Nanobiotechnologies- applications, markets and companies

SUMMARY

Summary

Nanotechnology is the creation and utilization of materials, devices, and systems through the control of matter on the nanometer-length scale (a nanometer is one billionth of a meter. Nanobiotechnology, an integration of physical sciences, molecular engineering, biology, chemistry and biotechnology holds considerable promise of advances in pharmaceuticals and healthcare. The report starts with an introduction to various techniques and materials that are relevant to nanobiotechnology. It includes some of the physical forms of energy such as nanolasers. Some of the technologies are scaling down such as microfluidics to nanofluidic biochips and others are constructions from bottom up. Application in life sciences research, particularly at the cell level sets the stage for role of nanobiotechnology in healthcare in subsequent chapters.

Some of the earliest applications are in molecular diagnostics. Nanoparticles, particularly quantum dots, are playing important roles. In vitro diagnostics, does not have any of the safety concerns associated with the fate of nanoparticles introduced into the human body. Numerous nanodevices and nanosystems for sequencing single molecules of DNA are feasible. Various nanodiagnostics that have been reviewed will improve the sensitivity and extend the present limits of molecular diagnostics.

An increasing use of nanobiotechnology by the pharmaceutical and biotechnology industries is anticipated. Nanotechnology will be applied at all stages of drug development - from formulations for optimal delivery to diagnostic applications in clinical trials. Many of the assays based on nanobiotechnology will enable high-throughput screening. Some of nanostructures such as fullerenes are themselves drug candidates as they allow precise grafting of active chemical groups in three-dimensional orientations. The most important pharmaceutical applications are in drug delivery. Apart from offering a solution to solubility problems, nanobiotechnology provides and intracellular delivery possibilities. Skin penetration is improved in transdermal drug delivery. A particularly effective application is as nonviral gene therapy vectors. Nanotechnology has the potential to provide controlled release devices with autonomous operation guided by the needs.

Nanomedicine is now within the realm of reality starting with nanodiagnostics and drug delivery facilitated by nanobiotechnology. Miniature devices such as nanorobots could carry out integrated diagnosis and therapy by refined and minimally invasive procedures, nanosurgery, as an alternative to crude surgery. Nanotechnology will markedly improve the implants and tissue engineering approaches as well.

There is some concern about the safety of nanoparticles introduced in the human body and released into the environment. Research is underway to address these issues. As yet there are no FDA directives to regulate nanobiotechnology but as products are ready to enter market, these are expected to be in place.

Future nanobiotechnology markets are calculated on the basis of the background markets in the areas of application and the share of this market by new technologies and state of development at any given year in the future. This is based on a comprehensive and thorough review of the current status of nanobiotechnology, research work in progress and anticipated progress. There is definite indication of large growth of the market but it will be uneven and cannot be plotted as a steady growth curve. Marketing estimates are given according to areas of application, technologies and geographical distribution starting with 2007. The largest expansion is expected between the years 2012 and 2017.

Profiles of 233 companies, out of over 500 involved in this area, are included in the last chapter along with their 182 collaborations.The report is supplemented with 39 Tables, 21 figures and 700 references to the literature.

TABLE OF CONTENTS

0. Executive Summary 17

1. Basics of Nanobiotechnology 19

• Introduction 19
• Classification of nanobiotechnologies 20
• Top-down and bottom-up approaches 21
• Landmarks in the evolution of nanobiotechnology 21
• Relation of nanobiotechnology to healthcare 22

2. Technologies 25

• Introduction 25
• Micro- and nano-electromechanical systems 25
• BioMEMS 25
• Microarrays and nanoarrays 26
• Dip Pen Nanolithography for nanoarrays 26
• Protein nanoarrays 27
• Microfluidics and nanofluidics 28
• Nanotechnology on a chip 28
• Microfluidic chips for nanoliter volumes 29
• Nanogen's NanoChip 30
• Use of nanotechnology in microfluidics 31
• Construction of nanofluidic channels 31
• Nanoscale flow visualization 32
• Moving (levitation) of nanofluidic drops with physical forces 32
• Electrochemical nanofluid injection 32
• Nanofluidics on nanopatterned surfaces 33
• Nano-interface in a microfluidic chip 33
• Nanofluidic channels for study of DNA 33
• Visualization and manipulation on nanoscale 34
• Atomic force microscopy 34
• Basic AFM operation 34
• Advantages of AFM 34
• Force sensing Integrated Readout and Active Tip 35
• Ultra-nanocrystalline diamond 35
• Magnetic resonance force microscopy 36
• Scanning probe microscopy 36
• Near-field scanning optical microscopy 36
• Nano-sized light source for single cell endoscopy 37
• Multiple single-molecule fluorescence microscopy 37
• Nanoparticle characterization by Halo™LM10 technology 37
• Nanoscale scanning electron microscopy 38
• Use of SEM to reconstruct 3D tissue nanostructure 39
• Visualizing atoms with high-resolution transmission electron microscopy 39
• Photoactivated localization microscopy 39
• Optical Imaging with a Silver Superlens 40
• Fluorescence Resonance Energy Transfer 40
• 4Pi microscope 40
• Principle and applications of cantilevers 41
• Companies that provide microscopes for nanobiotechnology 42
• Surface plasmon resonance 43
• Nanoparticles 43
• Quantum dots 44
• Gold nanoparticles 45
• Silica nanoparticles 45
• Lipoparticles 45
• Assembly of nanoparticles into micelles 46
• Biomedical applications of self-assembly of nanoparticles 46
• Paramagnetic and superparamagnetic nanoparticles 47
• Fluorescent nanoparticles 48
• Production techniques for nanoparticles 48
• Nanostructures 49
• Bacterial structures relevant to nanobiotechnology 49
• Bacterial spores 49
• Nanostructures based on bacterial cell surface layers 49
• Bacterial magnetic particles 50
• Cubosomes 50
• Dendrimers 51
• Properties 52
• Applications 52
• DNA-nanoparticle conjugates 53
• DNA octahedron 53
• Potential applications 53
• Fullerenes 54
• Nanoshells 54
• Nanotubes 55
• Carbon nanotubes 55
• Carbon nanotubes and DNA 56
• Applications of nanotubes 56
• NanoBuds 57
• Nanowires 57
• Nanostamping 57
• Nanoneedles 58
• Nanopores 58
• Nanoporous silica aerogel 59
• Nanostructured silicon 60
• Networks of gold nanoparticles and bacteriophage 60
• Polymer nanofibers 60
• Protein-nanoparticle combination 61
• Nanomaterials for biolabeling 61
• Quantum dots as labels 63
• Silver nanoparticle labels 63
• Silica nanoparticles for labeling antibodies 63
• SERS nanotags 64
• DNA Nanotags 64
• Fluorescent lanthanide nanorods 64
• Nanophosphor labels 65
• Organic nanoparticles as biolabels 65
• Molecular computational identification 66
• Companies providing services and products for nanobiotechnology 66

3. Applications in Life Sciences 69

• Introduction 69
• Nanotechnology and biology 69
• NanoSystems Biology 69
• Nanobiology and the cell 70
• Measuring mass of single cells 71
• Nanotechnology-based live-cell single molecule assays 71
• Quantum dots for cell labeling 71
• Quantum dots for study of apoptosis 72
• Single cell injection by nanolasers 72
• Nanostructures involved in endocytosis 72
• Study of complex biological systems 73
• Biosensing of cellular responses 73
• Control of T cell signaling activity 74
• Molecular motors 74
• Nanomotor made of nucleic acids 76
• phi29 DNA packaging nanomotor 76
• Light-activated ion channel molecular machines 77
• Application of AFM for biomolecular imaging 77
• Future insights into biomolecular processes by AFM 78
• 4Pi microscopy to study DNA double-strand breaks 78
• Multi-isotope imaging mass spectrometry 79
• Applications of biomolecular computing in life sciences 79
• Molecular electronics 80
• Microbial nanomaterials 80
• Use of bacteria to construct nanomachines 80
• Bacteriophage nanoshells 80
• Natural nanocomposites 81
• Nanotechnology in biological research 81
• Nanoparticles for biological research 81
• Disguising quantum dots as proteins for cell entry 82
• Molecular biology and nanotechnology 83
• Structural DNA nanotechnology 83
• Reversibly binding of gold nanospheres to DNA strands 84
• RNA nanotechnology 85
• Genetically engineered proteins for nanobiotechnology 85
• Single molecule studies 86
• Optical trapping and single-molecule fluorescence 86
• 3D single-molecular imaging by coherent X-ray diffraction imaging 86
• Studying the molecular mechanisms of enzymes 86
• Nanochemistry 87
• Nanoscale pH Meter 87
• Application of nanolasers in life sciences 87
• Nanomanipulation 88
• Nanomanipulation by combination of AFM and other devices 88
• Surgery on living cells using AFM with nanoneedles 89
• Optoelectronic tweezers 89
• Manipulation of DNA sequence by use of nanoparticles as laser light antennas 89
• Nanomanipulation of single molecule 90
• Fluorescence-force spectroscopy 90
• Nanomanipulation for study of mechanism of anticancer drugs 90
• Nanotechnology in genomic research 91
• Use of nanotechnology for separation of DNA fragments 91
• Nanotechnology-based DNA sequencing 91
• Single-molecule detection of DNA hybridization 92
• Role of nanobiotechnology in identifying single nucleotide polymorphisms 92
• Nanobiotechnology for study of mitochondria 92
• Nanomaterials for the study of mitochondria 93
• Study of mitochondria with nanolaser spectroscopy 93
• Role of nanotechnology in proteomics research 93
• Study of proteins by atomic force microscopy 93
• Single cell nanoprobe for studying gene expression of individual cells 94
• Nanoproteomics 94
• Multi Photon Detection 94
• Nanoflow liquid chromatography 95
• High-field asymmetric waveform ion mobility mass spectrometry 95
• Protein nanocrystallography 95
• QD-protein bioconjugate nanoassembly 96
• Nanoproteomics for study of misfolded proteins 96
• Dynamic reassembly of peptides 96
• Use of nanotube electronic biosensor in proteomics 97
• Nanometer photomasks from bacterial protein 97
• Proteomics at single molecule level 97
• Study of protein synthesis and single-molecule processes 97
• Protein expression in individual cells at the single molecule level 98
• Single-molecule mass spectrometry using a nanopore 99
• Biochips for nanoscale proteomics 99
• Protein biochips based on fluorescence planar wave guide technology 99
• Nanofilter array chip 100
• Role of nanotechnology in study of membrane proteins 100
• Nanoparticles for study of membrane proteins 100
• Study of single protein interaction with cell membrane 101
• Quantum dots to label cell surface proteins 101
• Study of single membrane proteins at subnanometer resolution 101
• Nanoparticle-protein interactions 101
• Protein engineering on nanoscale 102
• Nanowires for protein engineering 102
• A nanoscale mechanism for protein engineering 102
• Role of nanoparticles in self-assembly of proteins 103
• Role of nanotechnology in peptide engineering 103
• Manipulating redox systems for nanotechnology 103
• Self-assembling peptide scaffold technology for 3-D cell culture 104
• Nanobiotechnology and ion channels 104
• Aquaporin water channels 105
• Role of nanobiotechnology in engineering ion channels 105
• Application of nanobiotechnology in molecular electronics 106
• Nanotechnology and bioinformatics 107
• 3D nano-map of synapse 107
• Companies providing nanotechnology for life sciences research 108

4. Nanomolecular Diagnostics 109

• Introduction 109
• Nanodiagnostics 109
• Rationale of nanotechnology for molecular diagnostics 110
• Nanoarrays for molecular diagnostics 111
• NanoPro"! System 111
• Nanofluidic/nanoarray devices to detect a single molecule of DNA 111
• Self-assembling protein nanoarrays 112
• Fullerene photodetectors for chemiluminescence detection on microfluidic chip 112
• Nanofountain AFM probe 112
• Protein microarray for detection of molecules with nanoparticles 113
• Protein nanobiochip 113
• Nanoparticles for molecular diagnostics 113
• Gold nanoparticles 113
• Quantum dots for molecular diagnostics 114
• Quantum dots for detection of pathogenic microorganisms 115
• Bioconjugated QDs for multiplexed profiling of biomarkers 115
• Imaging of living tissue with quantum dots 115
• Magnetic nanoparticles 116
• Magnetic nanoparticles for bioscreening 116
• Superparamagnetic nanoparticles for cell tracking 116
• Monitoring of implanted NSCs labeled with nanoparticles 117
• Perfluorocarbon nanoparticles to track therapeutic cells in vivo 117
• Superparamagnetic iron oxide nanoparticles for calcium sensing 117
• Magnetic nanoparticles for labeling molecules 118
• Ferrofluids 118
• Super conducting quantum interference device 118
• Study of living cells by superparamagnetic nanoparticles 119
• Use of nanocrystals in immunohistochemistry 119
• Imaging applications of nanoparticles 119
• Gadonanotubes for MRI 119
• Gold nanorods and nanoparticles as imaging agents 120
• In vivo imaging using nanoparticles 120
• Manganese oxide nanoparticles as contrast agent for brain MRI 121
• Nanoparticles vs microparticles for cellular imaging 121
• Nanoparticles as contrast agent for MRI 121
• Quantum dots for biological imaging 122
• Superparamagnetic nanoparticles combined with MRI 122
• Study of chromosomes by atomic force microscopy 123
• Applications of nanopore technology for molecular diagnostics 123
• DNA-protein and -nanoparticle conjugates 124
• Resonance Light Scattering technology 125
• DNA nanomachines for molecular diagnostics 126
• Nanobarcodes technology 126
• Nanobarcode particle technology for SNP genotyping 126
• Qdot nanobarcode for multiplexed gene expression profiling 127
• Biobarcode assay for proteins 127
• Single-molecule barcoding system for DNA analysis 129
• Nanoparticle-based colorimetric DNA detection method 129
• SNP genotyping with gold nanoparticle probes 130
• Nanoparticle-based Up-converting Phosphor Technology 130
• Surface-Enhanced Resonant Raman Spectroscopy 130
• Near-infrared (NIR)-emissive polymersomes 131
• Nanobiotechnology for detection of proteins 131
• Captamers with proximity extension assay for proteins 132
• Nanobiosensors 132
• Cantilevers as biosensors for molecular diagnostics 132
• Advantages of cantilever technology for molecular recognition 133
• Antibody-coated nanocantilevers for detection of microorganisms 134
• Cantilevers for direct detection of active genes 134
• Portable nanocantilever system for diagnosis 135
• Carbon nanotube biosensors 135
• Carbon nanotube sensors coated with ssDNA and electronic readout 135
• Carbon nanotubes sensors wrapped with DNA and optical detection 136
• FRET-based DNA nanosensor 136
• Ion Channel Switch biosensor technology 136
• Electronic nanobiosensors 137
• Electrochemical nanobiosensor 137
• Quartz nanobalance biosensor 138
• Viral nanosensor 138
• PEBBLE nanosensors 138
• Nanosensors for glucose monitoring 139
• Microneedle-mounted biosensor 139
• Optical biosensors 139
• Laser nanosensors 140
• Nanoshell biosensors 140
• Plasmonics and SERS nanoprobes 141
• Novel optical mRNA biosensor 141
• Optonanogen biosensor 142
• Surface plasmon resonance technology 142
• Surface Enhanced Micro-optical Fluidic Systems 143
• Nanowire biosensors 143
• Nanowire biosensors for detection of single viruses 144
• Nanowires for detection of genetic disorders 144
• Nanowires biosensor for detecting biowarfare agents 145
• Concluding remarks and future prospects of nanowire biosensors 145
• Nanoscale erasable biodetectors 145
• Future issues in the development of nanobiosensors 146
• Applications of nanodiagnostics 147
• Nanotechnology for detection of biomarkers 147
• Nanotechnology for genotyping of single-nucleotide polymorphisms 147
• Nanoparticles for detecting SNPs 147
• Nanopores for detecting SNPs 148
• Nanobiotechnologies for single molecule detection 149
• Protease-activated quantum dot probes 149
• Labeling of MSCs with QDs 150
• Nanotechnology for detection of cancer 150
• QDs for cancer diagnosis 150
• Dendrimers for sensing cancer cell apoptosis 151
• Nanoparticles designed for dual-mode imaging of cancer 151
• Gold nanoparticles for cancer diagnosis 151
• Gold nanorods for detection of metastatic tumor cells 152
• Nanoatomic tubes for detection of cancer proteins 152
• Nanodots for tracking apoptosis in cancer 153
• Nanoparticles for the optical imaging of tumors 153
• Nanolaser spectroscopy for detection of cancer in single cells 154
• Nanotechnology-based single molecule assays for cancer 154
• Implanted magnetic sensing for cancer 154
• Nanotechnology for point-of-care diagnostics 155
• Nanotechnology-based biochips for POC diagnosis 155
• Nanoprobes for POC diagnosis 155
• Carbon nanotube transistors for genetic screening 156
• Nanocytometer 156
• POC monitoring of vital signs with nanobiosensors 156
• Detection of infectious agents 157
• Carbon nanotubes as biosensors for detection of viruses 157
• Detection of viruses by surface enhanced Raman scattering 158
• Detection of viral RNA by combined fluorescence and SERS 158
• Detection of single virus particles 158
• Electric fields for accelerating detection of viruses 158
• Fluorescent QD probes for detection of respiratory viral infections 159
• SEnsing of Phage-Triggered Ion Cascade for detection of bacteria 160
• Nanodiagnostics for the battle field and biodefense 160
• An integrated nanobio sensor 161
• Nanodiagnostics for integrating diagnostics with therapeutics 161
• Companies involved in nanomolecular diagnostics 162
• Concluding remarks about nanodiagnostics 164
• Future prospects of nanodiagnostics 165

5. Nanobiotechnology in Drug Discovery & Development 167

• Introduction 167
• Nanobiotechnology for drug discovery 167
• Gold nanoparticles for drug discovery 168
• Tracking drug molecules in cells 168
• SPR with colloidal gold particles 169
• Use of quantum dots for drug discovery 169
• Advantages of the use of QDs for drug discovery 169
• Drawbacks of the use of QDs for drug discovery 169
• Quantum dot for imaging drug receptors in the brain 170
• Ligand-conjugated nanocrystals 170
• Lipoparticles for drug discovery 170
• Biosensor for drug discovery with Lipoparticles 171
• Magnetic nanoparticles assays 171
• Micelles for drug discovery 172
• Nanolasers for drug discovery 172
• Analysis of small molecule-protein interactions by nanowire biosensors 172
• Cells targeting by nanoparticles with attached small molecules 173
• Role of AFM for study of biomolecular interactions for drug discovery 173
• Nanoscale devices for drug discovery 173
• Nanotechnology enables drug design at cellular level 174
• Nanobiotechnology-based drug development 174
• Dendrimers as drugs 174
• Fullerenes as drug candidates 175
• Nanobodies 176
• Role of nanobiotechnology in the future of drug discovery 177
• Companies using nanobiotechnology for drug discovery 177

6. Nanobiotechnology in Drug Delivery 181

• Introduction 181
• Micronization versus nanonization for drug delivery 181
• Nanoscale delivery of therapeutics 181
• Nanobiotechnology solutions to the problems of drug delivery 181
• Nanosuspension formulations 182
• Nanotechnology for solubilization of water-insoluble drugs 183
• Improved absorption of drugs in nanoparticulate form 183
• Ideal properties of material for drug delivery 183
• Nanomaterials and nanobiotechnologies used for drug delivery 183
• Viruses as nanomaterials for drug delivery 185
• Bacteria-mediated delivery of nanoparticles and drugs into cells 185
• Nanoparticle-based drug delivery 186
• Gold nanoparticles as drug carriers 186
• Calcium phosphate nanoparticles 186
• Cyclodextrin nanoparticles for drug delivery 187
• Dendrimers for drug delivery 187
• DNA-assembled dendrimers for drug delivery 188
• Fulleres for drug delivery 188
• Amphiphilic fullerene derivatives 188
• Fullerene conjugate for intracellular delivery of peptides 188
• Polymer nanoparticles 189
• PLGA-based nanodelivery technologies 189
• Polymeric micelles 189
• Chitosan nanoparticles 190
• Cationic nanoparticles 191
• Ceramic nanoparticles 191
• Nanocrystals 191
• Nanocrystalline silver 191
• Elan's NanoCrystal technology 192
• Eurand's Biorise system 193
• Nanoparticles bound together in spherical shapes 194
• Filomicelles vs spherical nanoparticles for drug delivery 194
• Encapsulating water-insoluble drugs in nanoparticles 194
• Trojan nanoparticles 195
• Prolonging circulation of nanoparticles by attachment to RBCs 195
• Self-assembling nanoparticles for intracellular drug delivery 196
• Therapeutic protein delivery from nanoparticle-protein complexes 196
• Drug delivery using "Particle Replication in Nonwetting Templates" 197
• Flash NanoPrecipitation 197
• Liposomes 198
• Basics of liposomes 198
• Stabilization of phospholipid liposomes using nanoparticles 199
• Lipid nanoparticles 199
• Polymerized Liposomal Nanoparticle 200
• Applications of lipid nanoparticles 200
• Lipid nanocapsules 200
• Lipid emulsions with nanoparticles 201
• Nanostructured organogels 202
• Liposomes incorporating fullerenes 202
• Arsonoliposomes 202
• Liposome-nanoparticle hybrids 202
• Nanogels 203
• Nanogel-liposome combination 203
• Nanospheres 204
• Nanosphere protein cages 204
• Nanovesicle technology for delivery of peptides 204
• Nanotubes 204
• Carbon nanotubes for drug delivery 205
• Lipid-protein nanotubes for drug delivery 205
• Halloysite nanotubes for drug delivery 206
• Nanocochleates 207
• Nanobiotechnology and drug delivery devices 208
• Coating of implants by ultrafine layers of polymers 208
• Nano-encapsulation 208
• Polymer nanocontainers 209
• Nanotechnology-based device for insulin delivery 209
• Mirocontainer delivery systems for cell therapy 210
• Nanopore membrane in implantable titanium drug delivery device 210
• Measuring the permeability of membranes 210
• Nano-valves for drug delivery 211
• Nanochips for drug delivery 211
• Nanobiotechnology for vaccine delivery 212
• Bacterial spores for delivery of vaccines 212
• Nanoparticles for DNA vaccines 212
• Proteosomes"! as vaccine delivery vehicles 212
• "Smart" nanoparticles for delivery of vaccines 212
• Nanospheres for controlled release of viral antigens 213
• Nanobiotechnology for antisense drug delivery 213
• Antisense nanoparticles 213
• Dendrimers for antisense drug delivery 214
• Polymethacrylate nanoparticles for antisense delivery system 214
• Nanoparticle-mediated siRNA delivery 214
• Polyethylenimine nanoparticles for siRNA delivery 214
• siRNA-PEG nanoparticle-based delivery 215
• Chitosan-coated nanoparticles for siRNA delivery 215
• Quantum dots to monitor RNAi delivery 216
• Calando's technology for targeted delivery of anticancer siRNA 216
• Nanobiotechnology for gene therapy 217
• Nanoparticle-mediated gene therapy 217
• Calcium phosphate nanoparticles as nonviral vectors 218
• Carbonate apatite nanoparticles for gene delivery 218
• Gelatin nanoparticles for gene delivery 218
• Immunolipoplex for delivery of p53 gene 219
• Intravenous nanoparticle formulation for delivery of FUS1 gene 219
• Lipid nanoparticles for targeted delivery of nucleic acids 220
• Nanoparticles as nonviral vectors for CNS gene therapy 220
• Nanoparticles linked to viral vectors for photothermal therapy 221
• Nanoparticles for p53 gene therapy of cancer 221
• Silica nanoparticles for gene delivery 221
• Targeted nanoparticle-DNA delivery to the cardiovascular system 222
• Dendrimers for gene transfer 223
• DNA-PEG complexes as nanoparticles 223
• Compacted DNA nanoparticles 223
• Cochleate-mediated DNA delivery 224
• Nanorod gene therapy 224
• Nanodel™gene vector 224
• Nanomagnets for targeted cell-based cancer gene therapy 225
• NanoNeedles for delivery of genetic material into cells 225
• Nanomachines for gene delivery 225
• Application of pulsed magnetic field and superparamagnetic nanoparticles 226
• Nanocomposites for gene therapy 226
• Nonionic polymeric micelles for oral gene delivery 226
• Nanocarriers for simultaneous delivery of anticancer drugs and DNA 227
• Delivery of siRNA by nanosize liposomes 227
• Nanobiotechnology-based drug delivery in cancer 228
• Nanoparticle formulations for drug delivery in cancer 229
• Anticancer drug particles incorporated in liposomes 229
• Cyclosert system for targeted delivery of anticancer therapeutics 229
• Encapsulating drugs in hydrogel nanoparticles 230
• Exosomes 231
• Folate-linked nanoparticles 232
• Iron oxide nanoparticles 232
• Lipid based nanocarriers 232
• Micelles for drug delivery in cancer 232
• Minicells for encapsulation and targeted delivery of nanoparticles 234
• Nanomaterials for delivery of poorly soluble anticancer drugs 234
• Nanoparticle formulations of paclitaxel 235
• Nanoparticles containing albumin and antisense oligonucleotides 236
• Non-aggregating nanoparticles 236
• Pegylated nanoliposomal formulation 236
• Perfluorocarbon nanoparticles 237
• Protosphere nanoparticle technology 237
• Multifunctional nanoparticles for treating brain tumors 237
• Nanoparticles for targeted delivery of drugs into the cancer cells 238
• Antiangiogenic therapy using nanoparticles 239
• Canine parvovirus as a nanocontainer for targeted drug delivery 239
• Carbon magnetic nanoparticles for targeted drug delivery in cancer 239
• Carbon nanotubes for targeted drug delivery to cancer cells 240
• Fullerenes for enhancing tumor targeting by antibodies 240
• Gold nanoparticles for targeted drug delivery in cancer 241
• Lipoprotein nanoparticles targeted to cancer-associated receptors 242
• Magnetic nanoparticles for remote-controlled drug delivery to tumors 242
• Nanocell for targeted drug delivery to tumor 243
• Nanodroplets for site-specific cancer treatment 244
• Nanoimmunoliposome-based system for targeted delivery of siRNA 244
• Nanoparticles for targeted antisense therapy of cancer 244
• Nanoparticles for delivery of suicide DNA to prostate tumors 245
• Polymer nanoparticles for targeted drug delivery in cancer 245
• Polymersomes for targeted cancer drug delivery 245
• Quantum dots and quantum rods for targeted drug delivery in cancer 246
• Targeted drug delivery with nanoparticle-aptamer bioconjugates 246
• Dendrimers for anticancer drug delivery 247
• Application of dendrimers in boron neutron capture therapy 248
• Application of dendrimers in photodynamic therapy 248
• Dendrimer-based synthetic vector for targeted cancer gene therapy 249
• Devices for nanotechnology-based cancer therapy 249
• Convection-enhanced delivery with nanoliposomal CPT-11 249
• Nanocomposite devices 250
• Nanoengineered silicon for brachytherapy 250
• Nanoparticles combined with physical agents for tumor ablation 250
• Nanoparticles for laser-induced cancer destruction 250
• Nanoparticles and thermal ablation 251
• Nanoparticles combined with ultrasound radiation of tumors 252
• Nanoparticles as adjuncts to photodynamic therapy of cancer 252
• Nanoparticles for boron neutron capture therapy 253
• RNA nanotechnology for delivery of cancer therapeutics 254
• Delivery of siRNAs for cancer 254
• Nanocarriers for simultaneous delivery of multiple anticancer agents 255
• Nanotechnology-based drug delivery to the CNS 255
• Nanoencapsulation for delivery of vitamin E for CNS disorders 255
• Nanoparticle technology for drug delivery across BBB 255
• Delivery across BBB using NanoDel™technology 256
• NanoMed technology to mask BBB-limiting characteristics of drugs 256
• Nanovesicles for transport across BBB 256
• Nanotechnology-based drug delivery to brain tumors 257
• Nanoparticles for delivery of drugs to brain tumors across BBB 257
• Intravenous gene delivery with nanoparticles into brain tumors 258
• Nanotechnology-based devices and implants for CNS 258
• Nanobiotechnology in cardiovascular drug delivery 259
• Liposomal nanodevices for targeted cardiovascular drug delivery 259
• Drugs encapsulated in biodegradable nanoparticles 259
• Nanotechnology-based drug-eluting stents 259
• Drugs encapsulated in biodegradable nanoparticles 259
• Magnetic nanoparticle-coated DES 260
• Nanopores to enhance compatibility of drug-eluting stents 261
• Low molecular weight heparin-loaded polymeric nanoparticles 261
• Injectable peptide nanofibers for myocardial ischemia 261
• Nanotechnology approach to the vulnerable plaque as cause of cardiac arrest 261
• Nanobiotechnology-based transdermal drug delivery 262
• Delivery of nanostructured drugs from transdermal patches 263
• Ethosomes for transdermal drug delivery 263
• NanoCyte transdermal drug delivery system 264
• Nanoparticle-based drug delivery to the inner ear 264
• Nanoparticles for pulmonary drug delivery 264
• Systemic drug delivery via pulmonary route 265
• Nanoparticle drug delivery for effects on the respiratory system 265
• Fate and toxicology of nanoparticles delivered to the lungs 265
• Nanoparticle drug formulations for spray inhalation 265
• Inhalation of glucose-sensitive nanoparticle for regulated release of insulin 266
• Pulmonary drug delivery by surface acoustic wave technology 266
• In vivo lung gene transfer using compacted DNA nanoparticles 266
• Nasal drug delivery using nanoparticles 267
• Mucosal drug delivery with nanoparticles 267
• Companies involved in nanobiotechnology-based drug delivery 268
• Future prospects of nanotechnology-based drug delivery 272
• Nanomolecular valves for controlled drug release 272
• Nanosponge for drug delivery 272
• Nanomotors for drug delivery 273

7. Clinical Applications of Nanobiotechnology 275

• Introduction 275
• Nanomedicine 275
• Clinical nanodiagnostics 276
• Nano-endoscopy 276
• Application of nanotechnology in radiology 277
• High-resolution ultrasound imaging using nanoparticles 277
• Nanobiotechnology combined with stem cell-based therapies 278
• Nanobiotechnology in tissue engineering 279
• 3D nanofilament-based scaffolds 279
• Electrospinning technology for bionanofabrication 280
• Carbon nanotubes for artificial muscles 280
• Nanomaterials for combining tissue engineering and drug delivery 281
• Nanobiotechnology for organ replacement and assisted function 281
• Exosomes for drug-free organ transplants 282
• Nanobiotechnology and organ-assisting devices 282
• Nanotechnology-based human nephron filter for renal failure 283
• Blood-compatible membranes for renal dialysis 283
• Nanosurgery 284
• Miniaturization in surgery 284
• Nanotechnology for hemostasis during surgery 284
• Minimally invasive surgery using catheters 284
• Nanorobotics 285
• Nanoscale laser surgery 285
• Nanooncology 286
• Nanobiotechnology for early detection of cancer to improve treatment 286
• Impact of nanotechnology-based imaging in management of cancer 287
• Nanoparticle-MRI for tracking dendritic cells in cancer therapy 287
• Nanoparticle-CT scan 287
• QDs aid lymph node mapping in cancer 287
• Nanosensor device as an aid to cancer surgery 288
• Role of nanoparticle-based imaging in oncology clinical trials 288
• Nanoparticle-based anticancer drug delivery to overcome MDR 289
• Nanoparticle-based management of cancer metastases 289
• Nanoshells for thermal ablation in cancer 289
• Nanobody-based cancer therapy 291
• Nanoparticles for targeting tumors 291
• Nanocarriers with TGF-β inhibitors for targeting cancer 292
• Nanoshell-based cancer therapy 292
• Nanobomb for cancer 292
• Combination of diagnostics and therapeutics for cancer 293
• Biomimetic nanoparticles targeted to tumors 293
• Dendrimer nanoparticles for targeting and imaging tumors 293
• Gold nanorods for diagnosis plus photothermal therapy of cancer 293
• Magnetic nanoparticles for imaging as well as therapy of cancer 294
• Nanoparticles, MRI and thermal ablation of tumors 294
• pHLIP nanotechnology for detection and targeted therapy of cancer 295
• QD conjugates combine cancer imaging, therapy and sensing 295
• Radiolabeled carbon nanotubes for tumor imaging and targeting 295
• Self-assembling nanoparticles for imaging and therapy of cancer 296
• Targeted therapy with magnetic nanomaterials guided by antibodies 296
• Ultrasonic tumor imaging and targeted chemotherapy by nanobubbles 296
• A cancer killing device based on nanotechnology 297
• Nanoparticles for protection against adverse effects of radiation therapy 297
• Fullerenes for protection against chemotherapy-induced cardiotoxicity 297
• Role of nanobiotechnology in personalized management of cancer 298
• Concluding remarks on nanooncology 298
• Nanoneurology 299
• Nanobiotechnology for study of the nervous system 299
• Nanowires for monitoring brain activity 299
• Nanoparticles and MRI for macrophage tracking in the CNS 300
• Nanoparticles for tracking stem cells for therapy of CNS disorders 300
• Nanobiotechnology for neurotherapeutics 301
• Nanoparticles for neuroprotection 301
• Nanotube-neuron electronic interface 302
• Nanofibers as an aid to CNS regeneration by neural progenitor cells 302
• Nanobiotechnology-based devices for restoration of neural function 302
• Nanobiotechnology-based artificial retina 303
• Nanoneurosurgery 303
• Femtolaser neurosurgery 303
• Nanofiber brain implants 303
• Nanoparticles as an aid to neurosurgery 304
• Nanoparticles for repair of spinal cord injury 304
• Nanoscaffold for CNS repair 305
• Electrospun nanofiber tubes for regeneration of peripheral nerves 305
• PEBBLEs for brain tumor therapy 306
• Bucky balls for brain cancer 306
• Application of nanotechnology to pain therapeutics 307
• Nanotechnology-based management of diabetes 307
• Nanocardiology 307
• Nanotechnology-based diagnosis and treatment 308
• Use of perfluorocarbon nanoparticles in cardiovascular disorders 308
• Cardiac monitoring in sleep apnea 308
• Detection and treatment of atherosclerotic plaques in the arteries 308
• Nanolipoblockers for atherosclerotic arterial plaques 309
• IGF-1 delivery by nanofibers to improve cell therapy for myocardial infarction 309
• Tissue engineering and regeneration of the cardiovascular system 309
• Restenosis after percutaneous coronary angioplasty 310
• Nanotechnology-based personalized medicine for cardiovascular disorders 310
• Monitoring for disorders of blood coagulation 311
• Nanoorthopedics 311
• Application of nanotechnology for bone research 311
• Reducing reaction to orthopedic implants 312
• Enhancing the activity of bone cells on the surface of orthopedic implants 312
• Nanobone implants 312
• Synthetic nanomaterials as bone implants 313
• Carbon nanotubes as scaffolds for bone growth 314
• Aligning nanotubes to improve artificial joints 314
• Cartilage disorders of knee joint 315
• Role of nanotechnology in engineering of a replacement for cartilage 315
• Nanotechnology as an aid to arthroscopy 315
• Scanning force arthroscope 316
• Nanodentistry 316
• Bonding materials 316
• Dental caries 317
• Nanospheres for dental hypersensitivity 317
• Nanomaterials for dental filling 317
• Nanomaterials for dental implants 318
• Nanoophthalmology 318
• Nanocarriers for ocular drug delivery 318
• Nanoparticle-based topical drug application to the eye 319
• Chitosan nanoparticles for topical drug application to the eye 319
• Polylactide nanoparticles for topical drug application to the eye 320
• Ophthalmic drug delivery through nanoparticles in contact lenses 320
• Nanoparticles for intraocular drug delivery 320
• DNA nanoparticles for nonviral gene transfer to the eye 321
• Nanotechnology for treatment for age-related macular degeneration 321
• Nanotechnology-based therapeutics for eye disorders 321
• Nano-engineered cornea 321
• Use of dendrimers in ophthalmology 322
• Nanotechnology for prevention of neovascularization 322
• Regeneration of the optic nerve 323
• DNA nanoparticles for gene therapy of retinal degenerative disorders 323
• Nanobiotechnology for treatment of glaucoma 323
• Nanomicrobiology 324
• Nanobiotechnology and virology 324
• Study of interaction of nanoparticles with viruses 324
• Study of pathomechanism of viral diseases 324
• Nanofiltration to remove viruses from plasma transfusion products 324
• Role of nanobacteria in human diseases 325
• Nature of nanobacteria 325
• Nanobacteria and kidney stone formation 326
• Nanobacteria in cardiovascular disease 326
• Nanotechnology-based microbicidal agents 327
• Nanoscale bactericidal powders 327
• Nanotubes for detection and destruction of bacteria 327
• Carbon nanotubes for protection against anthrax attack 328
• Nanoemulsions as microbicidal agents 328
• Silver nanoparticle coating as prophylaxis against infection 329
• Nanotechnology-based antiviral agents 329
• Nanocoating for antiviral effect 329
• Fullerenes as antiviral agents 330
• Nanoviricides 330
• Nanotechnology-based vaccines 331
• Nanofiltration of blood in viral diseases 331
• Nanoparticles to combat biological warfare agents 332
• Companies developing antiinfective agents 332
• Nanoimmunology 333
• Nanomedical aspects of oxidative stress 333
• Nanoparticle antioxidants 334
• Fullerene-based antioxidants 334
• Ceria nanoparticles as neuroprotective antioxidants 334
• Antioxidant nanoparticles for treating diseases due to oxidative stress 334
• Nanotechnology for wound healing 335
• Nanotechnology-based products for skin disorders 335
• Nanoparticles for improving targeted topical therapy of skin 335
• Topical nanocreams for inflammatory disorders of the skin 335
• Nanoparticle-based sun screens 336
• Cubosomes for treating skin disorders of premature infants 336
• Nanobiotechnology for disorders of aging 337
• Personal care products based on nanotechnology 337
• Nanotechnology for hair care 338
• Nanoparticles for chemo-radioprotection 338
• Role of nanobiotechnology in biodefense 339
• Nanosuspension formulations for treating bioweapon-mediated diseases 339
• Use of antidotes as nanoparticulate formulations 339
• Removal of toxins from blood 339
• Blood substitutes 340
• Artificial red cells 340
• Companies using nanotechnology for healthcare 340
• Nanobiotechnology for public health 342
• Nanobiotechnology and nutrition 342
• Nanobiotechnology and food industry 343
• Role of nanobiotechnology in personalized nutrition 343
• Nanobiotechnology research in the academic centers 343
• Future potential of nanomedicine 346
• US Federal funding for nanobiotechnology 347
• Nanomedicine initiative of NIH 347
• NIH Nanomedicine Center for Nucleoprotein Machines 348
• NCI Alliance for Nanotechnology in Cancer 348
• Research in cancer nanotechnology sponsored by the NCI 348
• Global Enterprise for Micro-Mechanics and Molecular Medicine 351

8. Ethical, Safety and Regulatory issues 353

• Introduction 353
• Ethical and social implications of nanobiotechnology 353
• Nanoethics 353
• Nanotechnology patents 354
• Quantum dot patents relevant to healthcare applications 355
• Challenges and future prospects of nanobiotechnology patents 355
• Legal aspects of nanobiotechnology 356
• Nanotechnology standards 356
• Preclinical testing of nanometerials for biological applications 357
• Safety concerns about nanobiotechnology 357
• Environmental safety of aerosols released from nanoparticle manufacture 358
• Toxicity of nanoparticles 358
• Testing for toxicity of nanoparticles 358
• Quantum dot safety issues 359
• Fullerene toxicity 360
• Gold nanoparticle toxicity 360
• Safety of carbon nanotubes in the body 360
• Fate of nanoparticles in the human body 361
• Pulmonary effects of nanoparticles 362
• Blood compatibility of nanoparticles 363
• Carbon nanoparticle-induced platelet aggregation 363
• Compatibility of lipid-based nanoparticles with blood and blood cells 363
• Transfer of nanoparticles from mother to fetus 363
• Cytotoxicity of nanoparticles 364
• Nanoparticle deposits in the brain 364
• Measures to reduce toxicity of nanoparticles 364
• A screening strategy for the hazard identification of nanomaterials 365
• Concluding remarks on safety issues of nanoparticles 366
• Research into environmental effects of nanoparticles 366
• Role of US government agencies in research on safety of nanoparticles 366
• Work at NanoSafety Laboratories Inc UCLA 367
• Center for Biological and Environmental Nanotechnology 367
• European NEST project for risk assessment of exposure to nanoparticles 368
• Efforts by nanotechnology companies to establish safety of nanoparticles 369
• Public perceptions of the safety of nanotechnology 369
• Evaluation of consumer exposure to nanoscale materials 370
• Safety of nanoparticle-based cosmetics 370
• Regulations in the European Union 370
• Nanotechnology-based sunscreens 371
• Cosmetic industry's white paper on nanoparticles in personal care 371
• Skin penetration of nanoparticles used in sunscreens 372
• EPA safety requirements for silver nanoparticles 372
• FDA regulation of nanobiotechnology products 372
• FDA and nanotechnology-based medical devices 374
• FDA's Nanotechnology Task Force 375
• FDA collaboration with agencies/organizations relevant to nanotechnology 376
• Regulation of nanotechnology in the European Union 377
• UK government policy on safety of nanoparticles 378
• Safety recommendations of the Royal Society of UK 378
• European Commission and safety of nanocosmetics 379

9. Nanobiotechnology Markets 381

• Introduction 381
• Markets according to areas of applications 382
• Markets for nanomedicine 383
• Markets for nanodiagnostics 383
• Imaging agents 384
• Pharmaceuticals 384
• Role of nanobiotechnology in drug delivery market 384
• Nanobiotechnology in life sciences research market 384
• Markets according to technologies 385
• Markets for nanomaterials 385
• Markets for biomedical nanodevices 385
• Markets for nanosensors 385
• Markets for nanotools 386
• Geographical distribution of markets 386
• Nanobiotechnology in the US 387
• Nanobiotechnology in the European Union 387
• Nano2Life 388
• European Technology Platform on NanoMedicine 389
• Nanobiotechnology in Australia 389
• Nanobiotechnology in Asia 390
• Japan 390
• South Korea 391
• China 391
• Taiwan 392
• India 393
• Nanobiotechnology in Russia 394
• Nanobiotechnology in the developing world 394
• Venture capital investment in nanotechnology 394
• Big pharma and nanotechnology 395
• Impact of nanobiotechnology on markets for current pharmaceuticals 395
• Unmet needs in nanobiotechnology 395
• Drivers for the development of nanobiotechnology markets 396
• Strategies for developing markets for nanobiotechnology 396
• Collaborations of industry with academic research centers 397
• Collaborations of pharmaceutical and nanotechnology companies 397
• Collaboration of chemical industry and the government 398
• Cost-benefit of nanotechnology-based drug delivery 398
• Education of healthcare professionals 398
• Education of the public 398

10. References 401

Tables

• Table 1-1: Dimensions of various objects in nanoscale 19
• Table 1-2: Classification of basic nanobiotechnologies 20
• Table 1-3: Historical landmarks in the evolution of nanotechnology 22
• Table 2-1: Companies with nanoliter devices and biochip technologies 30
• Table 2-2: Applications of optical nanoscopy 38
• Table 2-3: Applications of cantilever technology 41
• Table 2-4: Companies that provide microscopes for nanobiotechnology 42
• Table 2-5: Nanobiotechnological applications of S-layers 50
• Table 2-6: Potential applications of dendrimers in nanobiotechnology 52
• Table 2-7: Nanomaterials for biolabeling 62
• Table 2-8: Companies providing services and products for nanobiotechnology industry 66
• Table 3-1: Nanomaterials for the study of mitochondria 93
• Table 3-2: Companies that provide nanotechnologies for life sciences research 108
• Table 4-1: Nanotechnologies with potential applications in molecular diagnostics 110
• Table 4-2: Nanobiotechnologies for single molecule detection 149
• Table 4-3: Companies developing nanomolecular diagnostics 162
• Table 5-1: Basic nanobiotechnologies relevant to drug discovery 168
• Table 5-2: Companies involved in nanobiotechnology-based drug discovery and development 178
• Table 6-1: Comparison of features of drug delivery by micronization vs nanonization 181
• Table 6-2: Nanomaterials used for drug delivery 184
• Table 6-3: Liposome-nanoparticle hybrid systems 203
• Table 6-4: Examples of application of nanoparticles for gene therapy 217
• Table 6-5: Classification of nanobiotechnology approaches to drug delivery in cancer 228
• Table 6-6: Companies involved in nanobiotechnology-based drug delivery 268
• Table 7-1: Nanomedicine in the 21st century 276
• Table 7-2: Applications of nanobiotechnology for neurological disorders 299
• Table 7-3: Nanoparticles used for drug delivery in ophthalmology 319
• Table 7-4: Companies using nanotechnology-based antiinfective agents 332
• Table 7-5: Companies using nanotechnology for healthcare and therapeutics 340
• Table 7-6: Applications of nanotechnologies in food and nutrition sciences 342
• Table 7-7: Non-commercial institutes/laboratories involved in nanobiotechnology 344
• Table 8-1: FDA-approved nanotechnology based drugs 373
• Table 9-1: Nanobiotechnology markets according to areas of application 2007-2017 382
• Table 9-2: Markets for nanobiotechnology according to technologies 2007-2017 385
• Table 9-3: Geographical distribution of nanobiotechnology markets 2007-2017 386
• Table 9-4: Drivers for the development of nanobiotechnology markets 396
• Table 9-5: Strategies for developing markets for nanobiotechnology 397
• Table 9-6: Cost-benefit of nanotechnology-based drug delivery 398

Figures

• Figure 1-1: Top-down and bottom-up approaches 21
• Figure 1-2: Relationship of nanobiotechnology to healthcare and related technologies 23
• Figure 2-1: Schematic representation of Dip Pen Nanolithography (DPN) 27
• Figure 2-2: The core, branching and surface molecules of dendrimers 51
• Figure 4-1: Scheme of bio-barcode assay 128
• Figure 4-2: Scheme of a novel optical mRNA biosensor 141
• Figure 4-3: Surface plasmon resonance (SPR) technology 142
• Figure 4-4: Concept of nanopore-based sequencing 148
• Figure 5-1: Application of nanobiotechnology at various stages of drug discovery 167
• Figure 6-1: Bacteria plus nanoparticles for drug delivery into cells 185
• Figure 6-2: A lipid nanoparticle 199
• Figure 6-3: Lipid-protein nanotubes for drug delivery 206
• Figure 6-4: Nanocochleate-mediated drug delivery 224
• Figure 6-5: Nanodel™gene vector 225
• Figure 6-6: Use of micelles for drug delivery 233
• Figure 7-1: Role of nanobiotechnology in personalized management of cancer 298
• Figure 9-1: Components of the $1 trillion market for nanotechnologies in the year 2015 381
• Figure 9-2: Nanobiotechnology markets according to applications 2007-2017 383
• Figure 9-3: Geographical distribution of nanobiotechnology markets 2007-2017 387
• Figure 9-4: Unmet needs in nanobiotechnology applications 396