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Photophysics and Nanophysics
in Therapeutics
Photophysics and
Nanophysics in Therapeutics

Edited by
Nilesh M. Mahajan
Dadasaheb Balpande College of Pharmacy, Rashtrasant Tukadoji Maharaj Nagpur University,
Nagpur, Maharashtra, India

Avneet Saini
Department of Biophysics, Panjab University, Chandigarh, India

Nishikant A. Raut
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University,
Nagpur, Maharashtra, India

Sanjay J. Dhoble
Department of Physics, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra,
India
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Contents

Contributors xv 2. Phototherapy for skin diseases

Renuka K. Mahajan, Dadasaheb M. Kokare,
Part I Nishikant A. Raut, Prakash R. Itankar
Phototherapeutics
2.1 Introduction 15
2.1.1 The epidermis 15
1. Phototherapy: A critical review
2.1.2 The hypodermis 17
Nilesh Rarokar, Shailendra Gurav, Dadasaheb 2.2 Major functions of the skin 17
M. Kokare, Vijay Kale, Nishikant A. Raut 2.3 Skin diseases and their etiology 18
2.4 Bacterial skin diseases 19
1.1 Introduction 3
2.5 Fungal skin diseases 20
1.2 Background 4
2.6 Viral skin diseases 20
1.2.1 Historical perspective of phototherapy 4
2.7 Tropical ulcers 20
1.2.2 Overview on various types of
2.8 HIV related skin diseases 20
phototherapies 5
2.9 Pigmentation disorders 21
1.3 Various light sources and methods of
2.10 Parasitic infections 21
phototherapy 7
2.11 Tumors and cancers 21
1.3.1 Fluorescent tubes 7
2.12 Trauma 21
1.3.2 Halogen spotlights 7
2.13 Skin tests 21
1.3.3 Fiberoptic blankets 7
2.14 Heliotherapy 21
1.3.4 Light-emitting diodes 7
2.15 Naturopathy modalities on inflammation
1.3.5 Filtered sunlight 7
and immunity 22
1.4 Applications and limitations of
2.16 Phototherapy for skin diseases 22
phototherapy 8
2.17 Methods 23
1.4.1 Application in neonatal jaundice 8
2.17.1 UVB radiations 23
1.4.2 Application for morphea, scleroderma,
2.17.2 UVA radiation 23
and other sclerosing skin conditions 8
2.17.3 PUVA 23
1.4.3 Application for cancer 8
2.17.4 Diseases and their treatment using
1.4.4 Limitations of home phototherapy
phototherapy 24
and sunlight 9
2.17.5 Limitations of phototherapy for skin
1.5 Recent developments and future scopes 9
diseases 25
1.5.1 The immunoregulatory effects of
2.17.6 Side effects of phototherapy 26
phototherapy: Possible pathways 9
2.17.7 Recent development and
1.5.2 Handheld phototherapy: Targeting
future scope 26
difficult-to-treat psoriasis in the office
2.18 Concluding remark 26
and at home 10
References 27
1.5.3 The excimer laser: A potential
new indication and a novel dosimetry
protocol 10 3. Phototherapy: The novel emerging
1.5.4 Phototherapy and biologic agents: treatment for cancer
Combination therapy for recalcitrant Sagar Trivedi, Nishant Awandekar, Milind Umekar,
psoriasis 11 Veena Belgamwar, Nishikant A. Raut
1.5.5 Future scope 11
References 11 3.1 Introduction 31

v
vi Contents

3.2 Photophysics and photochemistry 32 4.2 Basic concept of photodynamic therapy 52

3.2.1 Type I mechanism of photodynamic 4.2.1 Photosensitizers 52
reaction 32 4.3 Working mechanism 62
3.2.2 Type II mechanism of photodynamic 4.3.1 Mechanism of cell death following
reaction 33 photodynamic therapy 64
3.3 Photodynamic targets at the molecular 4.4 Advantages and disadvantages of
level 33 photodynamic therapy 65
3.3.1 Proteins 33 4.4.1 Apoptosis in photodynamic therapy 65
3.3.2 Photodynamic therapy-induced 4.4.2 Immunological effects of
lipid peroxidation 34 photodynamic therapy 67
3.3.3 Photosensitized modification of 4.4.3 Biological effects of photodynamic
nucleic acids 34 therapy 69
3.4 Light source 35 4.4.4 Summarizing the advantages
3.4.1 Near infrared (NIR) light 35 and disadvantages of photodynamic
3.4.2 X-ray 36 therapy 71
3.4.3 Interstitial light 37 4.5 Essential wavelength region in
3.4.4 Internal light 37 photodynamic therapy 72
3.5 Changes in cell signaling after photodynamic 4.6 Recent developments in photodynamic
therapy 37 therapy 74
3.5.1 Calcium 37 4.6.1 Metal-organic frameworks 74
3.5.2 Lipid metabolism 38 4.6.2 Photoactive materials for wavelength
3.5.3 Tyrosine kinases 38 response 75
3.5.4 Transcription factors 39 4.6.3 Photodynamic therapy and hypoxia-
3.5.5 Cellular adhesion 39 controlled nanomedicine 76
3.5.6 Cytokines 39 4.7 Future scopes and perspectives 77
3.5.7 Stress response 39 References 79
3.5.8 Hypoxia and angiogenesis 39
3.6 Method of excitation for photosensitizing
5. Photodynamic therapy for
agents 40
cancer treatment
3.6.1 Intermolecular chemically induced
electronic excitation 40 Sagar Trivedi, Anita Paunikar, Nishikant Raut,
3.6.2 Resonance energy transfer excitation 40 Veena Belgamwar
3.6.3 Two-stage photosensitizer excitation/
5.1 Introduction 89
excitation by radiation energy transfer
5.2 Background of photodynamic therapy 90
intermediary 41
5.2.1 Origin of photodynamic therapy 90
3.6.4 Cherenkov radiation energy transfer 41
5.2.2 Mechanism of photodynamic therapy 90
3.7 Photodynamic therapy modifications 42
5.2.3 Working principle of photodynamic
3.7.1 Nanotechnology on photodynamic
therapy 90
therapy 42
5.2.4 Mechanism of photodynamic therapy
3.7.2 Application of liposomes and
in treatment of cancer 92
lipoproteins 42
5.3 Novel strategies in photodynamic therapy 93
3.7.3 Photodynamic therapy supported by
5.3.1 Metronomic photodynamic therapy 93
electroporation 43
5.3.2 Photodynamic therapy molecular
3.8 Conclusion 43
beacons 93
Acknowledgment 43
5.3.3 Nanotechnology in photodynamic
Statement of informed consent 43
therapy 93
Conflict of interest 43
5.4 Role of photosensitizing agents in
References 43
photodynamic therapy 94
5.5 Application of photodynamic therapy in
4. Fundamentals of photodynamic therapy treatment of various cancers 102
Mrunal M. Yawalkar, Samvit Menon, Hendrik C. Swart, 5.5.1 Skin tumors 103
Sanjay J. Dhoble 5.5.2 Head and neck tumors 103
5.5.3 Digestive system tumors 103
4.1 Introduction 51
 Contents vii

5.5.4 Urinary system tumors 103 7.2.3 Types of external beam radiation
5.5.5 Brain tumors 104 therapy 141
5.5.6 Nonsmall cell lung cancer and 7.2.4 General indications for the
mesothelioma 105 radiotherapy 143
5.6 Recent developments, future scope, and 7.2.5 Intent of radiotherapy treatment 143
challenges 105 7.2.6 Types of cancer treated using
5.7 Conclusion 106 radiotherapy 144
Acknowledgment 106 7.2.7 The role of radiotherapy in cancer
References 106 control 144
7.3 Development of radiation physics 145
6. Photodiagnostic techniques 7.3.1 History 145
7.3.2 External radiotherapy 146
Anurag Luharia, Gaurav Mishra, Nilesh Haran,
7.3.3 Clinical radiation generators 147
Sanjay J. Dhoble
7.3.4 Dose planning 148
6.1 Introduction 115 7.4 Recent advancement in radiotherapy 149
6.1.1 Ionizing radiations 115 7.4.1 Instigation 149
6.2 Fundamentals of light used in diagnostic 7.4.2 Radiotherapy principle and mechanism 149
techniques 116 7.4.3 Technology development 150
6.2.1 X-ray production 118 7.4.4 Image-guided radiotherapy treatment 151
6.2.2 X-ray beam intensity 119 7.4.5 Adaptive radiotherapy 152
6.2.3 Target material 120 7.4.6 Stereotactic radiosurgery and
6.2.4 Voltage applied 120 radiotherapy 152
6.2.5 X-ray tube current 120 7.4.7 Particle therapy 152
6.3 Various photo diagnostic techniques 120 7.4.8 Summary 153
6.3.1 Plain radiography and digital 7.5 Radiosurgery for noncancerous tumor
radiography 120 and diseases 153
6.3.2 Computed tomography 121 7.5.1 Introduction 153
6.3.3 Fluoroscopy 123 7.5.2 History 153
6.3.4 Digital subtraction angiography 123 7.5.3 Treatment 154
6.3.5 Digital radiography and picture 7.5.4 Systems overview 154
archival and communication system 124 7.6 Summary and conclusion 157
6.3.6 Dual energy X-ray absorptiometry 124 References 157
6.3.7 Dual energy computed tomography 124
6.3.8 Orthopantomography 124 8. Physics in treatment of cancer radiotherapy
6.4 Physics of photodiagnostic techniques 125
Ravindra B. Shende, Sanjay J. Dhoble
6.4.1 Interaction of radiation with matter 125
6.4.2 Importance of interaction in tissue 127 8.1 Introduction 163
6.4.3 Picture archiving and communication 8.1.1 Physics of radiotherapy 163
system 130 8.1.2 Structure of matter 163
6.5 Opportunities, challenges, and limitations 8.1.3 Atom 163
of photodiagnostic techniques 134 8.1.4 Nucleus 164
References 135 8.1.5 Types of radiation 164
8.1.6 X-rays 165
7. The role of physics in modern radiotherapy: 8.1.7 Gamma rays 166
Current advances and developments 8.1.8 Particulate radiation 166
8.1.9 Interaction of radiation with matter 166
Anurag Luharia, Gaurav Mishra, D. Saroj, V. Sonwani, 8.1.10 Interaction of photon beam
Sanjay J. Dhoble (X-rays or γ rays) 166
7.1 Introduction 139 8.1.11 Coherent scattering 169
7.2 Role of radiotherapy in cancer treatment 140 8.1.12 Photoelectric effect 169
7.2.1 What is radiotherapy and how 8.1.13 Compton effects 170
it works? 140 8.1.14 Pair production 170
7.2.2 Types of radiotherapy 141 8.1.15 Photodisintegration 171
viii Contents

8.1.16 Interaction of charged particle 171 8.5.4 Particle fluence 188

8.1.17 Electron and electron interaction 172 8.5.5 Energy fluence 188
8.1.18 Electron and nucleus interaction 172 8.5.6 Exposure 188
8.1.19 Interaction of heavy charged particle 172 8.5.7 Kerma 188
8.1.20 Biological effect of radiation 173 8.5.8 Absorbed dose 189
8.1.21 Linear energy transfer 174 8.5.9 Methods of radiation dosimetry and
8.1.22 Relative biological effectiveness 174 dosimeters in radiation therapy 189
8.2 Principle of radiotherapy 175 8.5.10 Ionization chamber dosimetry 189
8.2.1 Radiotherapy facility 175 8.5.11 Film dosimetry 189
8.3 Traditional facility in treatment of 8.5.12 Luminescence dosimetry 190
radiotherapy 175 8.5.13 Thermoluminescence 190
8.3.1 Superficial therapy 175 8.5.14 Optically stimulated luminescence 191
8.3.2 Orthovoltage therapy or deep 8.5.15 Semiconductor dosimetry 191
therapy 175 8.5.16 Physical and clinical dosimetry in
8.3.3 Supervoltage therapy machines 176 radiotherapy 191
8.3.4 Cobalt-60 teletherapy unit 176 8.5.17 Physical dosimetry 191
8.3.5 Betatron and microtron 176 8.5.18 Clinical dosimetry 192
8.3.6 Advance facility in treatment of References 192
radiotherapy 177
8.3.7 Linear accelerator (Linac) 177 9. Role of carbon ion beam radiotherapy
8.3.8 Tomotherapy 178 for cancer treatment
8.3.9 CyberKnife 178
8.3.10 Proton and light ion therapy 178 Vibha Chopra, Nirupama S. Dhoble, Balkrishna
8.3.11 Cyclotron 178 Vengadaesvaran, Sanjay J. Dhoble
8.3.12 Synchrotron and synchrocyclotron 179 9.1 Introduction 193
8.3.13 Add-on facility in treatment of 9.2 Radiation therapy for the treatment
radiotherapy 179 of cancer 193
8.3.14 Conventional simulator 179 9.2.1 Gamma ray therapy 194
8.3.15 CT simulator 180 9.2.2 Proton therapy 194
8.3.16 Commissioning of radiotherapy 9.2.3 Ion beam therapy 194
facility and quality assurance 180 9.3 Role of carbon ion beam therapy 195
8.3.17 Technique of radiotherapy 180 9.4 Development of TLD materials for carbon
8.3.18 External beam radiation therapy 181 ion beam therapy 195
8.3.19 Conventional treatment techniques 9.4.1 Lithium-based phosphors 195
in EBRT 181 9.4.2 Calcium-based phosphors 198
8.3.20 Three-dimensional conformal 9.4.3 Some other phosphors 200
radiation therapy 181 9.5 Conclusion 202
8.3.21 Intensity modulated radiation References 202
therapy 182
8.3.22 Rotational therapy or volumetric
Part II
modulated arc therapy (VMAT) 184
8.3.23 Stereotactic radiosurgery and Nanotherapeutics
stereotactic radiotherapy 184
8.3.24 Image-guided radiotherapy 184 10. Nanomaterials physics: A critical review
8.3.25 Internal beam radiation therapy Khushwant S. Yadav, Sheeba Jacob, Anil M. Pethe
or brachytherapy 185
8.3.26 Process and treatment of radiotherapy 186 10.1 Introduction 207
8.4 Patient preparation and simulation 187 10.2 Fundamental concepts of nanomaterial
8.5 Target delineation and treatment planning 187 physics 208
8.5.1 Treatment verification and treatment 10.2.1 Structure sensitive and structure
delivery 187 insensitive properties 209
8.5.2 Dosimetry in radiation therapy 188 10.2.2 Phases and their distribution 209
8.5.3 Activity 188 10.2.3 Defects in body nanomaterials 209
 Contents ix

10.3 Properties of materials 210 11.7.3 CRISPR/Cas 9-associated brain

10.3.1 Factors affecting properties tumor therapy 232
of a material 210 11.7.4 Nose to brain drug delivery 232
10.4 Rationale of nanoparticle physics 11.8 Clinical translation of nanotherapeutic
with diverse functions involving systems for brain cancers: From bench
nanomaterials 211 to bedside 232
10.5 Self-assembly of nanostructures 212 11.9 Conclusion and future prospects 232
10.6 Clinical applications of nanomaterials References 233
physics 212
10.6.1 Applications of nanomaterials 12. Progress in nanotechnology-based
physics in cancer 212 targeted cancer treatment
10.7 Conclusion: Nanotechnology, physics,
and clinical outcome 213 Shagufta Khan, Vaishali Kilor, Dilesh Singhavi,
Acknowledgments 214 Kundan Patil
References 214 12.1 Introduction 239
12.2 Tumor microenvironment: Comparison
11. Nanotherapeutic systems for drug with normal cells 239
delivery to brain tumors 12.2.1 Angiogenesis and endothelial
permeability in cancer 240
Keshav S. Moharir, Vinita Kale, Mallesh Kurakula
12.2.2 Microenvironment pH 240
11.1 Introduction 217 12.2.3 Microenvironment temperature 240
11.2 An overview of brain tumors 218 12.3 Nanotechnology-based diagnosis
11.2.1 Malignant brain tumors 218 of cancer 240
11.2.2 Benign brain tumors 218 12.4 Nanotechnology-based drug targeting
11.3 Barriers and challenges in the treatment strategies in cancer 241
of brain cancer 219 12.4.1 Passive targeting 241
11.3.1 BBB as a main hurdle 219 12.4.2 Active targeting 242
11.3.2 Chemoresistance and efflux 220 12.4.3 Physical targeting 245
11.3.3 Tumor microenvironment (TME) 12.5 Progress in nanotherapeutics for
dynamics and lack of brain tumor treating breast and lung cancer 245
classification based on genetics 220 12.5.1 Breast cancer 245
11.3.4 Resistance due to cancer stem 12.5.2 Lung cancer 246
cells (CSCs) of gliomas and GBM 220 12.6 Future of nanotechnology in cancer
11.3.5 Lack of proper brain cancer treatment 247
mimicking models 221 12.7 Conclusion 248
11.4 Conventional vs nanomedicines in drug References 248
delivery for brain cancers 221
11.5 Approaches and mechanisms of 13. Nanotherapeutics for colon cancer
nanocarriers for chemotherapeutic
Nilesh M. Mahajan, Alap Chaudhari, Sachin More,
drug delivery to brain tumors 222
Purushottam Gangane
11.5.1 Passive targeting 222
11.5.2 Active targeting 222 13.1 Introduction 251
11.5.3 Stimuli responsive nanocarriers 13.1.1 Anatomy 251
systems 224 13.1.2 Pathogenesis and molecular
11.6 Types of nanotherapeutic platforms pathways for CRC 252
for drug delivery to treat brain cancer 225 13.1.3 Risk factors 253
11.6.1 Inorganic (metallic) nanoparticles 225 13.1.4 Stages of CRC 254
11.6.2 Lipid-based and polymeric 13.1.5 Signs and symptoms 254
nanoparticles 228 13.2 Diagnosis 254
11.7 Novel therapies to treat brain cancers 229 13.2.1 Endoscopy 255
11.7.1 Artificial intelligence (AI)-enabled 13.2.2 Imaging 255
nanocarriers for oncotherapy 229 13.2.3 Laboratory 255
11.7.2 Gene-based nanotherapy 231 13.2.4 Pathology 255
x Contents

13.3 Current therapies 256 15. Role of nanocarriers for the effective
13.3.1 Conventional treatment strategies 256 delivery of anti-HIV drugs
13.3.2 Targeted therapy 259
13.3.3 Targeted therapies using Rohini Kharwade, Nilesh M. Mahajan
nanocarriers 260 15.1 Introduction 291
13.4 Nanodrug delivery in cancer therapy 261 15.1.1 HIV life cycle and pathogenesis 291
13.4.1 Polymers used in formulations 15.1.2 Pathophysiology 293
of NPs 261 15.2 Conventional antiretroviral therapy 293
13.5 Polymeric nanoparticles (PNPs) 262 15.3 Types of nanocarriers for antiretroviral
13.5.1 Lipid-based nanoparticles 263 drugs delivery 295
13.5.2 Superparamagnetic iron oxide 15.3.1 Pure drug nanoparticles 296
nanoparticles (SPIONs) 263 15.3.2 Polymeric nanoparticles 297
13.5.3 Gold nanoparticles (AuNPs) 263 15.3.3 Dendrimers 299
13.5.4 Enteric-coated nanoparticles 264 15.3.4 Polymeric micelles 301
13.6 Conclusion 264 15.3.5 Liposomes 302
References 265 15.3.6 Solid lipid nanoparticles 303
15.4 Nanaotechnological approaches for
14. Nanoparticles for the targeted drug antiretroviral therapy 304
delivery in lung cancer 15.4.1 Immunotherapy for antiretroviral 304
15.4.2 Gene therapy 305
Veena Belgamwar, Vidyadevi Bhoyar, Sagar Trivedi,
15.4.3 Vaccines 305
Miral Patel
15.5 Nanotechnology for improving latency
14.1 Introduction 269 reservoir 306
14.1.1 Stages of LC 269 15.6 Conclusion 307
14.1.2 Current treatment strategies on LC 270 References 307
14.1.3 Novel strategies for LC treatment
by pulmonary route of
16. Drug delivery systems for rheumatoid
administration 272
14.1.4 Pulmonary physiology and drug
arthritis treatment
absorption 273 Mangesh Bhalekar, Sachin Dubey
14.1.5 Role of nanoparticulate technology
16.1 Introduction 311
in the diagnosis and treatment
16.1.1 Stages of rheumatoid arthritis 311
of LC 273
16.1.2 Causes of RA 311
14.1.6 Nanocarriers used for the diagnosis
16.1.3 Symptoms of RA 312
of lung diseases 274
16.1.4 Pathology of rheumatoid arthritis 312
14.2 Nanocarriers in LC treatment 275
16.2 Management of rheumatoid arthritis 314
14.2.1 Solid–lipid nanocarriers 275
16.3 Targeted delivery strategies to inflamed
14.2.2 Polymeric nanocarriers 276
synovium 314
14.2.3 Nanoemulsions as potential
16.4 Passive targeting 315
carrier in LC 276
16.4.1 Enhanced permeability and
14.2.4 Metal-based NPs 277
retention (EPR) effect 315
14.2.5 Dendrimers-based drug delivery 277
16.4.2 Hypoxia and acidosis 315
14.2.6 Target-mediated targeted therapy 279
16.4.3 Stimuli responsive drug delivery 316
14.2.7 Quantum dots (QDs) as a drug
16.4.4 Angiogenesis 316
delivery system 279
16.5 Active targeting 316
14.2.8 Bio-NPs for LC 280
16.6 Factors for the selection of delivery
14.2.9 Hydrogel-based drug delivery
system 316
for pulmonary cancer 281
16.6.1 Carrier type 316
14.2.10 Inhalation-based nanomedicine
16.6.2 Particle size 316
for pulmonary cancer 281
16.6.3 Shape 317
14.3 Marketed formulation 282
16.6.4 Surface modifications 317
14.4 Toxicity issues of inhaled NPS 283
16.6.5 Prolonged circulation time 317
14.5 Conclusion 284
16.6.6 Strategies for active targeting 317
References 285
 Contents xi

16.7 Drug delivery vehicles for rheumatoid 17.6.3 Magnetic nanoparticles 336
arthritis 318 17.6.4 Quantum dots 337
16.7.1 Liposomes 318 17.7 Techniques enabling microorganism
16.7.2 Dendrimers 319 detection 337
16.7.3 Nanoparticles 319 17.7.1 Colorimetric detection 337
16.7.4 Polymeric micro- and 17.7.2 Fluorescence-based detection 338
nanoparticles 320 17.7.3 Microscopic techniques 338
16.7.5 Macromolecules and the 17.7.4 Spectroscopic detection 338
enhanced permeability and 17.8 Recent advances in on-site detection
retention effect 320 of microorganisms using peptide
16.7.6 Arthritis-specific antigens 321 functionalized nanosensors 339
16.7.7 The complement system 321 17.8.1 Bacteria detection 339
16.7.8 Specific surface receptors 321 17.8.2 Detection of fungal spores 339
16.7.9 Monoclonal antibodies 322 17.8.3 Virus detection 340
16.7.10 mAbs targeted against B cells 322 17.9 Conclusion and future perspectives 341
16.7.11 mAbs directed against References 341
IL-6function 322
16.7.12 mAb directed against 18. Theranostic nanoagents: Future of
NFKB ligand 323 personalized nanomedicine
16.8 Conclusion 323
References 323 Vidya Sabale, Shraddha Dubey, Prafulla Sabale
18.1 Introduction 349
17. Peptide functionalized nanomaterials 18.1.1 Theranostics 349
as microbial sensors 18.1.2 Nanoagents 349
18.1.3 Nanotheranostics 349
Shubhi Joshi, Sheetal Sharma, Gaurav Verma,
18.2 Recent approaches versus theranostic
Avneet Saini
nanoagents 350
17.1 Introduction 327 18.2.1 Contemporary treatment methods
17.2 Conventional techniques for and their drawbacks 350
microorganism detection 328 18.3 Nanotheranostics and neurological
17.2.1 Pure culture-based protocols 328 disorders 350
17.2.2 Immunological techniques 328 18.3.1 Blood–brain barrier 350
17.2.3 Nucleic acid-based assays 329 18.3.2 Theranostic nanoparticles
17.3 Principle behind using biosensors for employed in neurology 351
microorganism detection 330 18.3.3 Theranostic applications of
17.4 Commonly used biosensing recognition nanosystems in neurological
elements 331 disorders 355
17.4.1 Antibodies as biosensing 18.4 Nanotheranostics and rheumatoid
recognition elements 331 arthritis 360
17.4.2 Aptamers as biosensing 18.4.1 Rheumatoid arthritis (RA) 360
recognition elements 332 18.4.2 Current treatments and their
17.4.3 Bacteriophages as biosensing drawbacks 360
recognition elements 332 18.4.3 Nanotheranostic approach for
17.4.4 Carbohydrates as biosensing rheumatoid arthritis 361
recognition elements 332 18.5 Nanoparticle-based theranostic agents 363
17.4.5 Peptides as biosensing 18.5.1 Iron oxide nanoparticle-based
recognition elements 333 theranostic agents 363
17.5 Advantages and challenges of using 18.5.2 Quantum dot-based theranostic
peptide-based detection of agents 365
microorganisms 335 18.5.3 Gold nanoparticle-based
17.6 Properties of nanomaterials making theranostic agents 366
them suitable for construction of 18.5.4 Carbon nanotube-based
microbial sensors 335 theranostic agents 367
17.6.1 Carbon-based nanoparticles 335 18.5.5 Silica nanoparticle-based
17.6.2 Metallic nanoparticles 336 theranostic agents 368
xii Contents

18.6 Theranostic nanoagents: future of 20.1.4 Characteristics features of ideal

nanomedicine 369 targeting moieties 421
18.7 Conclusion 369 20.1.5 The potential of nanocarriers
References 370 as drug delivery systems 421
20.1.6 Nanoparticle properties 421
19. Improving the functionality of a 20.1.7 Cancer therapy: Selective targeting
nanomaterial by biological probes of tissues by nanotechnology 421
20.2 Nanodrug carriers 422
Panchali Barman, Shweta Sharma, Avneet Saini 20.2.1 Classification of nanoparticles
19.1 Introduction to nanomaterials 379 as drug carriers 422
19.2 Classifications of nanoparticles 380 20.2.2 Micelles 423
19.2.1 Metallic nanoparticles 380 20.2.3 Solid-lipid nanoparticles (SLNs) 423
19.2.2 Semiconductor quantum dots 383 20.2.4 Cubosomes 423
19.2.3 Metal oxide nanoparticles 384 20.2.5 Drug-polymer conjugates 424
19.2.4 Organic nanoparticles 385 20.2.6 Antibody-drug conjugates 424
19.2.5 Upconversion nanoparticles 387 20.2.7 Inorganic nanoparticles 425
19.3 Common conjugation approaches 20.2.8 Carbon nanotubes (CNTs) 425
for biomolecule functionalized 20.2.9 Gold nanoparticles (GNPs) 426
nanomaterials 389 20.2.10 Porous silicon particles (PSiPs) 426
19.3.1 Conjugation approaches 389 20.2.11 Quantum dots (QDs) 426
19.3.2 Functionalization of nanoparticles 391 20.2.12 Iron oxide nanoparticles (IONPs) 427
19.4 Basic chemistries behind conjugation 20.2.13 IONPs 427
approaches 397 References 428
19.4.1 Functional groups and
conjugation reactions 397 21. Photo-triggered theranostics
19.4.2 Polyhistidine–nitrilotriacetic acid nanomaterials: Development and
chelation 398 challenges in cancer treatment
19.4.3 Biotin–avidin chemistry 399
Neha S. Raut, Divya Zambre, Milind J. Umekar,
19.5 Applications 400
Sanjay J. Dhoble
19.5.1 Detection of DNA, protein,
and metal ions 400 21.1 Introduction of nanomaterials in
19.5.2 Detection of human pathogens 401 phototherapeutics 431
19.5.3 Enhancement of antibacterial 21.2 Types of nanomaterials 432
and anti-inflammatory activity 402 21.2.1 Magnetic nanoparticles 432
19.5.4 Theranostics 403 21.2.2 Properties and materials for
19.6 Conclusion and future perspective 404 preparation of photo-based
References 405 nanomaterials 433
21.2.3 Gold-based nanoparticles 433
20. Nanostructures for the efficient oral 21.2.4 Carbon nanotubes 433
delivery of chemotherapeutic agents 21.3 Polymeric nanocarriers for photosensitizer/
dye encapsulation 434
Ravindra Satpute, Nilesh Rarokar, Sunil Menghani,
21.4 Nanoconstructs for photodynamic
Anjali Ganjare, Vivek S. Dave, Nishikant A. Raut,
therapy 434
Pramod B. Khedekar
21.5 Photo-triggered theranostic
20.1 Introduction 419 nanocarriers 435
20.1.1 Limitations of conventional 21.6 Approaches to measure drug release
chemotherapy 420 through theranostic nanomedicine 436
20.1.2 Edges of nanoparticles over 21.6.1 Silicon photonic crystals
the other delivery system 420 with pores 436
20.1.3 Components of nanoparticles 21.6.2 Fluorescent nanoparticles 437
as a targeting system 420 21.6.3 Upconversion nanoparticles 437
21.6.4 Radioluminescent nanoparticles 437
 Contents xiii

21.7 Magnetic resonance imaging for 22.1.3 Various methods of characterization

monitoring release of drug 437 of nanocrystals formulations 444
21.8 Photo-triggered theranostics nanomaterials: 22.2 Production methods and technology
Principle and applications 438 of nanocrystals 445
21.8.1 Applications of photo-triggered 22.2.1 Top down technology 445
theranostics nanomaterials in 22.2.2 Bottom up technology 446
cancer treatments 438 22.2.3 Top down and bottom up
21.8.2 Therapeutic applications of photo- technology 446
based theranostic nanoparticles 438 22.2.4 Spray drying 447
21.9 Opportunities and limitations of 22.3 Advantages and Disadvantages of
nanomaterials 439 nanocrystals 448
21.10 Preclinical challenges 439 22.3.1 Potential advantages and
21.11 Future aspects of nanomaterials in the disadvantages of nanocrystals 448
therapeutics 439 22.3.2 Disadvantages of nanocrystals 448
References 440 22.4 Pharmaceutical Nanocrystals of API 448
22.4.1 Case studies of drug loaded
22. Nanocrystals in the drug delivery system in the nanocrystals 448
22.4.2 Application of nanocrystals-
Raju Ramesh Thenge, Amar Patel, Gautam Mehetre
loaded carrier 449
22.1 Introduction to nanocrystals and 22.5 Conclusion 452
nanosuspension 443 References 452
22.1.1 Properties of nanocrystals 443
22.1.2 Nanocrystals and bioavailability 444 Index 455
Contributors
Nishant Awandekar Smt. Kishoritai Bhoyar College of
Pharmacy, Kamptee, Nagpur, India
Panchali Barman Institute of Forensic Science and
Criminology (UIEAST), Panjab University, Chandigarh,
India
Veena Belgamwar Department of Pharmaceutical Sci-
ences, Rashtrasant Tukadoji Maharaj Nagpur University,
Nagpur, Maharashtra, India
Mangesh Bhalekar Department of Pharmaceutics,
AISSMS College of Pharmacy, Pune, India
Vidyadevi Bhoyar University Department of Pharma-
ceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur
University, Nagpur, Maharashtra, India
Alap Chaudhari Formulation R&D, Teva Pharmaceuti-
cals, Weston, FL, USA
Vibha Chopra P.G. Department of Physics & Electron-
ics, DAV College, Amritsar, Punjab, India
Vivek S. Dave Department of Pharmaceutical Sciences,
St. John Fisher College, Wegmans School of Pharmacy,
Rochester, NY, USA
Nirupama S. Dhoble Deaprtment of Chemistry, Sevadal
Mahila Mahavidhyalaya, Nagpur, Maharashtra, India
Sanjay J. Dhoble Department of Physics, Rashtrasant
Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra,
India
Sachin Dubey Drug Product and Analytical Devel-
opment, Ichnos Sciences SA, La Chaux-de-Fonds,
Switzerland
Shraddha Dubey Inselpital University of Bern, Bern,
Switzerland
Purushottam Gangane Dept of Pharmaceutics, Dada-
saheb Balpande College of Pharmacy, Besa, Nagpur, MS,
India
Anjali Ganjare Department of Pharmaceutical Sciences,
Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur,
Maharashtra, India
Shailendra Gurav Department of Pharmacognosy,
Goa College of Pharmacy, Goa University, Panaji, Goa,
India
Nilesh Haran Department of Radiology HCG-NCHRI
Cancer Centre, Near Automotive Square, Nagpur, Maha-
rashtra, India
Prakash R. Itankar Department of Pharmaceutical Sci-
ences, Rashtrasant Tukadoji Maharaj Nagpur University,
Nagpur, Maharashtra, India
Sheeba Jacob Virginia Commonwealth University, Rich-
mond, VA, USA
Shubhi Joshi Energy Research Centre, Panjab Univer-
sity, Chandigarh, India
Vijay Kale College of Pharmacy, Roseman University of
Health Sciences, South Jordan, UT, United States
Vinita Kale Pharmaceutics Deptt., Gurunanak College of
Pharmacy, Nagpur, Maharashtra, India
Shagufta Khan Department of Pharmaceutics, Insti-
tute of Pharmaceutical Education and Research, Borgaon
(Meghe) Wardha, Maharashtra, India
Rohini Kharwade Dadasaheb Balpande College of Phar-
macy, Rashtrasant Tukadoji Maharaj Nagpur University,
Nagpur, Maharashtra, India
Pramod B. Khedekar Department of Pharmaceutical
Sciences, Rashtrasant Tukadoji Maharaj Nagpur University,
Nagpur, Maharashtra, India
Vaishali Kilor Department of Pharmaceutics, Gurunanak
College of Pharmacy, Nagpur, Maharashtra, India
Dadasaheb M. Kokare Department of Pharmaceutical
Sciences, Rashtrasant Tukadoji Maharaj Nagpur University,
Nagpur, Maharashtra, India
Mallesh Kurakula Product Development, CURE Phar-
maceutical, Oxnard, CA, USA
Anurag Luharia Department of Radiology, Datta Meghe
Institute of Medical Science (Deemed to be University),
Sawangi, Wardha, Maharashtra, India
Renuka K. Mahajan Department of Pharmaceutical Sci-
ences, Rashtrasant Tukadoji Maharaj Nagpur University,
Nagpur, Maharashtra, India
Nilesh M. Mahajan Dadasaheb Balpande College of
Pharmacy, Rashtrasant Tukadoji Maharaj Nagpur Univer-
sity, Nagpur, Maharashtra, India
xv
xvi Contributors
Gautam Mehetre Dr. Rajendra Gode College of
Pharmacy, Malkapur, Buldana, MS, India
Sunil Menghani Department of Pharmaceutical Scienc-
es, Rashtrasant Tukadoji Maharaj Nagpur University, Nag-
pur, Maharashtra, India
Samvit Menon Department of Physics, University of the
Free State, Bloemfontein, South Africa
Gaurav Mishra Department of Radiology, Datta Meghe
Institute of Medical Science (Deemed to be University),
Sawangi, Wardha, Maharashtra, India
Keshav S. Moharir Pharmaceutics Deptt., Gurunanak
College of Pharmacy, Nagpur, Maharashtra, India
Sachin More Dept of Pharmacology, Dadasaheb Bal-
pande College of Pharmacy, Besa, Nagpur, MS, India
Amar Patel Bristol Myers Squibb, New Jersey, USA
Miral Patel Department of Pharmaceutical Sciences, Ar-
nold and Marie Schwartz College of Pharmacy and Health
Science, Long Island University, Brooklyn Campus, NY;
Office of Pharmaceutical Quality, Center for Drug Evalu-
ation and Research, Food and Drug Administration, Silver
Spring, MD, USA
Kundan Patil Department of Pharmaceutics, Govern-
ment College of Pharmacy, Amrawati, Maharashtra, India
Anita Paunikar Department of Pharmaceutical Sciences,
Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur,
Maharashtra, India
Anil M. Pethe Datta Meghe College of Pharmacy, Datta
Meghe Institute of Medical sciences, (Deemed-to-be) Uni-
versity, Sawangi (Meghe), Wardha, India
Nilesh Rarokar Department of Pharmaceutical Sciences,
Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur,
Maharashtra, India
Nishikant A. Raut Department of Pharmaceutical Sci-
ences, Rashtrasant Tukadoji Maharaj Nagpur University,
Nagpur, Maharashtra, India
Neha S. Raut Department of Pharmaceutical Chemis-
try, Smt. Kishoritai Bhoyar College of Pharmacy, Kamp-
tee, India
Vidya Sabale Dadasaheb Balpande College of Pharmacy,
Besa, Nagpur, Maharashtra, India
Prafulla Sabale Department of Pharmaceutical Sciences,
Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur,
Maharashtra, India
Avneet Saini Department of Biophysics, Panjab Univer-
sity, Chandigarh, India
D. Saroj Department of Radiotherapy, Allexis Hospital,
Mankapur, Nagpur, India
Ravindra Satpute Toxicology Laboratory, Defense R &
D Establishment, Nagpur, Maharashtra, India
Sheetal Sharma Department of Biophysics, Panjab Uni-
versity, Chandigarh, India
Shweta Sharma Institute of Forensic Science and
Criminology (UIEAST), Panjab University, Chandigarh,
India
Ravindra B. Shende Department of Radiation oncol-
ogy, Balco Medical Centre, New Raipur, Chhattisgarh,
India
Dilesh Singhavi Department of Pharmaceutics, Insti-
tute of Pharmaceutical Education and Research, Borgaon
(Meghe) Wardha, Maharashtra, India
V. Sonwani HCG NCHRI Cancer Center, Nagpur, India
Hendrik C. Swart Department of Physics, University of
the Free State, Bloemfontein, South Africa
Raju Ramesh Thenge Dr. Rajendra Gode College of
Pharmacy, Malkapur, Buldana, MS, India
Sagar Trivedi Department of Pharmaceutical Sciences,
Rashtrasant Tukadoji Maharaj Nagpur University, Nag-
pur, Maharashtra, India
Milind J. Umekar Department of Pharmaceutics, Smt.
Kishoritai Bhoyar College of Pharmacy, Kamptee, India
Balkrishna Vengadaesvaran Higher Institution Centre
of Excellence (HICoE), UM Power Energy Dedicated Ad-
vanced Centre (UMPEDAC), Level 4, Wisma R&D Univer-
sity of Malaya, Kuala Lumpur, Malaysia
Gaurav Verma Dr. S.S. Bhatnagar University Institute
of Chemical Engineering & Technology (Dr. SSBUICET),
Panjab University, Chandigarh, India; Centre for Nanosci-
ence and Nanotechnology (UIEAST), Panjab University,
Chandigarh, India
Khushwant S. Yadav Shobhaben Pratapbhai Patel
School of Pharmacy & Technology Management, SVKM’s
NMIMS, Mumbai, India
Mrunal M. Yawalkar Department of Physics, Rash-
trasant Tukadoji Maharaj Nagpur University, Nagpur,
India
Divya Zambre Department of Pharmaceutics, Smt.
Kishoritai Bhoyar College of Pharmacy, Kamptee, India
Section 1

Phototherapeutics

1. Phototherapy: A critical review 3 7. The role of physics in modern

2. Phototherapy for skin diseases 15 radiotherapy: Current advances
3. Phototherapy: The novel emerging and developments 139
treatment for cancer 31 8. Physics in treatment of cancer
4. Fundamentals of photodynamic therapy 51 radiotherapy 163
5. Photodynamic therapy for cancer treatment 89 9. Role of carbon ion beam radiotherapy
6. Photodiagnostic techniques 115 for cancer treatment 193
Chapter 1

Phototherapy: A critical review

Nilesh Rarokara, Shailendra Guravb, Dadasaheb M. Kokarea, Vijay Kalec, Nishikant A. Rauta
a
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra, India
b
Department of Pharmacognosy, Goa College of Pharmacy, Goa University, Panaji, Goa, India
c
College of Pharmacy, Roseman University of Health Sciences, South Jordan, UT, United States

1.1 Introduction
Phototherapy can be broadly defined as the use of photons for the treatment of diseases without the addition of an
exogenous photosensitizer. Ultraviolet B (UVB) radiations (280–320 nm) are the most biologically active radiation in
sunlight and are mainly responsible for erythema. The term “phototherapy” was used as a synonym for UVB radia-
tion in the management of psoriasis. Phototherapy has wide clinical applications like pityriasis lichenoides, vitiligo,
atopic eczema, polymorphous light eruption, pruritus, etc. (Morison, 1993). Recent work in phototherapy explores the
selective use of UV with a narrow wavelength centered on 311 ± 1 nm. It has been proven more effective and less ery-
themogenic than conventional broadband phototherapy (Larkö, 1989). Treatments are usually given three to five times
a week. The most widely used initial dose is 70% of the predetermined minimal erythema dose (MED) (Green et al.,
1988). Treatment is continued until the condition is resolved (Wainwright et al., 1998). Selective UV phototherapy is
the treatment of choice in children, which was used in the various study. The short-term side effects of phototherapy are
usually mild and consist of xerosis and erythema, partly due to occasional overexposure. Another risk can be the pho-
toactivation of herpes-virus. Long-term side effects of UVB phototherapy include premature photoaging and carcino-
genesis with an increased incidence of wrinkling, actinic keratoses, lentigines, telangiectasia, and basal, and squamous
cell carcinomas (De Gruijl, 1986). Radiation received from UVB phototherapy is cumulative with chronic sunlight
exposure. UVB in combination with UVA phototherapy (UVAB) has been shown to produce better therapeutic suc-
cess than UVB per se in treating mild to moderate atopic dermatitis (Falk, 1985; Hannuksela et al., 1985; Pašić et al.,
2003). Phototherapy uses UV radiation or visible light for the treatment of different diseases by the exposure of small,
well-defined anatomical areas to non-ionizing radiations using dichromic lamps, fluorescent lamps, light-emitting
diodes, lasers, polychromatic polarized light, or very bright, full-spectrum light for therapeutic advantages. The origin
of phototherapy can be traced back to 1500 BC, when Hindus treated vitiligo, an autoimmune skin disorder, with pho-
tosensitizing plant extracts and subsequent sunlight exposure. For many centuries only natural sunlight (heliotherapy)
was used to treat different skin conditions. Interestingly, it is still highly popular for psoriasis and atopic dermatitis in
many geographic areas in the world, especially in the Dead Sea region (Matos et al., 2016). As heliotherapy is only
feasible in certain periods of the year with additional dosing variables depending on the geographic locations, artifi-
cial light sources are developed to emit selective wavelengths of electromagnetic radiation. Furthermore, identifying
photosensitizers from plant extracts with unique photochemical properties resulted in the development of the photo-
chemotherapeutic approach. It was found to be most effective in the treatment of inflammatory skin diseases. Lasers
and intense pulse light (IPL) are well-established therapeutic tools to treat congenital and acquired vascular lesions.
The erythema, skin inflammation can be treated by targeting blood vessels with lasers or IPLs, and it has proven a good
alternative for the treatment of various skin diseases. Decades of research have been shown to improve inflammatory
skin conditions with variable success by using vascular lasers. In recent years, low-level light/laser treatments (LLLT)
emitting low-intensity visible light were tried for psoriasis and atopic dermatitis. Still, their efficacy and the mechanism
of action need further clarification. When selecting the appropriate treatment for patients, many different conditions,
such as comorbidities, age, and disease severity, must be considered (Kaushik and Lebwohl, 2019a, 2019b). Although
there are several traditional and biologically active agents for psoriasis and atopic dermatitis, phototherapy approaches
are still widely utilized (Kemény et al., 2019).

Photophysics and Nanophysics in Therapeutics. DOI: https://doi.org/10.1016/B978-0-323-89839-3.00018-X

Copyright © 2022 Elsevier Inc. All rights reserved. 3
4 SECTION | 1 Phototherapeutics

1.2 Background
1.2.1 Historical perspective of phototherapy
Modern scientific discoveries and technological inventions created the basis for applying artificial and modified light
sources in phototherapy. Undoubtedly, these achievements included Isaac Newton’s (1642–1727) splitting of a light beam
into seven basic colors, using a prism and his discovery of the color wheel, Friedrich Wilhelm Herschel’s (1738–1822)
discovery of the infrared spectrum of the sun in 1800, and the discovery of ultraviolet radiation (Roelandts, 2002) in 1801
independently by Johann Wilhelm Ritter (1776–1810) and William Hyde Wollaston (1766–1828). Michel Eugène Chevreul
(1786–1889) expanded upon Newton’s theory of seven colors by formulating the concept of simultaneous contrast in 1830.
He described the phenomenon of an interaction of two colors, side by side, changing human perception. This contrasting
effect is more distinct during the interaction between complementary colors (e.g., blue and yellow) (Chevreul, 1839).
The advancement of research on electricity and artificial light sources preceded the application of phototherapy in
clinical therapy. Thereafter, Hans Christian Oerstedt (1777–1851) discovered that electric current creates a magnetic field
(1777–1851). Michael Faraday (1791–1867) described electromagnetic induction as a source of electric power and built the
first electric generator and the motor. Subsequently, Thomas Alva Edison (1847–1931) invented the electric light bulb and
the battery as a source of light and electric power, respectively.
In the same historical period, scientific attempts were performed to explain the positive influence of light on humans.
The first modern scientific data on the effects of light and colors on human health was published in the early nineteenth
century by the German poet and writer Johann Wolfgang von Goethe (1749–1832). In 1810, he published a work on the
perception of color vision and the influence of light and colors on the human emotional state (Goethe, 1810). It is consid-
ered as the very first report on the psychological effects of colors. However, it is far from perfection as it includes several
erroneous assertions, like the thesis on light’s homogeneity inherent in the polemics of Newtonian optics. For example, he
contradicted Newton with reference to the view that colors arise from the decomposition of light emerging from a prism
into tiny particles called corpuscles but suggested that colors derive from the interaction of light and dark, and light is indi-
visible into any particles.
In the second half of the 19th century, scientific reports pointed to the healing properties of sunlight and reported the
bactericidal properties of sunlight along with its therapeutic application in the treatment of rickets (Downes et al., 1877;
Palm, 1890).
Activities of sanatoria, using natural solar radiation, were an important element in the historical process of creating
contemporary phototherapy. The end of the nineteenth century saw the development of these “sun sanatoria.” They became
the centers for heliotherapy and hydrotherapy. In addition, attempts were made to combat the tuberculosis epidemic by
associating phototherapy with climatic treatment (i.e., therapy by bathing in cold or warm water and walking in the fresh
air) (Roelandts, 2002). Pioneers in this therapeutic trend included the “Sunapostle” Arnold Rikli (1823–1906) (Levental,
1977), Oskar Bernhard (1861–1939), and August Rollier (1874–1954). Although from 1855, balneotherapy might include
light treatment, as found in the Alpine Bed in Slovenia (Zupanic-Slavec and Toplak, 1998), Rikli applied the principle
“Water is good, the air is better, and most of all the sunlight.” Bernhard promoted heliotherapy at the beginning of 1899
at a private clinic in St. Moritz, Switzerland. Finally, Rollier applied climatic treatment in combination with phototherapy
to treat tuberculosis of the bone, beginning in 1903 at a sanatorium in Leysin, Switzerland (Rollier and Rosselet, 1923).
The discoveries (e.g., ultraviolet radiation) and inventions (e.g., the electric generator or the electric-light bulb), as well
as balneological experiences of the treatment with the sunlight, contributed to the development of modern phototherapy and
the transition from heliotherapy to artificial light phototherapy at the end of the nineteenth century. Nils Ryberg Finsen’s
(1860–1904) studies on phototherapy led to its rise as a new field in physiotherapy (Grzybowski and Pietrzak, 2012). Finsen
is also famous for creating the Medical Light Institute in Copenhagen, Denmark in 1896 (Finsen, 1896) and use of an elec-
tric carbon arc torch to treat lupus vulgaris patients with ultraviolet radiation (Finsen and Forchhammer, 1904).

1.2.1.1 Progress in the twentieth century

Phototherapy was developed for neonatal jaundice in the late 1950s. Sister Jean Ward at Rochford General Hospital in
Essex, England noted in 1956 that sunshine decreased neonatal jaundice. Concurrently, hospital biochemists observed
significantly low bilirubin levels in samples exposed to sunlight before processing (Dobbs and Cremer, 1975). Thus, it was
the first evidence for effective light therapy for infantile hyperbilirubinemia (Cremer, Perryman and Richards, 1958). Jerold
Lucey, the editor of the journal Pediatrics, published the “1968 landmark randomized controlled trial” results showing the
efficacy of phototherapy (Lucey et al., 1968), which continued an important method for treating newborn jaundice (Weiss
and Zimmerman, 2013).
Another random document with
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á los cuales la virtud les dió el
nombre de dorados, porque se
admitía en ellos cualquiera
trabajo, recibiendo las
intenciones, y perdonando á los
talentos, como dones que Dios
reparte á su voluntad? De
manera, señora mia, que yo como
persona tan necessitada dellos, y
en este siglo, buscando amparo,
me subí en el teatro deste mundo,
y queriéndome arrojar en él, me
determiné entregarme en unas
manos que me defendiessen de
las injurias del tiempo. Y assi
volviendo los ojos por una y otra
parte, por ver á quien me
encomendaría para que me
librasse de las lenguas
murmuradoras de los mal
intencionados espíritus, y no
viendo alma ni cuerpo más propio
que el de V. E. para este efecto,
siendo persona que á todo el
mundo enamora, con justa y
debida razón se le debe la más
enamorada Diana encomendar,
echándome en el abrigo dessas
tan ilustríssimas partes, con la
confianza de que recibirá la
voluntad de la mano del curioso
que ha tomado el trabajo de
tornarme á poner á luz, por
mandamiento de personas que
hallaron la traza y el estilo muy
curioso, y que se iba á escurecer
del todo, por no se hallar ya este
tratado en el mundo. Ea, señora
mía, abra esos brazos, y
enciérreme en esse pecho, como
tan insigne y inexpugnable
fortaleza, en la qual vivirá mi alma
de todos los ya dichos espíritus
malinos descuidada y defendida
con solo el saber que V. E. es su
protectora; y con tal confianza
vivirá rogando á Dios por la
conservación de la persona
Ilustrissima de V. E. que viva un
millón de años, amparando á las
que se le encomiendan, y
particularmente á los del sexo que
tiene aún su particular
consideración.
La muy humilde servidora de V. E.
que le besa los pies,
Diana Enamorada.

DE DON ALONSO GIRÓN Y

DE REBOLLEDO

Soneto.
Lector. Diana.
Buen libro, Diana. En todo
extremo es bueno.
¿Qué sientes dél? Placer de
andar penada.
¿Y qué es la pena? Amar
cosa olvidada.
¿Y el gozo? Ver por cuya
industria peno.
¿Es Jorge ó Perez? No, que
es muy terreno
amarme á mí. ¿Qué cosa
hay más alzada?
Hacerme Gaspar Gil
enamorada,
que lo estoy ya más dél que
de Syreno.
¿En qué tuvo primor? En
verso y prosa.
¿Quién juzga eso? Ingenios
delicados.
¿Tanta luz da? Alumbra
todo el suelo.
¿Cuál quedará su patria? Muy
dichosa.
¿Y los poetas todos?
Afrentados.
¿Y él cómo se dirá? Polo
del cielo.

SONETO DE HIERONYMO
SAMPER
De fieras armas la inmortal
historia
cessa por celebrar simples
pastores;
canta Gaspar Gil Polo sus
amores,
y en ello no consigue menos
gloria.
A Marte da querellas la
victoria,
por ver que calla Polo sus
loores,
fama y honor á Palas dan
clamores,
viendo que da á Diana tal
memoria.
Dejad, númenes sacros, tal
querella;
que Apolo ha prometido á
su Diana
poeta el más famoso é
importante:
Y dióle al gran Gil Polo, que
por ella
con grave estilo y gracia
soberana
dulce canción en las
veredas cante.

DE MIGUEL JUAN TÁRREGA

Soneto.
Con la tuba Meonia y
Mantuana
su canto Gaspar Gil había
acordado
con tal furor, que el son ya
era llegado
desde el Indico Gange hasta
la Tana.
Mandóle en esto Apolo que á
Diana,
dejando el canto de Mavorte
airado,
cantasse al son que Píndaro
ha cantado:
tanto le es dulce el nombre
de su hermana.
Y ansi le dió la lira, en que él
tañía
siendo pastor de Admeto, y
alegrando
los prados y aguas del
dichoso Amphryso.
Y el sacro nombre Apolo á
Polo dando,
con usado favor dar honra
quiso
al que mayor renombre
merescía.

HERNANDO BONAVIDA,
CIUDADANO
VALENCIANO
Al lector.
Ovidio á su Corynna celebraba
con los sabrosos versos que
escribía,
dos mil hermosos cantos
componía
Propercio que á su Cynthia
sublimaba.
Con las dulces canciones que
cantaba,
á su Laura Petrarca
engrandescía,
y destos cada cual con lo
que hacía
al famoso laurel al fin
llegaba.
A lauro el Lusitano ha ya
llegado
á Diana pintando muy
ufana,
 mas Polo de otra suerte os
la ha pintado:
Aquí veréis una obra
sobrehumana,
y cuán bien el laurel Polo
ha ganado,
pues Proserpina es la otra,
ésta Diana.

LIBRO PRIMERO
DE DIANA ENAMORADA

Después que el apassionado

Syreno con la virtud del poderoso
liquor fué de las manos de Cupido
por la sabia Felicia libertado,
obrando Amor sus acostumbradas
hazañas, hirió de nuevo el
corazón de la descuidada Diana,
despertando en ella los olvidados
amores, para que de un libre
estuviesse captiva, y por un
essento viviesse atormentada. Y
lo que mayor pena le dió fué
pensar que el descuido que tuvo
de Syreno había sido ocasión de
tal olvido, y era causa del
aborrescimiento. Deste dolor y de
otros muchos estaba tan
combatida, que ni el yugo del
matrimonio, ni el freno de la
vergüenza fueron bastantes á
detener la furia de su amor, ni
remediar la aspereza de su
tormento, sino que sus
lamentables voces esparciendo, y
dolorosas lágrimas derramando,
las duras peñas y fieras alimañas
enternescía. Pues hallándose un
día acaso en la fuente de los
alisos, en el tiempo del estío, á la
hora que el sol se acercaba al
medio día, y acordándose del
contento que allí en compañía del
amado Syreno muchas veces
había recebido, cotejando los
deleites del tiempo passado con
las fatigas del presente; y
conosciendo la culpa que ella en
su tormento tenía, concibió su
corazón tan angustiada tristeza, y
vino su alma en tan peligroso
desmayo, que pensó que
entonces la deseada muerte diera
fin á sus trabajos. Pero después
que el ánimo cobró algún tanto su
vigor, fué tan grande la fuerza de
su passión, y el ímpetu, con que
amor reinaba en sus entrañas,
que le forzó publicar su tormento
á las simples avecillas, que de los
floridos ramos la escuchaban, á
los verdes árboles, que de su
congoja paresce que se dolían, y
á la clara fuente, que el ruido de
sus cristalinas aguas con el son
de sus cantares acordaba. Y assí
con una suave zampoña cantó
desta manera:

Mi sufrimiento cansado
del mal importuno y fiero,
á tal extremo ha llegado,
que publicar mi cuidado
me es el remedio postrero.
Siéntase el bravo dolor,
y trabajosa agonía
de la que muere de amor,
y olvidada de un pastor
que de olvidado moría.

¡Ay, que el mal que ha

consumido
la alma que apenas
sostengo,
nasce del passado olvido,
y la culpa que he tenido
causó la pena que tengo!
Y de gran dolor reviento,
viendo que al que agora
quiero,
le di entonces tal tormento,
que sintió lo que yo siento
y murió como yo muero.

Y cuando de mi crüeza
se acuerda mi corazón,
le causa mayor tristeza
el pesar de mi tibieza,
 que el dolor de mi passión.
Porque si mi desamor
no tuviera culpa alguna
en el presente dolor,
diera quejas del Amor
é inculpara la Fortuna.

Mas mi corazón esquivo

tiene culpa más notable,
pues no vió de muy altivo,
que Amor era vengativo
y la Fortuna mudable.
Pero nunca hizo venganza
Amor, que de tantas suertes
deshiciese una esperanza,
ni Fortuna hizo mudanza
de una vida á tantas
muertes.

¡Ay, Syreno, cuán vengado

estás en mi desventura,
pues después que me has
dejado,
no hay remedio á mi
cuidado,
ni consuelo á mi tristura!
Que según solías verme
desdeñosa en solo verte,
tanto huelgas de ofenderme,
que ni tú podrás quererme,
ni yo dejar de quererte.

Véote andar tan essento,

que no te ruego, pastor,
remedies el mal que siento,
mas que engañes mi
tormento
 con un fingido favor.
Y aunque mis males
pensando,
no pretendas remediallos,
vuelve tus ojos, mirando
los míos, que están
llorando,
pues tú no quieres mirallos.

Mira mi mucho quebranto,

y mi poca confianza
para tener entre tanto
no compassión de mi llanto,
mas placer de tu venganza.
Que aunque no podré
ablandarte,
ni para excusar mi muerte
serán mis lágrimas parte,
quiero morir por amarte
y no vivir sin quererte.

No diera fin tan presto la

enamorada Diana á su deleitosa
música, si de una pastora, que
tras unos jarales la había
escuchado, no fuera de improviso
estorbada. Porque viendo la
pastora, detuvo la suave voz,
rompiendo el hilo de su canto, y
haciendo obra en ella la natural
vergüenza, le pesó muy de veras
que su canción fuesse
escuchada, ni su pena conoscida,
mayormente viendo aquella
pastora ser extranjera, y por
aquellas partes nunca vista. Mas
ella, que de lejos la suavissima
voz oyendo, á escuchar tan
delicada melodía secretamente se
había llegado, entendiendo la
causa del doloroso canto, hizo de
su extremadíssima hermosura tan
improvisa y alegre muestra, como
suele hacer la nocturna luna, que
con sus lumbrosos rayos vence y
traspassa la espessura de los
escuros ñublados. Y viendo que
Diana había quedado algo
turbada con su vista, con gesto
muy alegre le dijo estas palabras:
—Hermosa pastora, grande
perjuicio hice al contento que
tenía con oirte, en venir tan sin
propósito á estorbarte. Pero la
culpa desto la tiene el deseo que
tengo de conoscerte, y voluntad
de dar algún alivio al mal de que
tan dolorosamente te lamentas; al
cual, aunque dicen que es
excusado buscalle consuelo, con
voluntad libre y razón
desapassionada se le puede dar
suficientemente remedio. No
dissimules conmigo tu pena, ni te
pese que sepa tu nombre y tu
tormento, que no haré por esso
menos cuenta de tu perfición, ni
juzgaré por menor tu
merescimiento.
Oyendo Diana estas palabras
estuvo un rato sin responder,
teniendo los ojos empleados en la
hermosura de aquella pastora, y
el entendimiento dudoso sobre
qué respondería á sus grandes
ofrescimientos y amorosas
palabras; y al fin respondió de
esta manera: Pastora de nueva y
aventajada gentileza, si el gran
contento que de tu vista recibo, y
el descanso que me ofrescen tus
palabras, hallara en mi corazón
algún aparejo de confianza, creo
que fueras bastante á dar algún
remedio á mi fatiga, y no dudara
yo de publicarte mi pena. Mas es
mi mal de tal calidad, que en
comenzar á fatigarme, tomo las
llaves de mi corazón y cierro las
puertas al remedio. Sabe que yo
me llamo Diana, por estos
campos harto conoscida;
conténtate con saber mi nombre,
y no te cures de saber mi pena:
pues no aprovechará para más de
lastimarte, viendo mi tierna
juventud en tanta fatiga y trabajo.
Este es el engaño, dijo la pastora,
de los que se hacen esclavos del
Amor, que en comenzalle á servir,
son tan suyos, que ni quieren ser
libres, ni les paresce possible
tener libertad. Tu mal bien sé que
es amar, según de tu canción
entendí, en la cual enfermedad yo
tengo grande experiencia. He sido
muchos años captiva, y agora me
veo libre; anduve ciega, y agora
atino al camino de la verdad;
passé en el mar de amor
peligrosas agonías y tormentos, y
agora estoy gozando del seguro y
sosegado puerto; y aunque más
grande sea tu pena, era tan
grande la mía. Y pues para ella
tuve remedio, no despidas de tu
casa la esperanza, no cierres los
ojos á la verdad ni los oídos á mis
palabras. Palabras serán, dijo
Diana, las que gastarán en
remediar el Amor, cuyas obras no
tienen remedio con palabras. Mas
con todo querría saber tu nombre,
y la ocasión que hacia nuestros
campos te ha encaminado, y
holgaré tanto en sabello, que
suspenderé por un rato mi
comenzado llanto, cosa que
importa tanto para el alivio de mi
pena. Mi nombre es Alcida, dijo
la pastora, pero lo demás que me
preguntas no me sufre contallo la
compassión que tengo de tu
voluntaria dolencia, sin que
primero recibas mis provechosos,
aunque para ti desabridos
remedios. Cualquier consuelo,
dijo Diana, me será agradable,
por venir de tu mano, con que no
sea quitar el amor de mi corazón:
porque no saldrá de allí, sin llevar
consigo á pedazos mis entrañas.
Y aunque pudiesse, no quedaría
sin él, por no dejar de querer al
que siendo olvidado, tomó de mi
crueldad tan presta y sobrada
venganza. Dijo entonces Alcida:
Mayor confianza me das agora de
tu salud, pues dices que lo que
agora quieres, en otro tiempo lo
has aborrescido, porque ya
sabrás el camino del olvido, y
ternás la voluntad vezada al
aborrescimiento. Cuánto más que
entre los dos extremos de amar y
aborrescer está el medio, el cual
tú debes elegir. Diana á esto
replicó: Bien me contenta tu
consejo, pastora, pero no me
paresce muy seguro. Porque si yo
de aborrescer he venido á amar,
más fácilmente lo hiciera si mi
voluntad estuviera en medio del
amor y aborrescimiento, pues
teniéndome más cerca, con
mayor fuerza me venciera el
poderoso Cupido. A esto
respondió Alcida: No hagas tan
gran honra á quien tan poco la
meresce, nombrando poderoso al
que tan fácilmente queda vencido,
especialmente de los que eligen
el medio que tengo dicho: porque
en él consiste la virtud, y donde
ella está, quedan los corazones
contra el Amor fuertes y
constantes. Dijo entonces Diana:
Crueles, duros, ásperos y
rebeldes dirás mejor, pues
pretenden contradecir á su
naturaleza, y resistir á la
invencible fuerza de Cupido. Mas
séanlo cuanto quisieren, que á la
fin no se van alabando de la
rebeldía, ni les aprovecha
defenderse con la dureza. Porque
el poder del amor vence la más
segura defensa, y traspassa el
más fuerte impedimento. De
cuyas hazañas y maravillas en
este mesmo lugar cantó un día mi
querido Syreno, en el tiempo que
fué para mí tan dulce, como me
es agora amarga su memoria. Y
bien me acuerdo de su canción, y
aun de cuantas entonces
cantaba, porque he procurado
que no se me olvidassen, por lo
que me importa tener en la
memoria las cosas de Syreno.
Mas esta que trata de las proezas
del Amor, dice:

Soneto.
Que el poderoso Amor sin
vista acierte
del corazón la más interna
parte;
que siendo niño venza al
fiero Marte,
haciendo que enredado se
despierte.
Que sus llamas me hielen de
tal suerte,
que un vil temor del alma no
se aparte,
que vuele hasta la aérea y
summa parte,
y por la tierra y mar se
muestre fuerte.
Que esté el que el bravo Amor
 hiere ó captiva
vivo en el mal, y en la
prisión contento,
proezas son que causan
grande espanto.
Y el alma, que en mayores
penas viva,
si piensa estas hazañas,
entretanto
no sentirá el rigor de su
tormento.

Bien encarescidas están, dijo

Alcida, las fuerzas del amor; pero
más creyera yo á Syreno, si
después de haber publicado por
tan grandes las furias de las
flechas de Cupido, él no hubiesse
hallado reparo contra ellas, y
después de haber encarescido la
estrechura de sus cadenas, él no
hubiesse tenido forma para tener
libertad. Y ansí me maravillo que
creas tan de ligero al que con las
obras contradice á las palabras.
Porque harto claro está que
semejantes canciones son
maneras de hablar, y sobrados
encarescimientos, con que los
enamorados venden por muy
peligrosos sus males, pues tan
ligeramente se vuelven de
captivos libres y vienen de un
amor ardiente á un olvido
descuidado. Y si sienten
passiones los enamorados,
provienen de su mesma voluntad,
y no del amor: el cual no es sino
una cosa imaginada por los
hombres, que ni está en cielo, ni
en tierra, sino en el corazón del
que la quiere. Y si algún poder
tiene, es porque los hombres
mesmos dejan vencerse
voluntariamente, ofresciéndole
sus corazones, y poniendo en sus
manos la propia libertad. Mas
porque el Soneto de Syreno no
quede sin respuesta, oye otro que
paresce que se hizo en
competencia dél, y oíle yo mucho
tiempo ha en los campos de
Sebetho á un pastor nombrado
Aurelio; y si bien me acuerdo
decía así:

Soneto.
No es ciego Amor, mas yo lo
soy, que guío
mi voluntad camino del
tormento;
no es niño Amor, mas yo
que en un momento
espero y tengo miedo, lloro
y río.
Nombrar llamas de Amor es
desvarío,
su fuego es el ardiente y
vivo intento,
sus alas son mi altivo
pensamiento
y la esperanza vana en que
me fío.
 No tiene Amor cadenas, ni
saëtas,
para prender y herir libres y
sanos,
que en él no hay más poder
del que le damos.
Porque es Amor mentira de
poetas,
sueño de locos, ídolo de
vanos:
mirad qué negro Dios el que
adoramos.

¿Parescete, Diana, que debe

fiarse un entendimiento como el
tuyo en cosas de aire, y que hay
razón para adorar tan de veras á
cosa tan de burlas como el Dios
de Amor? El cual es fingido por
vanos entendimientos, seguido de
deshonestas voluntades, y
conservado en las memorias de
los hombres ociosos y
desocupados. Estos son los que
le dieron al Amor el nombre tan
celebrado que por el mundo tiene.
Porque viendo que los hombres
por querer bien padescían tantos
males, sobresaltos, temores,
cuidados, recelos, mudanzas y
otras infinitas passiones,
acordaron de buscar alguna
causa principal y universal, de la
cual como de una fuente
nasciessen todos estos efectos. Y
assí inventaron el nombre de
Amor, llamándole Dios, porque
era de las gentes tan temido y
reverenciado. Y pintáronle de
manera que cuando veen su
figura tienen razón de aborrescer
sus obras. Pintáronle muchacho,
porque los hombres en él no se
fíen; ciego, porque no le sigan;
armado, porque le teman; con
llamas, porque no se le lleguen, y
con alas, para que por vano le
conozcan. No has de entender,
pastora, que la fuerza que al
Amor los hombres conceden, y el
poderío que le atribuyen, sea ni
pueda ser suyo: antes has de
pensar que cuanto más su poder
y valor encarescen, más nuestras
flaquezas y poquedades
manifiestan. Porque decir que el
Amor es fuerte, es decir que
nuestra voluntad es floja, pues
permite ser por él tan fácilmente
vencida; decir que el Amor tira
con poderosa furia venenosas y
mortales saetas, es decir que
nuestro corazón es descuidado,
pues se ofresce tan
voluntariamente á recebirlas;
decir que el Amor nuestras almas
tan estrechamente captiva, es
decir que en nosotras hay falta de
juicio, pues al primer combate nos
rendimos, y aun á veces sin ser
combatidos, damos á nuestro
enemigo la libertad. Y en fin,
todas las hazañas que se cuentan
del Amor no son otra cosa sino
nuestras miserias y flojedades. Y
puesto caso que las tales proezas
fuesen suyas, ellas son de tal
calidad que no merescen
alabanza. ¿Qué grandeza es
captivar los que no se defienden,
qué braveza acometer los flacos,
qué valentía herir los
descuidados, qué fortaleza matar
los rendidos, qué honra
desasossegar los alegres, qué
hazaña perseguir los
malaventurados? Por cierto,
hermosa pastora, los que quieren
tanto engrandescer este Cupido,
y los que tan á su costa le sirven,
debieran por su honra dalle otras
alabanzas; porque con todas
estas el mejor nombre que gana
es de cobarde en los
acometimientos, cruel en las
obras, vano en las intenciones,
liberal de trabajos y escaso de
gualardones. Y aunque todos
estos nombres son infames,
peores son los que le dan sus
mesmos aficionados,
nombrándole fuego, furor y
muerte; y al amar llamando arder,
destruirse, consumirse y
enloquecerse; y á sí mesmos
nombrándose ciegos, míseros,
captivos, furiosos, consumidos y
inflamados. De aquí viene que
todos generalmente dan quejas
del Amor, nombrándole tirano,
traidor, duro, fiero y despiadado.