Emphasizing four major classes of polymers for drug delivery-water-soluble polymers, hydrogels, biodegradable polymers, and polymer assemblies-this reference surveys efforts to adapt, modify, and tailor polymers for challenging molecules such as poorly water-soluble compounds, peptides/proteins, and plasmid DNA.
Author(s): Glen S. Kwon
Series: Drugs and the Pharmaceutical Sciences
Edition: 1
Publisher: Informa Healthcare
Year: 2005
Language: English
Pages: 679
Cover Page......Page 1
DRUGS AND THE PHARMACEUTICAL SCIENCES......Page 3
A Series of Textbooks and Monographs......Page 4
Title Page......Page 11
ISBN 0824725328......Page 12
Contents (with page links)......Page 13
Preface......Page 19
Contributors......Page 23
1. BACKGROUND......Page 27
2. HPMA COPOLYMER CONJUGATES—AN HISTORICAL PERSPECTIVE......Page 31
3.1. Polymer-Drug Conjugates......Page 34
3.2. Polymer-Drug Linkers......Page 39
3.3. Characterization and Formulation of Polymer-Drug Conjugates......Page 43
3.4. Polymer-Peptide and Polymer-Protein Conjugates......Page 45
4. BIOLOGICAL RATIONALE FOR DESIGN AND POTENTIAL APPLICATIONS......Page 47
4.1. Biocompatibility......Page 49
4.2. HPMA Copolymer-Anticancer Conjugates......Page 50
4.3. Conjugates for Intracellular Delivery of Oligonucleotides and Proteins......Page 73
5.1. HPMA Copolymer-Doxorubicin (PK1, FCE28068)......Page 76
5.3. HPMA Copolymer-Paclitaxel (PNU166945)......Page 78
5.4. HPMA Copolymer-Camptothecin (MAG-CPT; PNU 166148)......Page 79
5.5. HPMA Copolymer-Platinates (AP5280; AP5346)......Page 80
5.6. HPMA Copolymer-Antibody-Doxorubicin Conjugates......Page 81
6.1. Conjugates for Oral Delivery......Page 82
7.2. HPMA Copolymer-Coated Nanoparticles......Page 85
8. FUTURE PROSPECTS......Page 86
ACKNOWLEDGMENTS......Page 87
REFERENCES......Page 88
1. INTRODUCTION......Page 119
2. SYNTHESIS OF HETEROTELECHELIC POLY(ETHYLENE GLYCOL)S......Page 121
3. SYNTHESIS OF AN END-FUNCTIONALIZED BLOCK COPOLYMER POSSESSING A PEG SEGMENT......Page 127
3.2 Acetal-PEG-Poly(2-N,N-dimethylaminoethyl Methacrylate) Block Copolymer (46)......Page 129
3.3. Acetal-PEG=Linear-Poly(ethylenimine) Block Copolymer (50)......Page 131
4. BIOCONJUGATION USING HETEROTELECHELIC PEG......Page 134
4.1. Modification of Protein by Heterotelechelic PEG......Page 135
4.2. Modification of Oligodeoxynucleotide by Heterotelechelic PEG (56)......Page 136
5. FUNCTIONALIZED POLYMERIC MICELLES BY A SELF-ASSEMBLING OF END-FUNCTIONALIZED PEG BLOCK COPOLYMERS......Page 139
5.1. Aldehyde-PEG-PLA Core-Shell Type Polymeric Micelles (39,40)......Page 140
5.2. Targetable PIC Micelle Composed of Lactose-PEG=PAMA Block Copolymer and pDNA (58)......Page 142
5.3. pH-Responsive PIC Micelle Composed of Acetal-PEG=ODN Conjugate and Poly(ethylenimine) (56)......Page 146
6. CONCLUSION......Page 149
REFERENCES......Page 150
1. INTRODUCTION......Page 155
2. pH VARIATION IN THE BODY......Page 156
3. pH-SENSITIVE POLYMERS......Page 159
4.1. Enteric Coating......Page 161
4.2. Colon-Targeted Drug Delivery......Page 165
4.3. Protein=Peptide Oral Drug Delivery......Page 170
5.1. Tumor Extracellular pH (pHe) Targeting......Page 173
5.2. Cytosolic Delivery......Page 187
6. CONCLUSION......Page 206
REFERENCES......Page 207
1.1. Hydrogels......Page 221
1.2. Superporous Hydrogels......Page 224
2. APPLICATION OF HYDROGELS IN ORAL DRUG DELIVERY......Page 225
2.1. Oral Cavity......Page 226
2.2. Stomach......Page 229
2.3. Gastric Retention Devices......Page 230
2.4. Small Intestine......Page 232
2.5. Large Intestine and Colon......Page 233
3.1. Hydrotropic Hydrogels for Delivery of Poorly Soluble Drugs......Page 234
3.2. Alginate Hydrogels for Oral Vaccine Delivery......Page 235
REFERENCES......Page 237
1. INTRODUCTION......Page 241
2. HYDROGELS: GENERAL FEATURES......Page 242
3.1. Introduction......Page 243
3.2. Chemically Crosslinked Dextran Hydrogels......Page 244
3.3. Physically Crosslinked Dextran Hydrogels......Page 249
4.1. Introduction......Page 253
4.2. Protein Release from Poly(Ether Ester) Hydrogel Films......Page 254
4.3. Protein Release from Poly(Ether Ester) Microspheres......Page 256
4.4. In Vivo Protein Release......Page 257
4.5. Tissue Engineering......Page 260
5. THE STABILITY OF HYDROGEL-ASSOCIATED PHARMACEUTICAL PROTEINS......Page 261
6. CONCLUDING REMARKS......Page 266
Abbreviations......Page 267
REFERENCES......Page 268
1. INTRODUCTION......Page 277
2. POLY(N-ISOPROPYLACRYLAMIDE) AND ITS COPOLYMERS......Page 279
3. PEO-PPO-PEO TRIBLOCK COPOLYMERS......Page 284
4. THERMOSENSITIVE AND BIODEGRADABLE POLYMER HYDROGELS......Page 285
5. BIODEGRADABLE MICROSPHERES BASED ON THE THERMOSENSITIVE PROPERTY OF PLGA-PEG-PLGA......Page 291
REFERENCES......Page 295
1. INTRODUCTION......Page 301
2.1. Temperature Sensitive Polymeric Materials......Page 302
2.2. pH-Responsive Polymeric Hydrogel Systems......Page 320
2.3. Glucose-Responsive Hydrogel Systems for Possible Insulin-Release Devices......Page 325
2.4. Other Stimuli-Responsive Hydrogel Systems......Page 333
3. CONCLUSIONS......Page 337
REFERENCES......Page 338
8 Treatment of Malignant Brain Tumors with Controlled-Release Local-Delivery Polymers......Page 349
1. INTRODUCTION......Page 350
2. DRUG DELIVERY CONSIDERATIONS IN THE CNS......Page 351
3. BIOCOMPATIBLE POLYMER DEVELOPMENT: AN HISTORICAL PERSPECTIVE......Page 355
4.1. BCNU (Gliadel) Development and Clinical Use......Page 359
4.2. Other Neuro-Oncologic Applications of Polymer Delivery......Page 370
5. FUTURE DIRECTIONS......Page 385
6. CONCLUSIONS......Page 387
REFERENCES......Page 389
1. OVERVIEW AND HISTORICAL PERSPECTIVE......Page 407
2. EVIDENCE OF PROTEIN INSTABILITY......Page 408
3. WHAT IS THE INSTABILITY PATHWAY?......Page 409
3.1. Evaluating the Kinetics of Instability and Denatured State of Encapsulated BSA......Page 411
3.2. Simulating the Encapsulated Denatured State of BSA Outside the Polymer......Page 414
4. EXAMPLES OF STABILIZING PLGA-ENCAPSULATED PROTEINS......Page 415
4.1. Stabilization of BSA in PLGA Millicylinders......Page 416
4.2. Stabilization of BSA in PLGA Microspheres by Adding Insoluble Base......Page 419
4.3. Stabilization of BSA in PLGA Microspheres by Combination of High Molecular Weight PLA and PEG......Page 422
4.4. Stabilization of f-BSA in PLGA Microspheres......Page 425
4.5. Stabilization of Therapeutic Proteins in PLGA Millicylinders......Page 432
5. CONCLUDING REMARKS......Page 436
REFERENCES......Page 437
1. INTRODUCTION......Page 443
2. SYNTHESIS AND CHARACTERIZATION......Page 445
3. DRUG DELIVERY APPLICATIONS......Page 449
3.1. Polymers for Systemic Drug Delivery......Page 450
3.2. Hydrogel-Forming Polymers......Page 453
4. GENE DELIVERY APPLICATIONS......Page 461
4.1. Delivery of Plasmid DNA from Silk-Elastinlike Hydrogels......Page 462
4.2. Delivery of Adenoviral Vectors from Silk-Elastinlike Hydrogels......Page 467
4.3. Soluble Nucleic Acid Carriers......Page 468
5. TISSUE REPAIR APPLICATIONS......Page 470
6. BIOCOMPATIBILITY AND BIODEGRADATION......Page 471
7. CONCLUSIONS......Page 473
REFERENCES......Page 474
1. INTRODUCTION......Page 481
2. CANCER VACCINES: PROMISE AND PROBLEMS......Page 483
3.1. Antigen Delivery to Dendritic Cells......Page 484
3.2. Induction of Protective T Cell Responses......Page 486
3.3. Overcoming Immune Tolerance......Page 487
4. CANCER VACCINE DELIVERY: LIVING VS. NON-LIVING SYSTEMS......Page 489
5. PLGA-BASED PHARMACEUTICAL DELIVERY SYSTEMS......Page 490
6.1. Uptake of PLGA Nanoparticles by Dendritic Cells......Page 491
6.2. Antigen-loading of DCs by PLGA Nanoparticles Ex Vivo for Induction of T Cell Responses......Page 494
6.3. Immune Responses In Vivo: Th1=Th2 Balance and Anticancer Effects......Page 498
6.4. Dose Sparing of TLR Ligands by Nanoparticle Delivery......Page 499
6.5. Microparticles vs. Nanoparticles: Does Size Matter?......Page 500
ACKNOWLEDGMENTS......Page 502
REFERENCES......Page 503
1. INTRODUCTION......Page 517
2. RATIONALE FOR DELIVERY SYSTEM USING POLYMER ASSEMBLIES 2.1. Block Copolymers and Polymer Assemblies......Page 518
2.2. Distribution of Polymer Assemblies in the Body......Page 520
2.3. Targeting......Page 521
3.1. Polymeric Micelles......Page 523
3.2. Delivery of Hydrophobic Anticancer Drugs......Page 526
3.3. Delivery of Metal-Complex Anticancer Drugs......Page 529
4.1. Polyion Complex Micelles......Page 532
4.2. Protein Delivery......Page 533
4.3. Gene Delivery......Page 535
4.4. Delivery of Photosensitizers......Page 538
5. PROGRAMMED DELIVERY USING BLOCK COPOLYMER MICELLES......Page 541
5.1. Design of Modified Amphiphilic Block Copolymers......Page 542
5.2. Surface-Modified Block Copolymer Micelles......Page 543
5.3. Core-Modified Block Copolymer Micelles......Page 546
6. FUTURE PROSPECTS OF BLOCK COPOLYMER MICELLES......Page 550
REFERENCES......Page 551
1.1. What Is a Polymeric Micelle for Drug Targeting?......Page 559
1.2. The Advantages of Polymeric Micelles for Drug Targeting......Page 561
1.3. The Purposes of the Incorporation of Drugs into Polymeric Micelles......Page 564
2. THE HISTORY OF POLYMERIC MICELLE DRUG CARRIERS......Page 569
3.1. Choice of Polymerization for Block Copolymers......Page 571
3.2. Means of Drug Incorporation: Chemical Conjugation and Physical Entrapment......Page 575
3.3. Physical Factors for Targeting......Page 576
3.4. Additional Features......Page 585
4.1. Adriamycin (Doxorubicin)......Page 586
4.2. KRN-5500......Page 589
4.4. Taxol......Page 590
4.6. Methotrexate......Page 591
REFERENCES......Page 592
1. INTRODUCTION......Page 603
2. PLURONIC STRUCTURE AND SYNTHESIS......Page 604
3. SELF-ASSEMBLY OF PLURONIC BLOCK COPOLYMERS......Page 606
4.1. Sensitization of Drug-Resistant Cancers by Pluronic Block Copolymers......Page 607
4.2. Effects of Pluronic Block Copolymers on Drug Resistance Systems......Page 608
4.3. ATP Depletion Induced by Pluronic Block Copolymers in MDR Cells......Page 610
4.4. Membrane Interaction of Pluronic and Inhibition of Pgp ATPase Activity......Page 613
4.5. Clinical Trials of Doxorubicin-Pluronic Formulation (SP1049C)......Page 614
5.1. Effects of Pluronic on Brain Accumulation of Drugs: In Vitro and In Vivo Evaluation......Page 615
5.2. Enhancement of Oral Bioavailability of Drugs by Pluronic Block Copolymers......Page 618
6. OPTIMIZATION OF PLURONIC COMPOSITION FOR PGP INHIBITION......Page 619
7. PLURONIC BLOCK COPOLYMERS FOR GENE THERAPY......Page 622
7.1. Pluronic-Containing Polyplexes for Gene Delivery......Page 623
7.2. Pluronic Block Copolymers Enhance Gene Expression in Stably Transformed Cell Models......Page 626
7.3. Effect of Pluronic Block Copolymers on Gene Delivery In Vivo......Page 627
REFERENCES......Page 629
1. NON-VIRAL GENE THERAPY......Page 641
2. NOMENCLATURE OF GRAFT COPOLYMERS......Page 644
3. CATIONIC GRAFT COPOLYMERS......Page 645
lysine)......Page 647
2-hydroxypropyl)methacrylamide]......Page 654
3.3. Polyethyleneimine......Page 655
4. BIODEGRADABLE AND TARGETED POLYMERIC GENE CARRIERS......Page 660
REFERENCES......Page 664
A......Page 673
B,C......Page 674
G......Page 675
J,K,L......Page 676
O,P......Page 677
Q,R......Page 678
U,V,W......Page 679
