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Core-Shell Nanostructures for Drug Delivery
and Theranostics
This page intentionally left blank
Woodhead Publishing Series in Biomaterials

Core-Shell Nanostructures
for Drug Delivery
and Theranostics
Challenges, Strategies, and Prospects
for Novel Carrier Systems

Edited by

Maria Letizia Focarete

Anna Tampieri
Woodhead Publishing is an imprint of Elsevier
The Officers’ Mess Business Centre, Royston Road, Duxford, CB22 4QH, United Kingdom
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
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Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become
necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using
any information, methods, compounds, or experiments described herein. In using such information or methods
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liability for any injury and/or damage to persons or property as a matter of products liability, negligence or
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material herein.

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ISBN: 978-0-08-102198-9 (print)

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Contents

List of Contributors ix

Part I Fundamentals on Nanotechnology for Drug

Delivery 1
1 Introduction to “Core-shell nanostructures for drug delivery
and theranostics: Challenges, strategies, and prospects for novel
carrier systems” 3
Maria Letizia Focarete and Anna Tampieri

2 Physicochemical properties of nanosized polymeric drug carrier

systems 7
Nicoletta Rescignano and Jose Maria Kenny
2.1 Introduction 7
2.2 Polymeric nanocarrier systems 8
2.3 Main therapeutic agents encapsulated 10
2.4 Physical properties 11
2.5 Chemical properties 13
2.6 Conclusion 14
References 14

3 Biomineralization process generating hybrid

nano- and micro-carriers 19
Elisabetta Campodoni, Tatiana Patricio, Monica Montesi,
Anna Tampieri, Monica Sandri and Simone Sprio
3.1 Introduction 19
3.2 Biomineralization 20
3.3 Magnetic materials in medicine 25
3.4 Intrinsically magnetic and hybrid nanobeads as carriers in
nanomedicine 26
3.5 Intrinsically magnetic hybrid microspheres as smart
release systems 28
3.6 Interaction between cells and biomimetic magnetic carriers 31
3.7 Conclusion and future trends 33
Acknowledgment 34
References 34
vi Contents

4 Clinical applications of nanostructured drug delivery systems:

from basic research to translational medicine 43
Maria Mendes, João Sousa, Alberto Pais and Carla Vitorino
4.1 Introduction 43
4.2 Organic vs. inorganic NDS 46
4.3 Application of NDS in different therapeutic areas 90
4.4 Problems associated to translational nanomedicine 94
4.5 Conclusions 96
Acknowledgments 97
References 97

Part II Core-Shell Nanoparticles 117

5 Core-shell nanoparticles and their use for in vitro and in vivo
diagnostics 119
Sofia Dembski, Christine Schneider, Bastian Christ and Marion Retter
5.1 Introduction 119
5.2 Synthesis of core-shell NPs 120
5.3 Applications 131
5.4 Conclusion and future trends 135
References 135

6 Core-shell nanoparticles for cancer imaging and therapy 143

Xindong Wang, Hui Li and Guanying Chen
6.1 Introduction 143
6.2 Bioimaging 144
6.3 Therapy 153
6.4 Conclusion 168
References 168

7 Multifunctional hybrid nanoparticles for theranostics 177

Timur Saliev, Alma Akhmetova and Gulsim Kulsharova
7.1 Introduction 177
7.2 Liposomal hybrid NPs 179
7.3 Micellar hybrid NPs 182
7.4 Viral hybrid NPs 185
7.5 Silica-based hybrid NPs 187
7.6 Polymeric hybrid NPs 200
7.7 Gold-based hybrid NPs 203
7.8 Carbon nanotube-based hybrid NPs 206
7.9 Hybrid NPs for PDT and molecular imaging 210
7.10 Radioactive hybrid NPs 220
7.11 Conclusions and future perspectives 223
References 224
Contents vii

8 Stimuli-responsive core-shell nanoparticles 245

Nicoletta Rescignano and Jose Maria Kenny
8.1 Introduction 245
8.2 Different composition of NPs 247
8.3 Stimuli-responsive metal core 248
8.4 Synthesis and characterization 250
8.5 Main biomedical application 253
8.6 Conclusion and future perspectives 254
References 255

9 Magnetic core-shell nanoparticles: Remote driving, hyperthermia,

and controlled drug release 259
Alessio Adamiano, Michele Iafisco and Anna Tampieri
9.1 Introduction 259
9.2 MCNPs composition and design 261
9.3 Hyperthermia and controlled drug release 272
9.4 Remote magnetic driving 283
9.5 Future perspective 285
References 286
Further reading 296

10 Smart nanoconstructs for theranostics in cancer

and cardiovascular diseases 297
Antonio Cervadoro, Alessandro Coclite, Daniele Di Mascolo,
Miguel Ferreira, AnnaLisa Palange, Roberto Palomba, Rui C. Pereira
and Paolo Decuzzi
10.1 Introduction 297
10.2 Smart polymeric nanoconstructs 298
10.3 Multimodal imaging with polymeric nanoconstructs 302
10.4 Combination therapy with polymeric nanoconstructs 305
10.5 Organ-on-chips for assessing the efficacy of polymeric
nanoconstructs 308
10.6 Modeling the vascular dynamics of polymeric nanoconstructs 310
10.7 Conclusions and future perspectives 313
Acknowledgments 313
References 313
Further reading 321

Part III Core-Shell Nanofiber 323

11 Blend electrospinning, coaxial electrospinning, and emulsion
electrospinning techniques 325
Matej Buzgo, Andrea Mickova, Michala Rampichova
and Miroslav Doupnik
11.1 Advanced electrospinning techniques 325
viii Contents

11.2 Nanofibers as a drug delivery system 325

11.3 Functionalization of nanofibers by surface adsorption 326
11.4 Blend electrospinning (co-electrospinning) 328
11.5 Coaxial electrospinning 329
11.6 High-throughput electrospinning technologies 335
Acknowledgment 337
References 337

12 Drug release kinetics of electrospun fibrous systems 349

Dario Puppi and Federica Chiellini
12.1 Introduction 349
12.2 Drug-loaded electrospun fibers applications 350
12.3 Methods for the preparation of drug-loaded electrospun fibers 353
12.4 Drug release kinetics 358
12.5 Conclusion and future perspectives 366
References 367

13 Applications of core-shell nanofibers: Drug and biomolecules

release and gene therapy 375
Zeynep Aytac and Tamer Uyar
13.1 Introduction 375
13.2 Delivery of drugs from core-shell nanofibers 376
13.3 Delivery of proteins from core-shell nanofibers 385
13.4 Delivery of enzymes from core-shell nanofibers 386
13.5 Delivery of growth factors from core-shell nanofibers 388
13.6 Core-shell nanofibers for gene therapy 389
13.7 Stimuli-responsive core-shell nanofibers for delivery
of biomolecules 390
13.8 Delivery of multiple drug and biomolecules from core-shell
nanofibers 396
13.9 Conclusion 398
References 399

14 Advances in multidrug delivery from electrospun nanomaterials 405

Roberto Di Gesù, Andrea Merlettini, Chiara Gualandi
and Maria Letizia Focarete
14.1 Electrospinning as a smart tool for multidrug delivery systems 405
14.2 Monolithic nanofibers for multidrug delivery 407
14.3 Core-sheath nanofibers for multidrug delivery 412
14.4 Nanocarrier-in-fibers as multidrug delivery systems 418
14.5 Conclusions and future perspectives 426
References 427

Index 431
List of Contributors

Alessio Adamiano Institute of Science and Technology for Ceramics,

ISTEC
CNR, Faenza, Italy

Alma Akhmetova Centre for Life Sciences, National Laboratory Astana,

Nazarbayev University, Astana Kazakhstan; University of Essex, Colchester,
Essex, United Kingdom

Zeynep Aytac Institute of Materials Science & Nanotechnology, UNAM-National

Nanotechnology Research Center, Bilkent University, Ankara, Turkey

Matej Buzgo InoCure s.r.o., Klimentská 1652/36, 110 00 Prague, Czech Republic

Elisabetta Campodoni Institute of Science and Technology for Ceramics-National

Research Council (ISTEC-CNR), Faenza, Italy

Antonio Cervadoro NEST, Scuola Normale Superiore di Pisa, Pisa, Italy

Guanying Chen MIIT Key Laboratory of Critical Materials Technology for New
Energy Conversion and Storage, School of Chemistry and Chemical Engineering &
Key Laboratory of Micro-systems and Micro-structures, Ministry of Education,
Harbin Institute of Technology, Harbin, People’s Republic of China

Federica Chiellini BIOLab Research Group, Department of Chemistry and

Industrial Chemistry, University of Pisa, Pisa, Italy

Bastian Christ Translational Center Regenerative Therapies, Branch of Fraunhofer

Institute for Silicate Research ISC, Würzburg, Germany

Alessandro Coclite Laboratory of Nanotechnology for Precision Medicine,

Fondazione Istituto Italiano di Tecnologia, Genoa, Italy

Paolo Decuzzi Laboratory of Nanotechnology for Precision Medicine, Fondazione

Istituto Italiano di Tecnologia, Genoa, Italy

Sofia Dembski Translational Center Regenerative Therapies, Branch of Fraunhofer

Institute for Silicate Research ISC, Würzburg, Germany; Department of Tissue
Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg,
Germany
x List of Contributors

Roberto Di Gesù Department of Chemistry “G. Ciamician”, University of

Bologna, Bologna, Italy

Daniele Di Mascolo Laboratory of Nanotechnology for Precision Medicine,

Fondazione Istituto Italiano di Tecnologia, Genoa, Italy

Miroslav Doupnik InoCure s.r.o., Klimentská 1652/36, 110 00 Prague, Czech

Republic

Miguel Ferreira Laboratory of Nanotechnology for Precision Medicine,

Fondazione Istituto Italiano di Tecnologia, Genoa, Italy

Maria Letizia Focarete Department of Chemistry “G. Ciamician”, University of

Bologna, Bologna, Italy

Chiara Gualandi Department of Chemistry “G. Ciamician”, University of

Bologna, Bologna, Italy

Michele Iafisco Institute of Science and Technology for Ceramics, ISTEC
CNR,

Faenza, Italy

Jose Maria Kenny University of Perugia, Civil and Environmental Engineering

Department, Strada di Pentima 4, Terni, Italy

Gulsim Kulsharova University College London, London, United Kingdom

Hui Li MIIT Key Laboratory of Critical Materials Technology for New Energy
Conversion and Storage, School of Chemistry and Chemical Engineering & Key
Laboratory of Micro-systems and Micro-structures, Ministry of Education, Harbin
Institute of Technology, Harbin, People’s Republic of China

Maria Mendes Faculty of Pharmacy, University of Coimbra, Coimbra,

Portugal; Centre for Neurosciences and Cell Biology (CNC), University of
Coimbra, Coimbra, Portugal

Andrea Merlettini Department of Chemistry “G. Ciamician”, University of

Bologna, Bologna, Italy

Andrea Mickova InoCure s.r.o., Klimentská 1652/36, 110 00 Prague, Czech

Republic

Monica Montesi Institute of Science and Technology for Ceramics-National

Research Council (ISTEC-CNR), Faenza, Italy

Alberto Pais Coimbra Chemistry Center, Department of Chemistry, University of

Coimbra, Coimbra, Portugal
List of Contributors xi

AnnaLisa Palange Laboratory of Nanotechnology for Precision Medicine,

Fondazione Istituto Italiano di Tecnologia, Genoa, Italy

Roberto Palomba Laboratory of Nanotechnology for Precision Medicine,

Fondazione Istituto Italiano di Tecnologia, Genoa, Italy

Tatiana Patricio Institute of Science and Technology for Ceramics-National

Research Council (ISTEC-CNR), Faenza, Italy

Rui C. Pereira Laboratory of Nanotechnology for Precision Medicine, Fondazione

Istituto Italiano di Tecnologia, Genoa, Italy

Dario Puppi BIOLab Research Group, Department of Chemistry and Industrial

Chemistry, University of Pisa, Pisa, Italy

Michala Rampichova Laboratory of Tissue Engineering, Institute of Experimental

Medicine, Academy of Sciences of the Czech Republic, v.v.i, Vı́deňská 1083,142
20, Prague 4, Czech Republic

Nicoletta Rescignano University of Perugia, Civil and Environmental Engineering

Department, Strada di Pentima 4, Terni, Italy

Marion Retter Translational Center Regenerative Therapies, Branch of Fraunhofer

Institute for Silicate Research ISC, Würzburg, Germany

Timur Saliev Centre for Life Sciences, National Laboratory Astana, Nazarbayev
University, Astana Kazakhstan

Monica Sandri Institute of Science and Technology for Ceramics-National

Research Council (ISTEC-CNR), Faenza, Italy

Christine Schneider Department of Tissue Engineering and Regenerative

Medicine, University Hospital Würzburg, Würzburg, Germany

João Sousa Faculty of Pharmacy, University of Coimbra, Coimbra,

Portugal; LAQV REQUIMTE, Group of Pharmaceutical Technology, Porto,
Portugal

Simone Sprio Institute of Science and Technology for Ceramics-National

Research Council (ISTEC-CNR), Faenza, Italy

Anna Tampieri Institute of Science and Technology for Ceramics-National

Research Council (ISTEC-CNR), Faenza, Italy
xii List of Contributors

Tamer Uyar Institute of Materials Science & Nanotechnology, UNAM-National

Nanotechnology Research Center, Bilkent University, Ankara, Turkey

Carla Vitorino Faculty of Pharmacy, University of Coimbra, Coimbra,

Portugal; Centre for Neurosciences and Cell Biology (CNC), University of
Coimbra, Coimbra, Portugal; LAQV REQUIMTE, Group of Pharmaceutical
Technology, Porto, Portugal

Xindong Wang MIIT Key Laboratory of Critical Materials Technology for New
Energy Conversion and Storage, School of Chemistry and Chemical Engineering &
Key Laboratory of Micro-systems and Micro-structures, Ministry of Education,
Harbin Institute of Technology, Harbin, People’s Republic of China
Part I

Fundamentals on
Nanotechnology for Drug
Delivery
This page intentionally left blank
Introduction to “Core-shell
nanostructures for drug delivery 1
and theranostics: Challenges,
strategies, and prospects for
novel carrier systems”
Maria Letizia Focarete1 and Anna Tampieri2
1
Department of Chemistry “G. Ciamician”, University of Bologna, Bologna, Italy,
2
Institute of Science and Technology for Ceramics, ISTEC
CNR, Faenza, Italy

Research on nanoscience and nanotechnology is experiencing a dramatic develop-

ment. Advances in the preparation of nanosystems with applications in the field of
medicine have given rise to new challenges in the design of smart materials capable
of responding to new clinical requirements, among which various types of nanopar-
ticles play an important role. A main goal in this field is to develop new systems
able to deliver therapeutic agents to the patient in a more effective and safer fash-
ion, in comparison with systemic administration. In fact, in many cases this latter
approach implies the administration of high dosages to reach therapeutically rele-
vant amounts of the drug in the target site, which can however induce potentially
harmful side effects. This problem is particularly critical in oncology treatments,
where the risk
benefit ratio associated with chemotherapy often makes it difficult
to take a wise decision, as a consequence of the drugs cytotoxicity. Therefore, the
establishment of new therapeutic approaches acting locally, specifically, and along
defined spatial
temporal patterns is a highly desired condition that material scien-
tists are pursuing by developing smart, multifunctional nanocarriers. Relevant func-
tionalities in this respect include (1) load and subsequent release of different drugs,
(2) anchoring of biomolecules such as proteins, vectoring agents, or nucleic acids to
the external surface of the particle and towards therapeutic targets, (3) anchoring of
fluorescent molecules or active complexes for magnetic resonance imaging (MRI)
to perform optical monitoring, (4) inclusion of functional nanoparticles to enable
remote activation on demand, suitable for personalized applications.
Besides nanomedicine, also regenerative medicine approaches can receive great
benefit by the use of nanocarriers enabling co-delivery or sequential presentation of
biological cues to cells, to most efficiently guide cells along a differentiation or
dedifferentiation pathway.

Core-Shell Nanostructures for Drug Delivery and Theranostics. DOI: https://doi.org/10.1016/B978-0-08-102198-9.00001-6

© 2018 Elsevier Ltd. All rights reserved.
4 Core-Shell Nanostructures for Drug Delivery and Theranostics

Potential benefits of nanotechnology in medicine are outstanding, as it can open

to refined, highly targeted, blood
brain barrier-crossing drug delivery and imaging
platforms, unique transfection, labeling, bioseparation, as well as analytical and tis-
sue engineering approaches.
Among nanostructures that have recently raised great interest, engineered mag-
netic nanoparticles (MNPs) represent a cutting-edge tool in medicine because they
can be simultaneously functionalized and guided by a magnetic field, thus enabling
integrative theranostic (i.e., therapeutic and diagnostic) applications. The use of
MNPs is effective in advanced MRI, guided drug and gene delivery, hyperthermia-
based cancer therapy, tissue engineering, cell tracking, and bioseparation. The
development of drug delivery systems with selectivity to pathologic sites is an
ambitious goal. The principles of magnetic guidance of MNP-conjugated drugs
have been applied experimentally and have reached clinical trials as a cancer ther-
apy. Following intravenous delivery of MNPs, an external magnetic field is used to
concentrate MNPs at a specific target site, by a procedure well tolerated in cancer
patients. Nanoparticle-based drug and gene delivery systems may solve the
insurmountable obstacle of treating neurological diseases: delivery across the blood

brain barrier. But issues of potential embolization with MNP aggregates in capillaries
and the need of large distances between the pathological site and external magnetic
field are still a challenge.
The recent advancements in materials science approaches have prompted a rapid
progress in the preparation of core-shell nanostructures with tailored surface charac-
teristics, namely core-shell nanoparticles and core-shell nanofibers, thus opening
new perspectives in their use for diversified applications. Encapsulation of thera-
peutic agents or biologically active molecules in nanostructures with a core-shell
configuration represents a useful strategy to improve bioavailability of drugs with
poor water solubility; prevent burst release which might cause toxicological effects;
obtain a sustained and prolonged release; generate temporal and spatial controlled
release; encapsulate unstable bioactive molecules protecting their biological activ-
ity; load different drugs at the same time in the core and shell region of the nanos-
tructure to achieve a distinct multidrug release; and obtain nanostructures with
multifunctionality thus developing materials for “theranostics.” The coalescence of
bioengineering, biomedical, and toxicology disciplines will continue fostering
development of relevant strategies to engineer advanced nanodevices with biocom-
patible interfaces.
This book presents the state-of-the-art research on the design and fabrication of core-
shell nanostructured systems for the smart delivery of therapeutic and imaging agents.
The most important physicochemical properties of biocompatible polymeric
nanodevices (molecular weight, hydrophobicity, surface charge and size, etc.),
incorporating active pharmaceutical ingredients or therapeutic agents, are presented
and their influence on the release kinetics of the delivery systems are discussed.
Moreover, an overview of the clinical applications of nanosystems, ranging from
basic research to translation into clinical practice is presented, taking into account
regulatory issues, including those addressing safety concerns, as well as questions
related to the up-scaling processes and reproducibility.
Introduction 5

Novel biocompatible and bioresorbable magnetic materials, promising for new

therapeutic approaches and to overcome the use of cytotoxic superparamagnetic
carriers, are presented. Such innovative materials are obtained through a biominer-
alization process able to generate hybrid nano- and micro-carriers with superpara-
magnetic properties for application in nanomedicine as novel diagnostic nano-tools
or as smart drug delivery systems.
The different techniques used for the preparation of nanoparticles with a core-
shell structure, as well as stimuli responsive core-shell nanoparticles, are illustrated
and nanoparticle properties are discussed. In addition, the use of core-shell nanopar-
ticles in many advanced medical applications, such as theranostics, cancer imaging
and therapy, and cardiovascular diseases, is thoroughly described.
The last part of the book is related to core-shell nanofibers for drug delivery
applications in tissue engineering, wound healing, anticancer therapy, etc.
Electrospun fibers can be loaded with different agents, ranging from small mole-
cules to growth factors and proteins. Various loading methods, such as blend elec-
trospinning, coaxial electrospinning, and emulsion electrospinning techniques are
described. Moreover, an extensive overview of drug release kinetics in relevant
in vitro and in vivo environments is reported. Several applications of core-shell
nanofibers for drug and biomolecule release, as well as for gene therapy, are pre-
sented, including cutting-edge applications such as controlled multidrug delivery
and drug release on demand by external triggering.
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Branchipus, 25, 35, 233, 242, 511 n.;
thoracic limb, 10;
nervous system, 30;
B. spinosus, habitat, 33;
B. stagnalis, 35;
eggs, 32
Branchiura, 76
Brauer, on development of Scorpions, 263, 301 n., 305
Breeding (see Reproduction)
British forms, of Cladocera, 51;
of Pycnogons, 540
Bronteidae, 249
Bronteus, 228, 235, 249;
B. brongniarti, eye, 229;
B. palifer, eye, 229;
B. polyactin, hypostome, 233;
B. irradians, macula, 233
Brood-pouch, of Cladocera, 46, 47;
of Peracarida, 118
Broteas, 308
Broteochactas, 308
Brünnich, 502
Buckler, 330
Bucranium, 414
Bulb, of palpal organ of Spiders, 322
Bumastus, 235, 236, 249
Bunodella, 279
Bunodes, 279
Buthidae, 306
Buthinae, 306
Buthus, 306;
B. occitanus, 299, 300, 302
Bythotrephes, 38, 54;
reproduction, 47;
B. cederströmii, 42

Cabiropsidae, 130
Caecidotea nickajackensis, habitat, 210;
C. stygia, habitat, 210
Caeculinae, 472
Caeculus, 472
Calamistrum, 326, 354, 385, 392, 399, 410
Calanidae, 57
Calanus, 57;
C. finmarchicus, distribution, 203, 204;
C. hyperboreus, 55, 56, 58
Calappa, 187;
respiration, 186;
habitat, 198;
distribution, 201;
C. granulata, 186
Calappidae, 187
Calathocratus, 452
Calathura brachiata (Anthuridae), Duplorbis parasitic on, 95
Calicurgus annulatus, 369
Caligidae, 73
Caligus nanus, 74;
C. rapax, 74;
C. lacustris, 74
Callianassa, 167;
habitat, 198;
 C. subterranea, 167;
gut, 14
Callianassidae, 167
Callinectes, 191;
C. sapidus, 191
Calman, on classification of Crustacea, 112, 113
Calocalanus plumulosus, 58
Caloctenus, 418
Calommata, 391
Calymene, 225, 230, 235, 249;
C. senaria, 236;
C. tuberculata, 224
Calymenidae, 247
Calyptomera, 38, 51
Calyptopis, larva of Euphausia pellucida, 144
Cambaroides, distribution, 213
Cambarus, 157;
hermaphroditism, 103;
distribution, 213;
C. stygius, distribution, 213
Camerostome, 452
Campbell, 327
Camptocercus, 53;
C. macrurus, 48
Cancer, 191;
C. pagurus, 191
Cancerilla, 68;
C. tubulata, 68
Cancridae, 191
Candace, 60;
 C. pectinata, 60
Candacidae, 60
Candona, 107;
C. reptans, 107
Canestrini, 464
Canthocamptus, 62;
habitat, 206
Capitulum, of Cirripedia, 81;
of Acarina, 457, 468, 471
Caponia natalensis, 395
Caponiidae, 395
Caponina, 395
Caprella acutifrons, 140;
C. grandimana, 139
Caprellidae, 139
Carapace, of Phyllopoda, 19 f.;
of Cladocera, 38;
absence of, in Copepoda, 55;
of Malacostraca, 114
Carcinoplacidae, 195
Carrinoscorpius, 277;
C. rotundicauda, 277
Carcinus, 191;
C. maenas, 188, 191;
gut, 14;
respiration, 189, 190;
distribution, 198;
Portunion parasitic in, 135;
Sacculina parasitic on, 96
Cardisoma, 196;
distribution, 201
Caridea, 158, 163;
 metamorphosis, 161
Caridina, 163;
C. nilotica, distribution, 212
Carniola, caves of, 34
Carpenter, on segmentation of Arthropods, 6, 263;
on affinities of Trilobites, 242;
on Irish Pycnogons, 540
Caruncle, 470
Caspian Sea, Crustacea of, 215
Caspiocuma, 121
Catometopa, 193 f.;
habits, 194, 195
Catophragmus, 91
Caudal organs, 311
Caullery, on Liriopsidae, 132 n.
Causard, 332
Cavanna, 520
Cecrops, 74
Cenobita, 181;
relation to Birgus, 176
Cenobitidae, 181
Centropages hamatus, 203;
C. typicus, distribution, 203
Centropagidae, 58
Centropelma, 416
Centropleura, 247
Centrurinae, 306
Centrurus, 306
Cephalic shield, 223
Cepheus ocellatus, 467
Cerataspis, 162
Ceratolichas, 252
Ceratopyge, 247
Cercophonius, 308
Ceriodaphnia, 37, 39, 51
Ceroma, 429
Chactas, 308
Chactidae, 306, 307
Chaerilidae, 306, 307
Chaerilus, 307
Chaetolepas, 89
Chaetonymphon, 536;
C. hirtipes, 541;
C. hirtum, 509, 541;
C. macronyx, 506;
C. spinosissimum, 541, 542;
C. tenellum, 542
Chaetopelma, 389
Charontinae, 313
Chasmops, 249
Cheeks, of Trilobites, 223, 225
Cheese-mites, 466
Cheiracanthium, 397
Cheiruridae, 250
Cheirurus, 235, 251;
C. insignia, 250;
C. pleurexacanthus, 236
Chelicerae, of Xiphosura, 263 f.;
 of Eurypterida, 285;
of Scorpions, 303;
of Pedipalpi, 309;
of Spiders, 319;
of Palpigradi, 422;
of Solifugae, 426;
of Pseudoscorpions, 432;
of Podogona, 439;
of Phalangids, 443;
of Acarina, 458
Chelifer, 436, 437;
development, 435;
C. cancroides, 437;
C. cyrneus, 437;
C. ferum 437
Chelifera, 122
Cheliferidae, 436
Chelophores, of Pycnogons, 505
Chernes, 432, 436, 437, 438
Chernetes, 430
Chernetidea, 258, 430 f.
Cheyletinae, 473
Cheyletus, 458, 473
Chilaria, 260, 271, 287, 292
Chilobrachys, 390;
C. stridulans, 328, 329
Chilophoxus, 539
Chiltonia, 139;
distribution, 217
Chiridium, 432, 436, 437;
C. museorum, 437
Chirocephalus, 35;
 C. diaphanus, 20, 24, 25, 27, 29, 32, 33, 35
Chlorodinus, habitat, 198
Chlorodius, 191
Chondracanthidae, 72
Chondracanthus zei, 72
Choniostoma, 76
Choniostomatidae, 76
Chthonius, 436, 438
Chun, on phosphorescence and eyes, 150
Chydorus, 54
Cilunculus, 535
Circulatory (= vascular) system, of Crustacea, 11;
of Arachnids, 256;
of Limulus, 268 f.;
of Tardigrada, 482;
of Pentastomida, 491;
of Pycnogons, 516
Cirolana, 126
Cirripedia, 79 f.;
metamorphosis, 80;
anatomy, 83;
sex, 87, 105
Cladocera, 19, 37 f.;
carapace, 38;
dorsal organ, 39;
appendages, 40 f.;
alimentary canal, 42;
heart, 43;
reproduction, 43–50;
British genera, 51–54;
extra-European, 54;
pelagic, 207, 208
Claparède, 331, 462 n.
Clarke, J. M., on the eye of Calymene senaria, 229;
of Harpes, 231
Claus, on Copepoda, 55;
on Nebalia, 111;
on discovery of metamorphosis of Decapods, 153 n.;
on Pycnogonida, 527
Claw-tufts, 389
Clerck, 384, 408 n.
Clibanarius, 181
Clotenia conirostre, 541
Clubiona, 337, 368, 397;
C. compta, 397;
C. corticalis, 396, 397
Clubioninae, 397
Clypeus, 316
Clytemnestra, 61
Coelotes atropos, 416
Cole, 520, 524, 525, 528 n.
Colossendeis, 505, 532;
C. angusta, 542;
C. australis, 533;
C. gibbosa, 534;
C. gigas, 532;
C. gracilis, 505 n.;
C. proboscidea, 505, 508, 510, 533, 542
Colour, adaptation in, of Crustacea, 159
Colulus, 317, 319
Commensalism, of Hermit-crabs, 172;
of Pinnotheres, 195
Complemental males, of Cirripedes, 83, 86, 99, 106
Conchoderma, 88;
C. virgata, 88
Conocephalidae, 247
Conocoryphe, 231, 247;
C. sulzeri, 248
Conocoryphidae, 247
Conolichas, 252
Conothele, 388
Constantia (Macrohectopus), 138;
occurrence, 212
Cook, 425 n.
Copepoda, 55 f.;
fresh-water, 59, 62;
pelagic, 202;
life-cycle of fresh-water, 209
Copilia vitrea, 69, 70
Cordylochele, 506, 537;
C. longicollis, 507;
C. malleolata, 542
Corniger hilgendorfi, 535
Coronula diadema, 91
Corophiidae, 139
Corophium, 139
Corycaeidae, 69
Corystes, 188, 190;
habitat, 198;
C. cassivelaunus, respiration, 170, 189;
metamorphosis, 182, 183
Corystidae, 190
Cosmetidae, 449
Costa, da, 221
Coxal glands, 257;
of Limulus, 270;
of Scorpions, 306;
of Pedipalpi, 311;
of Spiders, 337
Coxopodite, of Trilobites, 237
Crab, Hermit-, 171–173;
River-, 214;
Robber-, 174;
Shore-, 188, 189, 198;
Edible, 188;
Spider-, 191;
Land-, 195;
enemies of, 192
Crab-spiders, 412 (= Thomisidae, q.v.)
Crangon, 164;
C. antarcticus, distribution, 200;
C. franciscorum, distribution, 200;
C. vulgaris, 158, 164;
distribution, 199
Crangonidae, 164;
distribution, 199
Crangonyx, 138
Crayfish, 154, 157;
distribution, 213, 215
Crevettina, 137
Cribellatae, 324, 385, 386 n.
Cribellum, 326, 354, 385, 386, 392, 398, 410
Croneberg, 460
Cruregens, 124;
C. fontanus, habitat, 210
Crustacea, organisation, 1 f.;
segmentation, 5;
appendages, 8 f.;
body-cavity and coelom, 11;
kidneys, 13;
alimentary canal, 14;
reproductive organs, 15;
respiratory organs, 16;
compound eyes, 146;
growth and sex in, 100;
metabolism, 104;
distribution, 197;
pelagic, 202, 207;
littoral, 197, 206;
abyssal, 204, 209;
fresh-water, 205;
subterranean and cave, 209
Crustacés aranéiformes, 501 n.
Cryphaeus, 249
Cryphoeca, 416
Cryptocellus, 439;
C. simonis, 439
Cryptocerus, 414
Cryptoniscidae, 130
Cryptoniscina, 129, 130
Cryptoniscus, larva of Epicarida, 129, 131, 132
Cryptophialus, 92;
C. minutus, 92, 93;
C. striatus, 93
Cryptostemma westermannii, 439
Cryptostemmatidae, 440
Cryptothele, 400
Ctenidae, 418
Cteninae, 418
Cteniza, 388;
C. ariana, 355
Ctenizinae, 388
Ctenocephalus, 247
Ctenophora, 412
Ctenopoda, 51
Ctenopyge, 232, 247
Ctenus, 418
Cucullus, 440
Cuma, 121
Cumacea, 114, 120;
of the Caspian, 215
Cumidae, 121
Cyamidae, 140
Cyamus ceti, 140
Cybaeinae, 415
Cybele, 251
Cyclaspis, 121
Cyclestheria, 37;
C. hislopi, 37
Cyclodorippe dromioides, eyes, 149
Cyclograpsus, 196;
distribution, 200
Cyclometopa, 188 f.;
respiration, 189, 190
Cyclopidae, 61, 62;
subterranean, 209
Cyclops, 62;
 C. fuscus, habitat, 207;
C. strenuus, habitat, 207, 208;
C. stygius, habitat, 210
Cyclosa conica, 409
Cyclosternum, 389
Cydrela, 399
Cymodoce, 126
Cymonomus, 188;
C. granulatus, 185;
eyes, 149, 186;
C. normani, 186;
C. quadratus, 186
Cymothoa, 126;
habitat, 211
Cymothoidae, 126
Cyphaspis, 251
Cyphophthalmi, 443, 444, 447
Cypridae, 107;
subterranean, 209
Cypridinidae, 108
Cypris, 107;
C. reptans, parthenogenesis, 108
Cypris larva, of Cirripedia, 80, 82;
of Sacculina, 97, 99
Cyrtauchenius, 388;
C. elongatus, funnel of, 356
Cythere dictyon, 108
Cytherellidae, 109
Cytheridae, 107
Dactylopisthes digiticeps, 405
Dactylopus tisboides, 62
Daesia, 429
Daesiinae, 429
Dajidae, 130
Dalmanites, 249;
D. imbricatulus, eye, 228;
D. limulurus, 250;
D. socialis, larvae, 240
Danalia curvata, 130, 131, 132
Daphnella, 51;
testes, 44
Daphnia, 37, 38, 39, 51;
ovary, 45, 48;
D. magna, 50;
D. obtusa, 51
Daphniidae, 51;
appendages, 40;
alimentary canal, 42;
reproduction, 48;
reactions, 50
Darwin, on Cirripedia, 80, 85, 86, 92, 94
Dasylobus, 450
Decapoda, 152 f.;
systematic position, 114;
alimentary canal, 14;
pelagic, 202;
subterranean, 210;
Rhizocephala parasitic on, 95, 101;
Bopyridae parasitic on, 133
Dechenella, 251
Decolopoda, 504, 529, 532;
 D. antarctica, 532;
D. australis, 531, 532
Decolopodidae, 531
Defective orb-webs, 349
Deiphon, 235, 251;
D. forbesi, 250
Delena, 414
Delobranchiata, 258, 259 f.
Demodex, 465;
D. folliculorum, 465
Demodicidae, 455, 465
Dendrogaster astericola, 94
Dermacentor, 469
Dermanyssinae, 471
Dermanyssus avium, 471
Dermaturus, 181;
D. hispidus, 178
Desis, 415
Deutovum, 462
Development, of Monstrillidae, 64;
of Cirripedia, 80;
of Rhizocephala, 96;
of Epicarida, 130;
of Stomatopoda, 142;
of Shrimps and Prawns, 159;
of Loricata, 165;
of Hermit-Crabs, 179;
of Brachyura, 181;
of Trilobites, 238 f.;
of Limulus, 275;
of Scorpio, 305;
of Pseudoscorpions, 434;
 of Mites, 462;
of Tardigrada, 483;
of Pentastomida, 493;
of Pycnogons, 520
Diaea, 412;
D. dorsata, 413
Diaphragm, of Solifugae, 427
Diaptomus, 59;
distribution, 208, 216;
D. caeruleus, habitat, 208;
D. castor, habitat, 206;
D. gracilis, habitat, 206
Diastylidae, 121
Diastylis, 121;
D. goodsiri, 121;
D. stygia, 120
Dichelaspis, 88
Dichelestiidae, 68;
classification, 63
Dichelestium, 68
Dick, 363
Dicranogmus, 252
Dicranolasma, 452
Dictyna, 398;
D. arundinacea, 399;
D. uncinata, 399
Dictynidae, 352, 353, 398
Digestive system, = alimentary canal, q.v.
Dikelocephalus, 247
Dimorphism, high and low;
in Decapoda, 103;
in Tanaids, 123
Dindymene, 251
Dinopinae, 410
Dinopis, 410
Dinorhax, 429
Diogenes, 181
Dionide, 245
Diphascon, 485;
D. alpinum, 487;
D. angustatum, 487;
D. bullatum, 487;
D. chilenense, 486, 487;
D. oculatum, 487;
D. scoticum, 487;
D. spitzbergense, 487
Diplocentrinae, 306, 307
Diplocentrus, 307
Diplocephalus bicephalus, 405
Diplostichous eyes, 301
Diplura, 390
Diplurinae, 390
Dipoena, 403
Discoarachne, 512, 535
Distribution, of Crustacea, 197 f.;
(stratigraphical) of Trilobites, 222
Doflein, on eyes of deep-sea Crustacea, 148, 150
Dohrn, 504, 513, 519
Doleschall, 365
Dolichopterus, 283, 291
Doliomelus, 415
Dolomedes fimbriatus, 416
Dolops, 78
Domed webs, 350
Donachochara, 406
Donnadieu, 457
Dorippe, 185, 188
Dorippidae, 188
Doropygus, 66;
D. pulex, 66
Dorsal organ, of Phyllopoda, 22;
of Cladocera, 39
Doublure, 232
Doyère, on Tardigrada, 481;
on their systematic position, 483
Doyeria, 485;
D. simplex, 480, 487
Drassidae, 324, 396
Drassinae, 396
Drassus, 397;
D. lapidosus, 396, 397
Drepanothrix, 53
Dromia, 184;
D. vulgaris, 184
Dromiacea, 183;
metamorphosis, 182;
relation to Macrura, 184;
habitat, 198
Dromidia, distribution, 200
Dromiidae, 184
Drymusa, 393
Dufour, 385
Dujardin, 464 n.;
on systematic position of Tardigrada, 483
Duplorbis, 95;
D. calathurae, 99
Dynomene, 184
Dynomenidae, 184
Dysdera, 394;
D. cambridgii, 394;
D. crocota, 395
Dysderidae, 317, 319, 336, 394
Dysderina, 394
Dysderinae, 394

Ebalia, 188
Echiniscoides, 485;
E. sigismundi, 477, 486
Echiniscus, 480, 485;
E. arctomys, 486;
E. gladiator, 486;
E. granulatus, 486;
E. islandicus, 486;
E. muscicola, 486;
E. mutabilis, 486;
E. oihonnae, 486;
E. quadrispinosus, 486;
E. reticulatus, 486;
E. spinulosus, 479;
E. spitzbergensis, 486;
E. testudo, 478;
E. wendti, 486
Echinoderms, Dendrogaster parasitic on, 94
Echinognathus, 283