Drug Delivery with Targeted Nanoparticles: In Vitro and In Vivo Evaluation Methods

Cover
Title Page
Copyright Page
Table of Contents
Preface
Chapter 1: Particle Size Determination of Targeted Nanoparticles
	1.1: Introduction
	1.2: Nanotechnology
	1.3: Nanoparticles
	1.4: Targeted Nanoparticles
	1.5: Particle Size Distribution
	1.6: Particle Size Determination Methods
		1.6.1: Photon Correlation Spectroscopy/Dynamic Light Scattering
		1.6.2: Laser Light Diffraction
		1.6.3: X-Ray Diffraction Peak Broadening Analysis
		1.6.4: Scanning Electron Microscopy
		1.6.5: Transmission Electron Microscopy
		1.6.6: Atomic Force Microscopy
		1.6.7: Other Methods
	1.7: Conclusion
Chapter 2: Zeta Potential Determination of Targeted Nanoparticles
	2.1: What Is Zeta Potential?
	2.2: Determination Methods
		2.2.1: Measuring the ZP by Electrophoresis
		2.2.2: Tunable Resistive Pulse Sensing
	2.3: Characteristics of the ZP
		2.3.1: pH
		2.3.2: Ionic Strength
		2.3.3: Size Effect
			2.3.3.1: Present charge
			2.3.3.2: Conductivity
			2.3.3.3: Concentration
			2.3.3.4: Dilution
			2.3.3.5: Stability
			2.3.3.6: Reproducibility
			2.3.3.7: Population
			2.3.3.8: Pores and surface coating
			2.3.3.9: Size
			2.3.3.10: Temperature
	2.4: Golden Standards and General Protocol for ZP Measurement
		2.4.1: Reagents and Dispersants
		2.4.2: Cleaning of the Zeta Cell or Cuvette
		2.4.3: Equipment
		2.4.4: Sample Preparation
		2.4.5: Colored and Fluorescent Samples
		2.4.6: Using Buffers with Metallic Ions
		2.4.7: Measuring the ZP in a Cell Culture Medium
	2.5: Effect of the ZP on Targeting
	2.6 Conclusion
Chapter 3: Stability of Targeted Nanoparticles
	3.1: Introduction
	3.2: Significance of Stability Assessment
	3.3: Physical Stability
		3.3.1: Particle Size and Size Distribution
		3.3.2: Structure and Morphology
		3.3.3: Surface Chemistry and Surface Charge
		3.3.4: Particle Growth via Aggregation or Agglomeration
		3.3.5: Reconstitution Properties
	3.4: Chemical Stability
		3.4.1: Amount of Drug and Degradation
		3.4.2: Drug Release
		3.4.3: Drug Leakage
		3.4.4: Light Stability
		3.4.5: Biological Activity
	3.5: Conclusions
Chapter 4: Impact of PEGylation on Targeted Nanoparticulate Delivery
	4.1: Introduction
	4.2: Passive Targeting
	4.3: Active Targeting
	4.4: Brain Targeting
	4.5: Tumor Targeting
Chapter 5: Ligands and Receptors for Targeted Delivery of Nanoparticles: Recent Updates and Challenges
	5.1: Introduction
	5.2: Approaches to Targeted Drug Delivery
		5.2.1: Passive Targeting
		5.2.2: Active Targeting
	5.3: Receptors for Targeted Drug Delivery and Challenges
		5.3.1: Receptor-Specific Challenges
			5.3.1.1: Identification of receptors
			5.3.1.2: Expression characteristics of receptors
			5.3.1.3: Receptor accessibility
			5.3.1.4: Cellular uptake of receptors
	5.4: Ligand-Based Targeted Drug Delivery: Opportunities and Challenges
		5.4.1: Selection of Ligand
		5.4.2: Ligand Size
		5.4.3: Conjugation of a Targeting Ligand with a Drug/Nanocarrier
		5.4.4: Ligand Immunogenicity
	5.5: Types and in vivo Fate of Targeted Nanoparticles
	5.6: Future Prospects and Conclusion
Chapter 6: Characterization of Biological Molecule–Loaded Nanostructures Using Circular Dichroism and Fourier Transform Infrared Spectroscopy
	6.1: Introduction
	6.2: Circular Dichroism
		6.2.1: Sample Preparation and Measurement
		6.2.2: Drug-Loaded Nanoparticle Characterization by CD
	6.3: Fourier Transform Infrared Spectroscopy
		6.3.1: Sample Preparation and Measurement
		6.3.2: Application of FTIR Spectroscopy for Drug-Loaded Nanoparticle Characterization
	6.4: Conclusion
Chapter 7: Evaluation of Stimuli-Sensitive Nanoparticles in vitro
	7.1: Introduction
	7.2: Stimuli-Responsive Nanocarriers
	7.3: Stimuli-Responsive Drug Release
		7.3.1: Internal Stimuli
			7.3.1.1: pH stimuli
			7.3.1.2: Redox stimuli
			7.3.1.3: Enzyme stimuli
		7.3.2: External Stimuli
			7.3.2.1: Light stimuli
			7.3.2.2: Ultrasound stimuli
			7.3.2.3: Thermal stimuli
			7.3.2.4: Magnetic stimuli
		7.3.3: Multistimulation
	7.4: Evaluation of Stimuli Response in Cell Culture
		7.4.1: Endolysosomal Escape
		7.4.2: Cytotoxicity
	7.5: Conclusion
Chapter 8: Analytical Techniques for Characterization of Nanodrugs
	8.1: Introduction
	8.2: Analytical Characterization of Nanodrugs
		8.2.1: Drug Encapsulation and Loading Capacity
			8.2.1.1: Drug-loading content and drug-loading efficiency
			8.2.1.2: Drug entrapment/incorporation efficiency
		8.2.2: Techniques for Chemical Composition of Nanodrugs
			8.2.2.1: Chromatographic techniques
			8.2.2.2: Spectroscopic techniques
			8.2.2.3: Calorimetric techniques
		8.2.3: Purification Techniques of Nanodrugs
			8.2.3.1: Filtration
			8.2.3.2: Centrifugation
			8.2.3.3: Dialysis
			8.2.3.4: Diafiltration
			8.2.3.5: Size-exclusion chromatography
			8.2.3.6: Electrophoresis
	8.3: Physicochemical Characterization of Nanodrugs
		8.3.1: Size and Surface Morphology
			8.3.1.1: Dynamic light scattering
			8.3.1.2: Microscopic techniques
		8.3.2: Surface Area
		8.3.3: Surface Charge
	8.4: In vitro Drug Release Test Methods for Nanodrugs
		8.4.1: In vitro Drug Release
			8.4.1.1: Sample and separate method
			8.4.1.2: Continuous flow method
			8.4.1.3: Dialysis membrane methods
			8.4.1.4: Combination methods
	8.5: Stability of Nanodrugs
		8.5.1: Effect of Dosage Form on Stability
		8.5.2: Stability Issues Affecting Nanomaterial Properties
			8.5.2.1: Changes to particle size and size distribution
			8.5.2.2: Changes to particle morphology/shape
			8.5.2.3: Self-association
			8.5.2.4: Sedimentation/creaming
			8.5.2.5: Changes in the surface charge
			8.5.2.6: Change in the dissolution/release rate of the active ingredient
			8.5.2.7: Drug leakage from a nanomaterial carrier
			8.5.2.8: Changes in the chemical composition
			8.5.2.9: Interaction with the formulation or container closure
			8.5.2.10: Changes in the solid state
			8.5.2.11: Changes in microbial stability
		8.5.3: Pharmaceutical Stability-Testing Conditions
Chapter 9: Cytotoxicity and Biological Compatibility
	9.1: Analysis of Cell Viability
		9.1.1: Determination of Membrane Disruption as a Measure of Cell Death
		9.1.2: Mitochondrial Activity Assessment for Viability Testing
		9.1.3: Impedance-Based Viability Assays
	9.2: Assays for Cellular Uptake of Nanoparticles
	9.3: Drug Delivery Testing through Biological Barriers
		9.3.1: In vitro Modeling of the Mucosal Barriers for Drug Delivery
		9.3.2: Blood–Brain Barrier Models
Chapter 10: Cellular Uptake and Transcytosis
	10.1: Introduction
	10.2: Cellular Uptake Mechanisms and Nanocarrier Uptake
		10.2.1: Cellular Uptake Mechanisms
			10.2.1.1: Phagocytosis
			10.2.1.2: Pinocytosis
			10.2.1.3 Receptor-mediated endocytosis
		10.2.2: Cellular Internalization of Nanocarriers
			10.2.2.1: Intracellular events
		10.3: Effect of Physicochemical Properties of Nanocarriers on Cellular Uptake
			10.3.1: Effect of Size and Polydispersity
			10.3.2: Effect of Shape
			10.3.3: Effect of Surface Charge and Surface Modification
			10.3.4: Effect of Hydrophobicity
			10.3.5: Effect of Elasticity
	10.4: Evaluation of Cellular Uptake Pathways of Nanocarriers in Cell Culture
	10.5: Transcytosis of Nanoparticles across Cellular Barriers
		10.5.1: Cell Culture Models for Nanoparticle Barrier Permeability
			10.5.1.1: Caco-2 cell line
			10.5.1.2: HT-29 cell line
			10.5.1.3: MDCK cell line
			10.5.1.4: T84 cell line
			10.5.1.5: 3D cell culture models
	10.6 Conclusion
Chapter 11: Evaluation of 3D Cell Culture Models for Efficacy Determination of Anticancer Nanotherapeutics
	11.1: Introduction
	11.2: Types of 3D Cell Culture Models
		11.2.1: Scaffold-Based 3D Cell Culture Models
			11.2.1.1: Polymeric hard scaffolds
			11.2.1.2: Biological scaffolds
			11.2.1.3: Micropatterned surface microplates
		11.2.2: Scaffold-Free 3D Cell Culture Techniques
		11.2.3: Microfluidic 3D Cell Culture
	11.3: 3D Cell Culture as a Promising Tool in Anticancer Therapy Development
	11.4: Utilization of 3D Cell Culture Models in Evaluationof Nanoparticles
	11.5: Conclusion
Chapter 12: In vitro and in vivo Blood–Brain Barrier Models for the Evaluation of Drug Transport with Targeted Nanoparticles
	12.1: Introduction
		12.1.1: The Blood–Brain Barrier
		12.1.2: Transport Across the BBB
	12.2: In vitro BBB Models
		12.2.1: Monocultures
		12.2.2: Co-cultures
	12.3: In vivo BBB Models
	12.4: Conclusion
Chapter 13: Sterility Evaluation of Targeted Nanoparticles
	13.1: Definitions and the Need for Testing
	13.2: Short Review of Methodologies for Sterilization
		13.2.1: Removal of Microorganisms
		13.2.2: Removal of Endotoxins
	13.3: Tests Available to Assess Sterility and Endotoxin Contamination
		13.3.1: Cultivation of Fungal and Bacterial Organisms
		13.3.2: In vivo and In vitro Endotoxin Testing
			13.3.2.1: Rabbit pyrogen test
			13.3.2.2: LAL-based assays
			13.3.2.3: The rFC assay
			13.3.2.4: Alternative assays
	13.4: Interference of Nanomaterials in Endotoxin-Testing Systems
		13.4.1: Description of Interference of Nanomaterials with in vitro Test Systems
		13.4.2: Interference of Nanomaterials with in vitro Endotoxin Testing
			13.4.2.1: Optical interference
			13.4.2.2: Inhibition/enhancement
	13.5: Generic Protocol to Test Interference of Nanomaterials in Endotoxin Tests
		13.5.1: Test for Optical Interference
		13.5.2: Test for Inhibition/Enhancement
	13.6 Summary and Conclusion
Chapter 14: Evaluation of Pharmacokinetics and Biodistribution of Targeted Nanoparticles
	14.1: Introduction
	14.2: Factors Affecting Pharmacokinetics and Biodistribution of Nanoparticles
		14.2.1: Blood Circulation and the Reticuloendothelial System
		14.2.2: Properties of Nanoparticles
			14.2.2.1: Surface properties
			14.2.2.2: Size
			14.2.2.3: Composition
			14.2.2.4: Shape
	14.3: Pharmacokinetics of Nanoparticles
		14.3.1: Absorption
		14.3.2: Distribution
		14.3.3: Metabolism
		14.3.4: Excretion
	14.4: Pharmacokinetic Evaluation of Nanoparticles
	14.5: Physiologically Based Pharmacokinetic Modeling for Nanoparticles
		14.5.1: PBPK Modeling for the Evaluation of Nanoparticle Biodistribution
		14.5.2: PBPK Modeling in the Formulation Development of Nanoparticles
	14.6 Conclusion
Chapter 15: Evaluation of the in vivo Preclinical Toxicity of Targeted Nanoparticles
	15.1: Introduction
	15.2: The Effects of Physicochemical Properties of Nanomaterials on Toxicity
		15.2.1: Important Exposure Routes
			15.2.1.1: The respiratory system
			15.2.1.2: Skin
			15.2.1.3: The gastrointestinal tract
		15.2.2: Nanotoxicity of Nanomaterials and NPs
			15.2.2.1: Nanoparticle–DNA interaction
			15.2.2.2: Effect on fetuses
			15.2.2.3: Toxic effect on the immune system
	15.3: Toxicity Studies
		15.3.1: Acute Toxicity
			15.3.1.1: Acute oral toxicity
			15.3.1.2: Acute inhalation toxicity
			15.3.1.3: Acute dermal toxicity
			15.3.1.4: Acute dermal irritation/corrosion
		15.3.2: Subacute Toxicity
			15.3.2.1: Subacute oral toxicity
			15.3.2.2: Subacute dermal toxicity
			15.3.2.3: Subacute inhalation toxicity
		15.3.3: Subchronic Toxicity
			15.3.3.1: Subchronic oral toxicity
			15.3.3.2: Subchronic dermal toxicity
			15.3.3.3: Subchronic inhalation toxicity
		15.3.4: Chronic Toxicity
			15.3.4.1: Chronic toxicity studies
			15.3.4.2: Combined chronic toxicity/carcinogenicity studies
		15.3.5: Special Toxicities
			15.3.5.1: Teratogenicity: prenataldevelopmental toxicity study
			15.3.5.2: One-generation reproduction toxicity
			15.3.5.3: Two-generation reproductiontoxicity
			15.3.5.4: Carcinogenicity studies
			15.3.5.5: Immunotoxicity
			15.3.5.6: Lymph node proliferation assay
Chapter 16: Transdermal Delivery of Targeted Nanoparticles and in vitro Evaluation
	16.1: Introduction
	16.2: Skin
		16.2.1: Structure of the Skin and Barriers
			16.2.1.1: Epidermis
			16.2.1.2: Dermis
			16.2.1.3: Hypodermis
			16.2.1.4: Skin appendages
		16.2.2: Ways of Drug Delivery through the Skin
			16.2.2.1: Intracellular transition
			16.2.2.2: Intercellular transition
			16.2.2.3: Transition through skin appendages
		16.2.3: Factors Affecting Transdermal Drug Delivery
			16.2.3.1: Features that depend on the drug active substance
			16.2.3.2: Features that depend on the drug delivery systems
			16.2.3.3: Physiological properties
	16.3: Transdermal Nanocarriers
	16.4: Nanoparticles
		16.4.1: Preparation Methods of Nanoparticles
			16.4.1.1: Emulsion-solvent evaporation
			16.4.1.2: Salting out method
			16.4.1.3: Emulsions diffusion method
			16.4.1.4: Nanoprecipitation
			16.4.1.5: Polymerization
			16.4.1.6: Dialysis
			16.4.1.7: Coacervation or ionic gelation
			16.4.1.8: Supercritical fluid technology
	16.5: In vitro Studies
		16.5.1: In vitro Characterization Studies
			16.5.1.1: Size and zeta potential of nanoparticles
			16.5.1.2: Drug release profile of nanoparticles
		16.5.2: In vitro Cell Studies
			16.5.2.1: Skin permeation studies
			16.5.2.2: Skin penetration studies
	16.6: Therapeutic Application of Transdermal Nanoparticles
	16.7: Conclusion
Chapter 17: In vivo and in vitro Evaluation of Nose-to-Brain Delivery of Nanoparticles
	17.1: Introduction
	17.2: Nasal Anatomy and Physiology
	17.3: Nose-to-Brain Delivery
	17.4: Nasal Delivery Systems
		17.4.1: Colloidal Systems in the Aspect of Nasal Delivery
			17.4.1.1: Liposomes
			17.4.1.2: Cationic liposomes
			17.4.1.3: Polymeric micelles
			17.4.1.4: Dendrimers
		17.4.2: Nanoparticular Systems in the Aspect of Nasal Delivery
			17.4.2.1: Solid lipid nanoparticles
			17.4.2.2: Polymeric nanoparticles
	17.5: Methods for Determining Efficiency of Nose-to-Brain Delivery of Nanoparticles
		17.5.1: In vitro Drug Release Methods
		17.5.2: In vitro Permeation Studies
		17.5.3: In vitro Toxicity Studies
		17.5.4: Ex vivo Permeation and Histopathological Studies
		17.5.5: In vivo Permeation Studies for Nasal Delivery of Nanoparticles
	17.6: Conclusion
Chapter 18: Evaluation of Targeted Nanoparticles for Ocular Delivery
	18.1: Introduction
	18.2: Pharmacokinetic and Bioavailability Studies
	18.3: Biodistribution Studies
	18.4: Tolerance Assays
	18.5: Conclusion
Chapter 19: Vaginally Applied Nanocarriers and Their Characterizations
	19.1: Introduction
	19.2: Novel Approaches for Vaginal Drug Delivery Systems
	19.3: Nanotechnology-Based Vaginal System
	19.4: Nanosized Dosage Forms Used for Vaginal Drug Delivery
		19.4.1: Vesicular systems for Vaginal Drug Delivery
			19.4.1.1: Liposomes
			19.4.1.2: Niosomes, ethosomes, and transethosomes
		19.4.2: Polymeric Nanoparticles
		19.4.3: Microemulsions
		19.4.4: Dendrimers
		19.4.5: Nanofibers
		19.4.6: Cyclodextrins
	19.5: Conclusion
Chapter 20: Oral Administration of Nanoparticles and Approaches for Design, Evaluation, and State of the Art
	20.1: Introduction
	20.2: Oral Drug Delivery
		20.2.1: Gastrointestinal Tract and Related Challenges
		20.2.2: Intestinal Absorption
	20.3: Nanoparticulate Drug Delivery Systems for Oral Administration
		20.3.1: Nanobased Strategies to Overcome the Challenges in Oral Drug Delivery
			20.3.1.1: Improving drug solubility
			20.3.1.2: Improving stability through the GIT
			20.3.1.3: Improving adhesion and diffusion through the GIT
	20.4: Oral Administrations of Nanoparticulate Drug Delivery Systems
		20.4.1: Cancer Therapy
		20.4.2: Protein and Peptide Drugs
		20.4.3: Intestinal Targeting
			20.4.3.1: Inflammatory bowel disease and colon targeting for colorectal cancer
Chapter 21: Drug Resistance Mechanisms and Strategies to Overcome Drug Resistance with Nanoparticulate Systems
	21.1: Introduction
	21.2: Antimicrobial Resistance
		21.2.3: Nanoparticles and AMR
			21.2.3.1: Metallic nanoparticles
			21.2.3.2: Polymeric nanoparticles
			21.2.3.3: Nitric oxide–releasing nanoparticles
		21.2.4: In vitro Antimicrobial Activity Methods
			21.2.4.1: Disk diffusion
			21.2.4.2: Dilution
			21.2.4.3: The checkerboard method
			21.2.4.3: Time–kill curves
		21.2.1: Antibiotic Resistance
		21.2.2: Development Mechanism of AMR
	21.3: Anticancer Resistance
		21.3.1: The Potential Mechanism of Anticancer Drug Resistance
			21.3.1.1: Tumor heterogeneity and microenvironment
			21.3.1.2: Mitochondria-mediated chemoresistance
			21.3.1.3: Epithelial–mesenchymal transition
			21.3.1.4: Altering drug targeting
			21.3.1.5: Increased drug efflux
		21.3.2: Nanoparticles in Overcoming Chemoresistance
			21.3.2.1: Targeted drug delivery
			21.3.2.2: Delivery of chemosensitizing molecules
			21.3.2.3: Subcellular drug delivery
		21.3.3: In vitro Chemosensitivity Assay
			21.3.3.1: MTT assay
			21.3.3.2: Clonogenic assay
Chapter 22: Clinical Trials of Targeted Nanoparticulate Drug Delivery Systems
	22.1: Introduction
	22.2: Clinical Trials of Targeted Nanoparticulate Drug Delivery Systems
		22.2.1: MM-302
		22.2.2: ThermoDox
		22.2.3: BIND-014
	22.3: Conclusion
Chapter 23: Evaluation of Targeted Mesoporous Silica Nanoparticles
	23.1: Synthesis and Manufacturing
	23.2: Biocompatibility
	23.3: Functionalization
	23.4: Targeting
		23.4.1: Passive Targeting
			23.4.1.1: Size and Shape
			23.4.1.2: Surface charge and composition
		23.4.2: Active Targeting
			23.4.2.1: Antibodies
			23.4.2.2: Proteins/peptides
			23.4.2.3: Vitamins
			23.4.2.4: Saccharides
	23.5: Conclusion
Chapter 24: Evaluation of Targeted Liposomes
	24.1: Introduction
	24.2: Classification of Liposomes
		24.2.1: Based on Structure and Size
			24.2.1.1: Unilamellar vesicles
			24.2.1.2: Multilamellar vesicles
		24.2.2: Based on the Drug Release Mechanism
	24.3: Manufacturing of Liposomes
		24.3.1: Composition
		24.3.2: Direct Mechanical Agitation/Sonication
		24.3.3: Thin-Film Hydration
		24.3.4: Solvent Dispersion/Injection
		24.3.5: Lyophilization of Liposomes
		24.3.6: Sterilization Methods for Liposomes
	24.4: Characterization of Liposomes
		24.4.1: Size, Size Distribution, and Concentration
		24.4.2: Determination of Encapsulated Molecules inside Liposomes
		24.4.3: Physicochemical Characterization
			24.4.3.1: Determination of lamellarity
			24.4.3.2: Transition temperature
			24.4.3.3: Surface charge
			24.4.3.4: Zeta potential
		24.4.4: Surface Morphology and Polymer Modification
		24.4.5: Liposome–Drug Interaction
		24.4.6: Determination of the Residual Organic Solvent
		24.4.7: Regulatory Perspective for Liposome Registration
Chapter 25: Prospects of Nanomedicine with Nanocrystal Technology
	25.1: Nanonization Techniques and Application Areas
	25.2: Nanoparticle Systems
		25.2.1: Nanocrystal Definition
		25.2.2: Properties of Nanocrystals
			25.2.2.1: Increase in dissolution rate by surface area enlargement
			25.2.2.2: Increase in saturation solubility
			25.2.2.3: Increased adhesion to cell membranes
		25.2.3: Production of Nanocrystals
			25.2.3.1: Bottom up processes
			25.2.3.2: Top-down processes
			25.2.3.3: Other techniques for the production of drug nanocrystals
		25.2.4: Advantages and Application Areas of Orally Applied Nanocrystalline Formulations
Chapter 26: Characteristics of Marketed Nanopharmaceutics
	26.1: Different Types of Nanocarriers and Their Main Advantages
	26.2: From Laboratory to Market
	26.3: Approved Nonopharmaceutics and Their Features
		26.3.1: Liposomal-Based Nanopharmaceutics
			26.3.1.1: Liposomal-based nanodrugs approved for anticancer treatment
			26.3.1.2: Liposomal nanodrugs approved for antifungal treatment
			26.3.1.3: Liposome-based drugs approved for analgesic treatment
			26.3.1.4: Liposome-based drug approved for neovascularization treatment
			26.3.1.5: Lipid-based drug approved for hereditary transthyretin-mediated amyloidosis treatment
		26.3.2: Polymer-Based Nanopharmaceutics
		26.3.3: Protein-Based Nanopharmaceutics
		26.3.4: Micelle-Based Nanopharmaceutics
		26.3.5: Crystalline-Based Nanopharmaceutics
		26.3.6: Inorganic/Metallic Nanopharmaceutics
	26.4: Nanopharmaceutical Market Size
	26.5: Future Perspective
Chapter 27: Regulatory Guidelines of the US Food and Drug Administration and the European Medicines Agency for Actively Targeted Nanomedicines
	27.1: Introduction
	27.2: The European Medicines Agency’s Scientific Guidelines for Actively Targeted Nanomedicines
		27.2.1: Reflection Paper on Surface Coatings: General Issues for Consideration Regarding Parenteral Administration of Coated Nanomedicine Products
		27.2.2: Data Requirements for Intravenous Liposomal Products Developed with Reference to an Innovator Liposomal Product
		27.2.3: Development of Block-Copolymer-Micelle Medicinal Products
		27.2.4: Data Requirements for Intravenous Iron-Based Nanocolloidal Products Developed with Reference to an Innovator Medicinal Product
	27.3: The Food and Drug Administration’s Scientific Guidelines for Actively Targeted Nanomedicines
		27.3.1: Considering whether an FDA-Regulated Product Involves the Application of Nanotechnology
		27.3.2: Drug Products, Including Biological Products, That Contain Nanomaterials
			27.3.2.1: Quality: chemistry, manufacturing, and controls
			27.3.2.2: Nonclinical studies
			27.3.2.3: Clinical development
		27.3.3: Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation
			27.3.3.1: Chemistry, manufacturing, and controls
			27.3.3.2: Human pharmacokinetics: Bioavailability and bioequivalence
			27.3.3.3: Labeling
	27.4: Conclusion
Index