Biomaterials for cancer therapeutics: evolution and innovation

Front Cover......Page 1
Biomaterials for Cancer Therapeutics: Evolution and Innovation......Page 4
Copyright Page......Page 5
Contents......Page 6
List of contributors......Page 20
Preface......Page 26
 1.1 Introduction......Page 28
 1.2 General classification of cancers......Page 30
 1.3 Early detection—still the best medicine......Page 31
 1.4 Cancer genetics and epigenetics......Page 32
 1.5 Factors that make a cell cancerous......Page 34
 1.6 The concept of a transition from chronic inflammation to cancer......Page 35
 1.7 Current methods to treat various cancers......Page 36
 1.8 Cancer as a real estate concept—location, location, location......Page 38
 1.9 Areas of greatest unmet need in treating cancers......Page 40
 1.10 Conclusion and future trends......Page 42
 References......Page 44
  2.1.1 Phenotypic overview of cancer progression......Page 50
  2.1.2 Evolution of the organization of nuclei in cancer cells......Page 51
  2.1.4 The extracellular matrix component of the tumor microenvironment......Page 52
  2.1.5 Drug resistance in cancer......Page 54
  2.2.1 Matrix remodeling in cancerous tissue......Page 55
  2.2.2 Influence of matrix stiffness and tissue geometry on cancer phenotype......Page 56
  2.2.3 Future directions: design of “intelligent” biomaterials that respond to microenvironmental changes......Page 58
  2.3.1 Physical properties of the cell nucleus......Page 60
  2.3.2 Nuclear proteins involved in mechanosensing......Page 61
  2.3.3 Future directions: identification of internal nuclear features that have the ability to link microenvironmental chang.........Page 63
  2.4.1 Drug resistance and survival in cancer cell populations......Page 64
  2.4.2 Nuclear dynamics and alterations in genome functions......Page 66
  2.4.3 Future directions: platforms and biomaterials to integrate nuclear reorganization and cell survival in tumors......Page 67
 2.5 Conclusion......Page 69
 References......Page 70
 3.1 Introduction......Page 80
   3.2.1.2 Biological activities of polyethyleneimine......Page 81
   3.2.2.1 Pluronic polymers as an inactive ingredient of drug products......Page 88
   3.2.2.2 Biological activities of Pluronics......Page 89
  3.2.3 Polymeric drugs......Page 90
   3.3.1.2 Antitumor activities of chitosan......Page 91
   3.3.2.1 Hyaluronic acid in drug delivery and wound healing......Page 92
   3.3.3.2 Biological activities of chondroitin sulfate......Page 94
   3.3.5.1 Pectin as a drug carrier......Page 95
  3.4.2 Antiproliferative or immune adjuvant activities of polypeptides......Page 96
  3.5.2 Anticancer activities of polar lipids......Page 98
  3.5.3 Immune activities of polar lipids......Page 99
   3.6.1.1 α-Tocopherol succinate as a drug carrier......Page 100
   3.6.2.1 d-α-Tocopheryl polyethylene glycol 1000 succinate as a drug carrier......Page 102
   3.7.1.2 Biological activities of iron oxide......Page 103
   3.7.2.2 Biological activities of graphene oxide......Page 104
  3.7.3 Others: Au, SiO2, and TiO2......Page 105
 References......Page 107
 4.1 Introduction......Page 122
  4.2.1 Top-down approach......Page 123
  4.2.2 Bottom-up approach......Page 124
  4.3.1 Cellular uptake and hybrid nanocrystals......Page 126
  4.3.2 Hybrid nanocrystals with environment-sensitive fluorophores......Page 129
 4.4 In vivo performance......Page 133
 4.5 Conclusion......Page 136
 References......Page 137
 5.1 Introduction......Page 144
  5.2.1 Polymer therapeutics for cross-linking of antigens on the cell surface......Page 145
 5.3 Polymeric drugs inhibiting chemokine receptors......Page 147
  5.4.1 Multidrug resistance by P-glycoprotein......Page 150
  5.4.2 Classes of polymeric P-glycoprotein inhibitors......Page 151
    5.4.2.1.1 Recent examples of Pluronic-based delivery systems to reverse multidrug resistance......Page 152
    5.4.2.1.2 Clinical trials of Pluronic-based formulations......Page 153
    5.4.2.1.3 Mechanism of action for P-glycoprotein inhibition by Pluronics......Page 154
   5.4.2.2 A polymeric derivative of vitamin E (d-α-tocopheryl polyethylene glycol succinate)......Page 155
    5.4.2.2.1 d-α-Tocopheryl polyethylene glycol succinate as a P-glycoprotein inhibitor for overcoming multidrug resistance......Page 157
     5.4.2.2.2.1 d-α-Tocopheryl polyethylene glycol succinate–biodegradable aliphatic polyester......Page 158
     5.4.2.2.2.2 d-α-Tocopheryl polyethylene glycol succinate–hyaluronic acid......Page 159
     5.4.2.2.2.4 Other classes of d-α-tocopheryl polyethylene glycol succinate–based polymer formulations......Page 160
 References......Page 161
 6.1 Introduction......Page 168
  6.2.1 Protonation/deprotonation......Page 169
  6.2.2 Acid-labile bonds......Page 172
 6.3 Tumor pH probe......Page 174
  6.4.1 Simultaneous activation by extracellular/subcellular pH by design......Page 175
  6.4.2 Sequential activation by tumor extracellular/subcellular pH......Page 176
  6.5.1 Drug delivery......Page 177
   6.5.1.1 Small-molecule anticancer drug delivery......Page 178
   6.5.1.2 Biomacromolecule delivery......Page 181
  6.5.2 Tumor imaging......Page 183
 References......Page 184
 7.1 Introduction......Page 192
  7.2.1 siRNA (short interfering RNA)......Page 193
  7.2.3 microRNA......Page 196
   7.2.3.2 Antagomirs......Page 197
  7.2.4 Splice-switching oligonucleotides......Page 198
  7.2.6 DNAzyme......Page 199
  7.4.1 Oligonucleotides that stimulate the immune system......Page 200
  7.4.2 Aptamers......Page 201
  7.5.1 Carbohydrate modifications......Page 202
  7.5.2 Backbone modification......Page 204
 References......Page 205
 8.1 Introduction......Page 214
 8.2 Gene editing platform......Page 215
  8.2.1 Zinc finger nuclease......Page 216
  8.2.2 Transcription activator–like effector nuclease......Page 217
  8.2.3 Clustered regularly interspaced short palindromic repeat–associated nuclease Cas9......Page 218
  8.2.4 Others......Page 219
  8.3.1 Delivery vectors......Page 220
  8.3.2 Barriers for intracellular delivery......Page 221
  8.4.1 Polymers......Page 222
   8.4.1.1 Polyethylenimine......Page 226
   8.4.1.2 Chitosan......Page 227
   8.4.1.3 Polypeptide......Page 228
   8.4.1.4 Fluorinated polymers......Page 230
   8.4.1.5 Other polymers......Page 231
   8.4.2.1 Lipid nanoparticles......Page 233
   8.4.2.2 Lipid nanoshells......Page 234
   8.4.2.3 Ligand-modified lipid nanoparticles......Page 235
  8.4.3 Peptides......Page 236
   8.4.3.1 Cell-penetrating peptides for delivery of nucleases......Page 237
   8.4.3.2 Modification with peptides for specific purposes......Page 238
  8.4.4 Inorganic materials......Page 239
  8.4.5 Nucleic acid–based nanostructures......Page 240
 8.5 Clinical trials......Page 242
 8.6 Challenges and future perspectives......Page 247
 References......Page 249
 9.1 Introduction......Page 260
   9.2.1.1 Antibody-based targeting of circulating tumor cells......Page 262
   9.2.1.2 Size-based isolation of circulating tumor cells......Page 263
   9.2.2.1 Cell-free DNA......Page 264
   9.2.2.4 Detecting epigenetic modifications......Page 265
 9.3 Technologies for liquid biopsies based on genetic and epigenetic mutations......Page 266
 9.4 Exosomes......Page 267
 9.6 Classic methods of cytokine detection in biospecimens......Page 269
  9.6.2 Radioimmunoassays......Page 270
  9.6.5 Multiparametric flow cytometry in conjunction with using (magnetic) beads......Page 271
  9.6.6 Enzyme-linked immunospots (ELISPOT and FLUOROSPOT)......Page 272
  9.6.8 Cytokine detection by means of surface-enhanced Raman spectroscopy......Page 273
  9.7.1 Protease activity and cancer......Page 274
 9.8 Outlook: cost-effectiveness will be an important factor......Page 276
 References......Page 277
 10.1 Introduction......Page 288
  10.1.1 Biosensing and screening of biomarkers......Page 289
 10.2 Nanotechnology for cancer diagnosis......Page 290
  10.2.1 Properties and advantages of nanoparticles and nanomaterials......Page 291
 10.3 Nanotechnology-based biosensing platforms......Page 292
  10.3.2 Sphere-based platforms......Page 293
  10.4.1 Screening—enhancing biomarkers detection......Page 294
  10.4.2 Detecting circulating tumor cells......Page 295
 10.5 Nanotechnology for cancer imaging......Page 296
  10.5.1 Targeted molecular imaging......Page 297
   10.5.3.2 Nanomaterials as enhancing contrast agents for magnetic resonance imaging......Page 298
  10.5.4 Nano-based multimodal imaging......Page 299
  10.5.7 Concerns with using nanomaterials in imaging......Page 300
 10.6 Conclusion and future trends......Page 301
 References......Page 302
 11.1 Current state of tumor imaging in the clinic......Page 318
  11.1.1 Positron emission tomography......Page 319
  11.1.2 Magnetic resonance imaging......Page 320
  11.1.3 X-ray computed tomography......Page 322
 11.2 Potential clinical uses of novel biomaterials for tumor imaging......Page 326
  11.3.1 Quantum dots......Page 327
   11.3.1.1 Applications in cancer imaging......Page 328
   11.3.1.2 Lymph node mapping......Page 329
   11.3.1.3 Quantum dots for multimodal cancer imaging......Page 330
   11.3.1.4 Safety concerns of quantum dots......Page 331
  11.3.2 Carbon-based materials......Page 333
  11.3.3 Lipid-based materials......Page 336
  11.3.4 Polymer-based materials......Page 338
 11.4 Risk–benefit assessment and perspectives......Page 343
 References......Page 344
 12.1 Assessment of target engagement in drug delivery......Page 358
  12.2.1 Enhanced permeability and retention effect......Page 359
  12.2.3 Förster resonance energy transfer to quantify target engagement......Page 360
  12.3.1 Positron emission tomography versus optical imaging......Page 361
  12.3.2 Visible and near-infrared fluorescence lifetime imaging......Page 362
  12.3.3 Preclinical applications of fluorescence lifetime imaging Förster resonance energy transfer imaging......Page 363
  12.4.1 Transferrin–transferrin receptor-mediated drug delivery......Page 366
  12.4.2 Wide-field time-resolved macroscopy fluorescence lifetime imaging optical imager......Page 367
  12.4.3 MFLI Förster resonance energy transfer imaging of transferrin–transferrin receptor binding......Page 369
  12.4.4 Advantages and limitations of MFLI Förster resonance energy transfer imaging......Page 372
 12.5 Imaging with high-resolution beyond the microscopy limit: mesoscopic fluorescence molecular tomography of thick tissues......Page 373
 12.6 Future directions of MFLI Förster resonance energy transfer imaging in the clinic......Page 374
 References......Page 376
 Further reading......Page 390
  13.1.1 Models of cancer origin......Page 392
  13.1.2 Characteristics of cancer stem cells......Page 393
  13.1.4 Cancer stem cell drug resistance......Page 394
 13.2 Pharmacological strategies for suppressing cancer stem cells......Page 395
   13.2.1.2 Inhibitors of the Notch pathway......Page 396
   13.2.1.3 Inhibitors of Wnt/β-catenin......Page 397
   13.2.1.5 Inhibitors of phosphatidylinositol 3-kinase/Akt/mTOR pathway......Page 398
  13.2.2 Gene therapies for cancer stem cells......Page 399
  13.3.1 Delivery of small drugs to cancer stem cells......Page 400
   13.3.1.1 Polymer nanoparticles and micelles......Page 401
   13.3.1.2 Liposomes......Page 403
  13.3.2 Gene delivery to cancer stem cells......Page 404
   13.3.2.1 Polymeric systems......Page 405
   13.3.2.2 Lipid systems......Page 406
  13.3.3 Targeting to cancer stem cells......Page 407
 13.4 Concluding remarks......Page 408
 Acknowledgments......Page 409
 References......Page 410
 14.1 Introduction......Page 426
 14.2 A brief history of two- and three-dimensional in vitro cancer models......Page 429
 14.3 Methods used for high-throughput testing of potential chemotherapeutics in vitro......Page 431
  14.4.2 Gel-like substances/scaffold structures (hydrogels)......Page 434
  14.4.3 The hanging drop format......Page 437
  14.4.5 Magnetic levitation......Page 438
  14.4.7 Microencapsulation......Page 439
  14.4.9 Bioprinting......Page 440
 14.5 The future of three-dimensional cancer models......Page 442
 References......Page 443
 15.2 Complexities of cancers and the tumor microenvironment......Page 450
 15.3 Design and development of tumor models......Page 453
  15.3.1 Spheroids and organoids......Page 454
  15.3.2 Animal models......Page 455
  15.3.3 Microfluidic models......Page 456
 15.4 Challenges and opportunities......Page 462
 References......Page 463
 16.1 What is mechanotransduction?......Page 472
 16.2 Native mechanobiology through cancer’s progression......Page 474
  16.2.1 The primary tumor microenvironment......Page 475
  16.2.2 The premetastatic niche and primary cell motility......Page 478
  16.2.3 Secondary tumor sites: dormancy, reactivation, and drug resistance......Page 480
 16.3 Researching mechanotransduction......Page 481
   16.3.1.2 Optical tweezers......Page 482
   16.3.1.4 Traction force microscopy......Page 484
   16.3.1.6 Fluorescence staining......Page 485
   16.3.2.2 Micro/nanopillars......Page 486
   16.3.2.3 Substrate stiffness......Page 488
   16.3.2.5 Microfluidics......Page 489
  16.3.3 Material selection......Page 490
 16.4 Conclusion and future trends......Page 493
 References......Page 494
  17.2.1 General mechanisms of immunostimulation: antigen-presenting cells and Toll-like receptors......Page 498
  17.2.2 Cellular mediators of immune dysregulation within the tumor microenvironment......Page 502
  17.3.1 Sustained delivery of immunomodulators......Page 503
 17.4 Enhancing immunostimulation via nanobiomaterials......Page 504
  17.4.1 Designing nanoscale biomaterials for cellular targeting......Page 505
  17.4.2 Biodistributions of administered nanobiomaterials......Page 508
  17.4.3 Antigen-presenting cells as key targets of therapeutic immunostimulation......Page 510
  17.4.4 Nanobiomaterials for RNA interfering-based cancer therapy......Page 514
  17.4.5 Nanobiomaterials to enhance cancer vaccination......Page 515
  17.4.6 Nanobiomaterials to enhance adoptive T-cell therapy......Page 516
 References......Page 517
   18.1.1.1 Tumor-targeting antibodies......Page 526
   18.1.1.2 Immunostimulatory antibodies......Page 527
  18.1.2 Delivery of immunomodulators......Page 528
   18.1.2.2 Cytokines......Page 529
   18.1.2.3 Agonists of pattern recognition receptors......Page 530
   18.1.3.1 Engineered protein scaffolds......Page 531
  18.2.1 Artificial antigen-presenting cells......Page 532
   18.2.1.1 Spherical artificial antigen-presenting cells......Page 533
  18.2.2 Artificial T cells......Page 534
   18.3.1.1 Tumor-infiltrating lymphocytes......Page 535
   18.3.1.3 Chimeric antigen receptor T cells......Page 536
  18.3.2 Natural killer cells......Page 537
  18.3.3 Macrophages......Page 538
  18.4.1 Small interfering RNA......Page 539
   18.4.2.1 Messenger RNA use in dendritic cells......Page 540
   18.4.2.2 Messenger RNA use in T cells......Page 541
 References......Page 542
 19.1 Introduction......Page 554
  19.2.1 The role of lymphatic vessels and lymph node in vaccination......Page 555
  19.2.2 Lymphatic system in cancer conditions......Page 556
  19.3.1 Direct intranodal injection......Page 557
  19.3.2 Passive draining of nanoparticulate vaccines from the interstitial space......Page 558
  19.3.4 Albumin “hitchhiking” approach......Page 561
 19.4 The dilemma between lymph node targeting and uptake and retention in antigen-presenting cells......Page 562
  19.5.1 Polymeric micelles......Page 564
  19.5.2 Lipid-coated inorganic nanoparticles......Page 565
  19.5.3 Polymeric nanoparticles......Page 566
 19.6 Summary, prospection, and conclusion......Page 567
 References......Page 569
 20.1 Introduction......Page 576
  20.2.1 Conventional cancer vaccines: past and present......Page 577
  20.2.2 Limitations and challenges of conventional cancer vaccines......Page 578
 20.3 Immunogenic clearance......Page 579
  20.3.2 Enhancing tumor cell phagocytosis by innate immune cells......Page 581
  20.3.4 Biomaterials for immunogenic clearance......Page 585
 20.4 Enhancing the response rate of immune checkpoint blockades to tumors......Page 586
 20.5 Conclusion......Page 587
 References......Page 588
 21.1 Introduction......Page 596
  21.2.1 Tumor heterogeneity and complexity......Page 597
  21.2.2 Multidrug resistance......Page 598
  21.2.3 Biological barriers......Page 599
  21.2.4 Physiological barriers......Page 601
  21.3.1 Drug encapsulation and stability......Page 602
  21.3.2 Tumor-specific delivery and targeting......Page 603
  21.3.3 Pharmacokinetic modulation......Page 605
  21.3.4 Intracellular and subcellular delivery......Page 607
 21.4 Safety challenges with nano-drug delivery......Page 608
  21.4.1 Material safety issues......Page 609
  21.4.2 Limitations of characterization tools and biological models......Page 610
  21.4.3 Immunological profiling and immunotoxicity......Page 612
 21.5 Formulation challenges with nano-drug delivery......Page 613
  21.5.1 Nanoparticle design......Page 615
  21.5.2 Analytical characterization......Page 616
  21.5.3 Manufacturing and scale-up issues......Page 617
  21.6.1 Lipid nanoparticles......Page 618
  21.6.2 Polymeric nanoparticles......Page 619
  21.6.3 Protein nanoparticles......Page 620
 21.7 Conclusion and future perspective......Page 621
 References......Page 623
 22.1 “Executive” overview......Page 626
  22.2.1 So, you want to develop a clinically effective formulation?......Page 629
  22.2.2 My motivation and goal......Page 630
  22.3 It is actually not that difficult to get drugs approved (there are lots of them)......Page 632
  22.4 What about cancer statistics and cancer trials?......Page 633
  22.5 This regulated process costs money to cross “the valley of death”......Page 635
   22.5.1 So what does a clinical trial cost?......Page 636
   22.5.2 What about R&D?......Page 637
   22.6.2 Treatment of osteosarcoma has not improved in over 30 years......Page 638
  22.7 And there are people who want to make money and are making money (which is fine)......Page 639
   22.7.1 Doxil......Page 640
   22.7.2 Abraxane......Page 642
   22.7.3 So, are they making money? And who benefits?......Page 646
  22.8 For cancer though, yes, it is difficult (but I think it is not impossible)......Page 647
   22.8.1 A brief biographical-scientific sketch......Page 648
  22.9 The intravenous dosing problem for cancer: from here to there......Page 649
  22.10 What is nanomedicine? And why?......Page 651
   22.10.1 Because we can......Page 652
    22.10.1.1 niclosamide-conjugated polypeptide nanoparticles, CP-NIC......Page 654
     22.10.1.1.3 Equivalent efficacy for CP-NIC versus NIC dosing (4× more niclosamide in the CP-NIC yields a growth delay of on.........Page 655
     22.10.1.2.2 ODDA-PTX human effective dose (1.6g of PTX/patient; 19g of albumin)......Page 656
     22.10.1.2.5 %Loading by volume (104.5nm3 equivalent drug molecular volume per particle)......Page 657
   22.10.2 Because we have to? some things to consider starting with the drugs themselves......Page 659
    22.10.2.1 A suggestion: start with the drugs themselves......Page 660
    22.10.2.2 Extreme hydrophobicity and low water solubility (Sw ∼2–40µM, LogP 4–7)......Page 661
   22.10.3 Success-ratio between drug solubility and efficacy......Page 662
   22.10.4 The drug-absorbing sink......Page 664
   22.10.5 Laws theories and models......Page 666
   22.11.1 It takes two: Mark Dewhirst was an expert in hyperthermia......Page 667
   22.11.2 Doxil is not working......Page 668
    22.11.2.1 In vitro live-cell imaging data......Page 669
    22.11.2.3 What properties of the drug are responsible for this failure?......Page 672
    22.11.2.4 Doxil was almost the perfect nanomedicine; except for using the wrong drug for that technology......Page 673
   22.11.3 The low-temperature-sensitive liposome: invention and testing......Page 674
    22.11.3.1 Lysolipid exchanges with a lipid bilayer membrane vesicle......Page 675
    22.11.3.4 11/11 tumors completely regressed out to 60 days after a single injection and 1hour of heating......Page 678
    22.11.3.5 This data have also been confirmed in other preclinical studies......Page 679
    22.11.3.6 How to treat local tumors that can be warmed to 42°C: we did not need the enhanced permeability and retention!......Page 680
    22.11.3.7 This successful mechanism is ultimately based on the drug’s physicochemical properties......Page 684
    22.11.3.8 Its science, so follow the protocol......Page 685
    22.11.3.9 Follow the protocol: A pig study in bladder cancer shows how effective ThermoDox can be......Page 687
   22.11.4 A final word about the enhanced permeability and retention effect (because this drives the next invention)......Page 688
  22.12 “Make the drug look like the cancer’s food”: our efforts to treat osteosarcoma......Page 690
   22.12.1 Osteosarcoma: relatively few chemotherapeutic advances over the past 30 years......Page 693
   22.12.2 No two tumors are the same, but they all have to eat......Page 694
   22.12.3 Cancers have an altered lipid metabolic reprogramming......Page 695
   22.12.4 Our drug of choice is niclosamide: repurposed for cancer......Page 696
   22.12.5 Oral-niclosamide has low bioavailability that hampers its repurposing in cancer......Page 697
   22.12.7 In vitro cell studies......Page 698
   22.12.10 An endogenous-inspired formulation for niclosamide......Page 699
   22.12.11 Summary of our work so far......Page 700
   22.12.12 Nanoparticle-fabrication by a rapid solvent-exchange process......Page 701
   22.12.13 Eight aspects (steps) of nanoprecipitation and drug bioavailability......Page 703
   22.12.14 The niclosamide stearate prodrug therapeutic component design......Page 706
   22.12.15 Nanoparticle data......Page 709
    22.12.16.1 Niclosamide is a dirty drug (in a good way)......Page 711
    22.12.16.2 Targeted drugs......Page 713
    22.12.16.3 Niclosamide’s target could be the inner mitochondrial membrane rather than a protein......Page 715
    22.12.16.4 The drugability of niclosamide: the secret is in its small size, polar surface area, pKa, LogP, and LogD......Page 717
    22.12.16.5 How does niclosamide kill the cell, or make it kill itself?......Page 718
   22.12.17 Bioluminescence and pulmonary metastasis assay......Page 719
   22.12.18 In vivo tests in an osteosarcoma lung metastasis mouse model......Page 720
    22.12.18.1 The Day-0-inoculatio Day-1 chase study also avoided the need for enhanced permeability and retention......Page 722
    22.12.18.2 What about more established metastases? We do not know but plan to find out......Page 724
  22.13 Final thoughts......Page 725
   22.13.1 Here is where we are and where we have to go......Page 726
    22.13.2.1 Non-or-limited profit......Page 728
     22.13.2.2.1 Prostate and chest wall recurrence trials that were not completed but could have been......Page 729
     22.13.2.2.2 Let us go for primary liver in China because there are 500,000 cases per year......Page 730
    22.13.2.4 Start generic......Page 731
 References......Page 732
 Dedication......Page 750
Index......Page 752
Back Cover......Page 783