexes) 1373 42.6.2.5 Core/Membrane Lipid-Based Nanoparticles (Lipopolyplexes) 1376 42.6.2.6 Chimeras 1379 42.7 Targeting Ligands 1381 42.7.1 Aptamers 1381 42.7.2 CPPs 1381 42.7.3 Antibodies 1381

Peptides and Proteins 1382 42.7.5 Ligands 1382 42.8 Therapeutic Application for Treatment of Cancer 1383 42.8.1 siRNA Therapeutic Mechanisms 1383 42.8.2 Examples in Cancer Treatment of RNA Delivery Technology 1383 42.9 Conclusions 1385

Acknowledgments 1385 References 1385

43 Local Gene Delivery for Therapy of Solid Tumors 1391 Wolfgang Walther, Peter M. Schlag, and Ulrike Stein

43.1 Introduction 1391 43.2 Gene Therapeutic Strategies for Cancer Treatment 3393 43.2.1 Gene Correction Therapy 1392 43.2.2 Therapy 1394 43.2.3 Suicide Gene Therapy 1397 43.2.4 Virotherapy 1397 43.2.5 Gene Suppression 3397 43.3 Vectors for Cancer Gene Therapy 1398 43.3.1 Viral Vectors 1399 43.3.2 Nonviral Vectors 1400 43.3.3 Bacterial Vectors 1401 43.4 Local Application Gene Therapy 1401 43.4.1 Specific Strategies for Local Gene Delivery 1402 43.4.2 Technologies for Local Gene Delivery 1404

XVI Contents

43.4.3 Jet-Injection Technology for Local Cancer Gene Therapy 1406 43.4.4 Clinical Application of Local Jet-Injection Gene Therapy 1406 43.5 Conclusions 1407

References 1408

44 Viral Vectors for RNA Interference Applications in Cancer Research and Therapy 1415 Henry Fechner and Jens Kurreck

44.1 Introduction 1415 44.2 Plasmid Expression of Short Hairpin RNAs 1418 44.3 Conditional RNAi Systems 1422 44.3.1 Irreversible Conditional Systems 1423 44.3.2 Reversible Systems 1423 44.4 Viral Vectors for shRNA Delivery 1426 44.4.1 Retroviral Vectors 1428 44.4.2 Adenoviral Vectors and Oncolytic Adenoviruses 1431 44.4.3 Vectors Based on AAVs 1433 44.5 Outlook 1435

Acknowledgments 1436 References 1436

45 Design of Targeted Protein Toxins 1443 Hendrik Fuchs and Christopher Bachran

45.1 Introduction 1443 45.1.1 Basic Idea 1443 45.1.2 Cell Death 1445 45.1.3 Combination with Other Therapy Strategies 1445 45.2 Rationale for the Respective Drug Delivery Concept 1446 45.2.1 Design 3446 45.2.1.1 Domains 1446 45.2.1.2 Targeting Moieties 3448 45.2.1.3 Toxins 1448 45.2.1.4 Toxin Delivery 1455 45.2.2 Obstacles and Circumvention 1458 45.2.2.1 Production 1458 45.2.2.2 Biological Half-Life 1459 45.2.2.3 Immunogenicity 1460 45.2.2.4 Tumor Penetration 1461 45.2.2.5 Undesirable Effects 1461 45.3 Examples 3462 45.3.1 Preclinical Development 1462 45.3.1.1 Drugs Based on Bacterial Toxins 1462 45.3.1.2 Drugs Based on Plant Toxins 3466 45.3.1.3 Drugs Based on Human Proteins 1468 45.3.2 Clinical Development 1472

Contents XVII

45.3.2.1 Diftitox 1472 45.3.2.2 BL22/HA22 1477 45.3.2.3 SS1P 1479 45.3.2.4 Besudotox 1479 45.3.2.5 Combotox 1480 45.3.2.6 Ranpirnase 1480 45.4 Conclusions and Perspectives 1480

Acknowledgments 1481 References 1481

46 Drug Targeting to the Central Nervous System 1489 Gert Flicker, Anne Mahringer, Melanie Ott, and Valeska Reichel

46.1 Introduction 1489 46.2 Anatomy of the BBB 3490 46.3 Alterations of the BBB in Brain Tumors 1495 46.4 Relevance of the BBB for Drug Delivery 1495 46.4.1 Prodrug Approaches to Overcome the BBB 1495 46.4.2 Inhibition of ABC Export Proteins 1497 46.4.3 Intrathecal or Intraventricular Injection 3498 46.4.4 Infusion of Hyperosmotic Solutions 1499 46.4.5 Focused Ultrasound Treatment 1499 46.4.6 Vector-Coupled Drugs 1499 46.4.7 Liposomal Drug Delivery to the CNS 3502 46.4.8 CNS Drug Delivery by Polymer Nanoparticles 1505 46.4.9 Magnetically Controlled CNS Drug Delivery 1507 46.4.10 Polymeric Micelles and Dendrimers 1508 46.4.11 Solid Lipid Nanoparticles 1508 46.5 Intranasal Delivery to Bypass the BBB 1509 46.6 Conclusion and Perspectives 1509

References 1510

47 Liver Tumor Targeting 1519 Katrin Giuseppina Di Stefano, Hiroshi Maeda, and Felix Kratz

47.1 Introduction 1519 47.1.1 Epidemiology and Incidence of HCC 3539 47.1.2 Therapeutic Options for Treating Liver Cancer 1520 47.1.2.1 Liver Resection 1521 47.1.2.2 Local Ablative Therapy 1521 47.1.2.3 Transarterial Chemoembolization 1521 47.1.2.4 Therapy 1522 47.2 Rationale for Drug Delivery Concepts for Treating Liver Cancer 1522 47.2.1 Receptor for ASGPs: A Target for Delivering Drugs to

Hepatocytes 1524

XVIII Contents

47.2.2 Designing Drug-Encapsulated Nanoparticles for Liver Tumor Uptake RES 1527

47.2.3 Liver Tumor Targeting Using HepDirect Prodrugs 1527 47.3 Preclinical Development of Hepatotropic Drug Delivery

Systems 1528 47.3.1 HepDirect Prodrugs 1529 47.3.2 Drug-Polymer Conjugates 1529 47.3.2.1 PK2: A HPMA-Based Copolymer 1529 47.3.2.2 Lactosaminated Albumin: A Safe and Efficient Hepatotropic Carrier for

Treating Liver Tumors 1532 47.3.2.3 SMANCS: A Conjugate of Poly(Styrene-co-Maleic Acid) and the

Antitumor Agent Neocarzinostatin 1543 47.3.3 Development of Nanoparticles for Treating Liver Tumors 1546 47.3.3.1 Doxorubicin Transdrug 1546 47.3.3.2 Mitoxantrone-Loaded Nanoparticles 1547 47.3.3.3 YCC-DOX: A Multifunctional DOX-Loaded Superparamagnetic Iron

Oxide Nanoparticle 1548 Clinical Development 1550

47.4.1 Phase I Study with PK2: A HPMA-Based Copolymer with N-Galactosamine 1551

47.4.2 Doxorubicin Transdrug: A DOX Nanoparticle with that Advanced to Phase Trials 1553

47.4.3 Phase Trials of Mitoxantrone-Loaded PBCA Nanoparticles 1553 ®

47.4.4 ThermoDox : A Heat-Sensitive Liposomal Formulation of DOX in Phase II Trials 1554

47.4.5 SMANCS: A Conjugate the Antitumor NCS 1555 47.5 Conclusions and Perspectives 1559

References 3560

48 Therapy: and Delivery 1569 Mroz, Sulbha K. Zhiyentayev, Ying-Ying Huang,

and Michael R. Hamblin 48.1 Introduction 1569 48.2 Photochemistry and Photophysics 1569 48.3 Photosensitizers 1571 48.4 Subcellular Localization 1573 48.5 Targeting in PDT 1573 48.6 Preclinical Developments 1573 48.6.1 Drug Delivery Vehicles: Liposomes Micelles and Nanoparticles 1573 48.6.2 Photosensitizer Targeting via Antibodies 1575 48.6.2.1 Conjugates 1578 48.6.2.2 Photosensitizer Linked to via Polymers or Other

Macromolecular Linkers 1578 48.6.3 Peptide or Growth Factor Conjugates 1579 48.6.4 Conjugates between Photosensitizer and Nonantibody Proteins 1580

Contents \ XIX

48.6.5 Conjugates 1584 48.6.6 Photosensitizer Conjugates 1586 48.6.7 Conjugates 1588 48.6.8 Photochemical Internalization 1589 48.7 Clinical Developments 1591 48.8 Conclusions and Perspectives 3592

Acknowledgments 1592 References 1593

49 Tumor-Targeting Strategies with Anticancer Platinum Complexes 3605 Markus Galanski and Bernhard K. Keppler

49.1 Introduction 3605 49.2 Mode of Action of Platinum-Based Anticancer Drugs and Rationale for

the Respective Drug Delivery Concept 1607 49.3 Examples 1611 49.3.1 Active and Organ-Specific Targeting 3632 49.3.2 Passive Targeting 1616 49.3.2.1 Liposomal Drug and LipOxal 1616 49.3.2.2 Polymeric Delivery 1619 Clinical Development 1622 49.4.1 LipoPlatin 1622 49.4.2 LipOxal 3624 49.4.3 ProLindac 1625 49.5 Conclusions and Perspectives 3626

Acknowledgments 1627 References 3627

Index 3633