Nanotherapeutics : from laboratory to clinic

336 Pages·2016·33.892 MB·English

by  Chowdhury, Ezharul Hoque

Pharmaceutical Science & Regulation C NANOTHERAPEUTICS
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The emergence of nanotherapeutics is attributable to the integration of w
nanotechnology, recombinant DNA technology, and synthetic organic chemistry d
h From Laboratory to Clinic
with medicine for treating critical human diseases in a more efficient and specific
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molecular approach than therapy with conventionally designed and formulated
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drugs. Nanotherapeutics: From Laboratory to Clinic comprehensively discusses
the current shortcomings for delivery of classical (small) drugs, macromolecular
therapeutics, and recombinant vaccine via the common intravascular and
extravascular routes.
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The book describes the synthetic/chemical engineering methods as well as
recombinant, hybridoma, and phage display technologies to fabricate different
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types of nanoparticulate carriers and drugs. It also reveals the diversified
approaches undertaken by harnessing nanotechnology to overcome the multistep
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extracellular and intracellular barriers and to facilitate the development of novel
strategies for therapeutic delivery and imaging. The author elaborates on the O
preclinical and clinical trials of potential nanoparticle-based products in animal
models and patients and the approval/commercialization of nanotherapeutics, T
addressing all relevant human diseases.
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A focus on the above issues in a concise but illustrative manner fills the gap between E
the laboratory findings originating from the research on identification of cellular and
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systemic barriers of classical and macromolecular drugs along with development
of strategies for fabrication and testing of nanotherapeutics, and the clinical
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outcomes emanating from the testing of the selected potential nanotherapeutics on
patients with particular diseases. The book also fills a gap in the existing literature P
between the design and development of diversified nanotherapeutics for various
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purposes and the investigation and evaluation of potential barriers and resultant
therapeutic efficacy of those nanomedicine formulations. U
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C
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K24894
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K24894 mech_FINAL.indd 1 2/22/16 10:33 AM

NANOTHERAPEUTICS
From Laboratory to Clinic

NANOTHERAPEUTICS
From Laboratory to Clinic
Ezharul H. Chowdhury
MONASH University (Sunway campus), Malaysia
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2016 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Version Date: 20160302
International Standard Book Number-13: 978-1-4987-0752-7 (eBook - PDF)
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Contents
Preface ..............................................................................................................xiii
Acknowledgments ...........................................................................................xv
Author .............................................................................................................xvii
Chapter 1 Emergence of nanotherapeutics: Challenges
in classical drug transport versus macromolecular
drug design ..................................................................................1
1.1 Administration of small-molecule drugs: Traffic routes
toward the bloodstream .........................................................................1
1.1.1 Barriers to the oral route ...........................................................1
1.1.2 Barriers to sublingual and buccal routes ...............................2
1.1.3 Barriers to the rectal route ........................................................3
1.1.4 Barriers to the intranasal route ................................................3
1.1.5 Barriers to the pulmonary route ..............................................3
1.1.6 Barriers to intramuscular and subcutaneous routes ............4
1.1.7 Barriers to the transdermal route ............................................4
1.2 Fates of the small-molecule drugs in blood .........................................4
1.2.1 Plasma drug concentration on intensity
of therapeutic action ..................................................................4
1.2.2 Drug transport from blood capillaries
to extracellular fluid ..................................................................5
1.2.3 Drug transport from extracellular fluid to cells ....................6
1.2.4 Elimination of drugs from the body .......................................7
1.3 Major problems associated with traditional formulations
of small-molecule drugs .........................................................................8
1.4 Alteration of pharmacokinetics of small- molecule drugs
with macromolecules ..............................................................................9
1.4.1 Enhancement of drug solubility and stability .......................9
1.4.2 Prolongation of retention time in blood ...............................10
1.4.3 Facilitating fast drug release ..................................................12
1.4.4 Enabling sustained release .....................................................12
1.4.5 Passive targeting by exploiting leaky vasculature
architecture ...............................................................................13
v
vi Contents
1.4.6 Active targeting through receptor-mediated delivery .......13
1.4.7 Magnetic targeting ..................................................................13
1.5 Protein-based macromolecular drugs ................................................15
1.5.1 Proteins as independent therapeutic drugs .........................15
1.5.2 Chemically modified and carrier-bound proteins ..............15
1.5.3 Proteins as drug carriers ........................................................17
1.6 DNA/RNA-based macromolecular drugs .........................................17
1.7 Macromolecules for prodrug therapy.................................................17
1.7.1 ADEPT .......................................................................................18
1.7.2 GDEPT .......................................................................................18
1.8 Macromolecules for vaccine delivery .................................................19
1.9 Nanoparticles for photodynamic therapy ..........................................19
1.10 Macromolecules for image-guided drug delivery ............................19
Chapter 2 The ultimate destinations for delivery and release
of nanotherapeutics ..................................................................21
2.1 Sustained-release formulations ...........................................................21
2.2 Intracellular delivery and release ........................................................21
2.2.1 Endocytosis of nanoparticles .................................................22
2.2.2 Influences of physicochemical properties on cellular
uptake of nanoparticles ..........................................................22
2.3 Factors involved in drug release from nanoparticles .......................24
2.3.1 Biodegradability of pure drug particles ...............................24
2.3.2 Hydrophilicity and biodegradability of drug carriers .......24
2.3.3 Stimuli responsiveness of drug carriers or drug
carrier complexes .....................................................................25
Chapter 3 Diversity of bioactive nanoparticles from biological,
chemical, and physical perspectives .....................................29
3.1 Viral vectors ............................................................................................29
3.1.1 Retroviral vectors ....................................................................29
3.1.2 DNA virus vectors ...................................................................30
3.2 Nonviral vectors ....................................................................................31
3.2.1 Lipid-based nonviral vectors .................................................31
3.2.2 Polymer-based nonviral vectors ............................................33
3.2.3 Inorganic carriers .....................................................................35
3.3 Hybrid particles .....................................................................................38
3.3.1 Lipid–polymer hybrid nanoparticles ....................................38
3.3.2 Organic–inorganic hybrid nanoparticles .............................39
3.3.3 Inorganic hybrid nanoparticles .............................................39
3.4 Genetically engineered drug carriers .................................................39
3.5 Bioconjugation schemes for functionalization of and ligand
attachment to nanoparticle surface .....................................................40
Contents vii
Chapter 4 Fabrication strategies for biofunctional nanoparticles .....43
4.1 Chemical synthesis and engineering..................................................43
4.1.1 Production of drug nanoparticles: Top-down approaches ...43
4.1.2 Production of nonviral vectors: Bottom-up approaches ....44
4.2 Recombinant DNA, hybridoma, and phage display techniques ....56
4.2.1 Synthesis of protein-based nanoparticles ............................56
4.2.2 Generation of monoclonal antibodies ..................................57
4.2.3 Production of viral vectors .....................................................58
Chapter 5 Interactions and orientation of therapeutic drugs
in the vicinity of nanoparticles ..............................................61
5.1 Dendrimer–drug interactions ..............................................................61
5.2 Amphiphilic block copolymer–drug interactions ............................62
5.2.1 Drug loading into polymeric micelles ..................................63
5.2.2 Polymeric micellar drug conjugate .......................................63
5.2.3 Electrostatic complexation with DNA/siRNA ....................63
5.3 Liposome–drug interactions ................................................................64
5.4 Inorganic nanoparticle–drug interactions .........................................65
Chapter 6 Variable interactions of nanoparticles with blood,
lymph, and extracellular and intracellular components ...67
6.1 Serum proteins with affinity to nanoparticles ..................................67
6.1.1 Surface hydrophobicity ...........................................................69
6.1.2 Surface charge ..........................................................................69
6.1.3 Size and curvature of nanoparticles .....................................69
6.1.4 Proteins with affinity for specific chemical groups
of nanoparticles ........................................................................70
6.2 Fates of the serum protein–coated nanoparticles .............................70
6.2.1 Removal by macrophage, thrombosis,
and hypersensitivity ...............................................................70
6.2.2 Aggregation ..............................................................................71
6.2.3 Dissociation of complex and leakage of drugs ....................71
6.3 Interactions of nanoparticles with interstitial fluid and lymph .....74
6.4 Extracellular matrix–nanoparticle interactions.................................75
6.5 Interactions between nanoparticles and cell components...............76
Chapter 7 Pharmacokinetics and biodistribution
of nanoparticles ..................................................................77
7.1 Influence of particle size .......................................................................77
7.2 Influence of plasticity of nanoparticles ..............................................79
7.3 Influence of protein corona formed around nanoparticles .............79
7.3.1 Opsonin-facilitated phagocytosis..........................................79
7.3.2 Dysopsonin-enhanced blood circulation time ....................79
7.3.3 Uptake by nonphagocytic cells ..............................................81
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7.4 Influence of charge and hydrophilicity ..............................................81
7.5 Influence of endogenous membrane coating .....................................82
7.6 Influence of ligand coating ...................................................................82
7.7 Influence of coating of CD47 as a “self” marker ...............................83
7.8 Extravasation from blood through vascular endothelium ..............84
7.8.1 Permeability of vascular endothelia .....................................84
7.8.2 Different routes of traffic across continuous endothelium ...85
7.8.3 Deregulated vascular endothelium ......................................86
7.8.4 Vascular endothelium as a target for drug delivery ..........87
7.9 Transport across the interstitium ........................................................87
7.10 Cellular uptake, metabolism, and excretion ......................................89
Chapter 8 Specific roles of nanoparticles in various steps
of drug transport .......................................................................91
8.1 Protection of nucleic acid– and protein-based drugs against
degradation .............................................................................................91
8.1.1 Determinants of polyplex stability .......................................91
8.1.2 Determinants of stability of lipoplex and other lipid-
based complexes ......................................................................92
8.2 Passive targeting to facilitate endothelial escape ..............................94
8.3 Drug delivery via the lymphatic system ............................................95
8.4 Targeting cell surface receptors and facilitated uptake ...................97
8.4.1 Monoclonal antibody–mediated targeting ..........................97
8.4.2 Carbohydrate-mediated targeting ........................................99
8.4.3 Peptide-mediated targeting ...................................................99
8.4.4 Aptamer-mediated targeting ...............................................100
8.4.5 Transferrin receptor–mediated targeting ..........................100
8.4.6 Folate-mediated targeting ....................................................102
8.5 Endosomal escape ...............................................................................104
8.5.1 Fusogenic lipids or peptides ................................................105
8.5.2 Endosomal buffering ............................................................105
8.6 Nuclear targeting .................................................................................106
Chapter 9 Nanotechnology approaches to modulate transport,
release, and bioavailability of classical and emerging
therapeutics ..............................................................................109
9.1 Controlled release and bioavailability of oral
nanoformulations ................................................................................109
9.1.1 Pharmaceutical techniques for controlling
drug release ...........................................................................109
9.1.2 Strategies for drug release from nanoparticles .................112
9.2 Sustained release and bioavailability of ocular drugs ....................114
9.2.1 Different routes for controlled release
of ophthalmic drugs ...............................................................114