Advanced Targeting of the Lymphatic System

Foreword
Preface
Contents
Contributors
About the Editors
Chapter 1: Lymphatic System: History, Anatomy, Physiology, Challenges, and Opportunities
	1 Introduction
	2 History
		2.1 Historical Origin
		2.2 Renaissance Findings
		2.3 Developments in the Seventeenth and Eighteenth Centuries
		2.4 The Modern Age
		2.5 Contemporary Studies
	3 Anatomy
		3.1 Lymphatic Capillaries
		3.2 Lymphatic Vessels
		3.3 Lymphatic Ducts
		3.4 Lymphatic System Valves
		3.5 Lymph Nodes
		3.6 Lymphoid or Lymphatic Organs
	4 Physiology
		4.1 Lymph Flow
			4.1.1 Formation of Lymph
			4.1.2 Lymph Propulsion
		4.2 Physiological Function
	5 Challenges and Opportunities of Lymphatic System
		5.1 Challenges
		5.2 Opportunities
			5.2.1 Lymphatic Imaging
			5.2.2 Opportunities in Research
			5.2.3 Opportunities in Clinical Frontiers
			5.2.4 Mathematical Modeling and System Engineering
			5.2.5 Engineering Solutions for Lymphedema
	6 Conclusion
	References
Chapter 2: Advancements in Brain Lymphatic System and Its Involvement in Neurological Diseases
	1 Introduction
		1.1 Alzheimer’s Disease
		1.2 Multiple Sclerosis
		1.3 Parkinsonism
		1.4 Other Diseases
	2 G-Lymphatic Pathway: The Garbage Truck of the Brain
		2.1 Vital Components of the Brain Lymphatic System
			2.1.1 Perivascular Drainage Pathways
			2.1.2 Glymphatic System
			2.1.3 The Relationship Between CSF Circulation and the Olfactory/Cervical Lymphatic Drainage Route and Meningeal Lymphatic Vessels
			2.1.4 Connection Between the Components of the Brain Lymphatic Drainage System
		2.2 Physiological Function of the Brain Lymphatic System
			2.2.1 Aging
			2.2.2 Genetic Factors
			2.2.3 Sleep
			2.2.4 Body Posture
			2.2.5 Aquaporin-4 (AQP4) Expression and Localization
			2.2.6 Disease Conditions
	3 Impairments and Dysfunctions in Brain Lymphatic System
	4 Targeting the Lymphatic System in Neurological Disorders
		4.1 Neurodegenerative Diseases
		4.2 Neurovascular Diseases
		4.3 Neuroinflammatory Diseases
		4.4 Brain Injury
		4.5 Brain Tumor
		4.6 HIV-Associated Neurocognitive Disorder (HAND)
	5 Conclusion and Outlook
	References
Chapter 3: Lymphatic System in the Eye
	1 Introduction
		1.1 Presence of Lymphatics in the Eye
		1.2 Distribution of Lymphatics Around the Eye
			1.2.1 Conjunctival Lymphatics
			1.2.2 Corneolimbus Lymphatics
			1.2.3 Ciliary Body
		1.3 Ocular Homeostasis Through Fluid Transport
		1.4 Molecular Mechanisms for Lymphatic Development in Eye
		1.5 General In Vivo Fate of Drug After Ocular Administration: Role of Lymphatics
	2 Scope of Drug Targeting and Therapeutic Applications in Ocular Lymphatics
		2.1 Applications in Corneal Transplants to Avoid Graft Rejection
		2.2 Ocular Inflammatory Conditions
			2.2.1 Dry Eye Disease (DED)
		2.3 Tumors in Ocular Area
			2.3.1 Melanoma of Ciliary Body
			2.3.2 Carcinoma of Conjunctiva
			2.3.3 Melanoma of Conjunctiva
	3 Conclusion
	References
Chapter 4: Lymphatic System in Pancreas
	1 Introduction
	2 Lymphatic Network of Pancreas
		2.1 Pancreatic Lymphatic System in Rodents
	3 Clinical and Anatomical Classification
		3.1 Radiologic Imaging
		3.2 Sentinel Lymph Node
		3.3 Tumours of the Pancreatic Head
		3.4 Tumours of the Body and Tail
		3.5 Neoadjuvant Treatment and Lymph Node Yield
		3.6 PDAC Invasion of Lymphatic Vessels and Metastasis to the Lymph Nodes
		3.7 Lymphatic Anatomy
	4 Physiology of the Lymphatic System as Related to Structures
	5 Pancreatitis
	6 Lymph Formation
	7 Conclusions and Future Perspectives
	References
Chapter 5: Lymphatic System in Cardiovascular Disease
	1 Introduction
	2 Anatomy of Cardiac Lymphatic System
	3 Physiology of the Cardiac Lymphatic System
	4 Flow of Lymph
	5 Development of the Lymphatic System
	6 Atherosclerosis
	7 Hypertension
	8 Heart Transplantation [105–114]
	9 Conclusion
	References
Chapter 6: Lymphatic System in Gastro-Intestinal Tract
	1 Introduction
	2 General Organization of Lymphatic System
		2.1 Anatomy of the Lymphatic System in the Small Intestine
	3 Intestinal Lymphatics and Related Diseases
		3.1 Intestinal Lymphatics and Cancer
	4 Modalities to Study the Intestinal Lymphatic System
	5 Concluding Remarks
	6 Future Perspectives
	References
Chapter 7: Lymphatic System in the Liver
	1 Introduction
	2 Contents of the Lymph
	3 Lymphatic Endothelial Cells and Their Functions in the Liver and Related Diseases
		3.1 Lymphatic Endothelial Cells in the Liver
		3.2 Functions of Lymphatic Endothelial Cells and Liver Disease
		3.3 Cirrhosis
		3.4 NASH
		3.5 Liver Cancer
		3.6 Transplant
	4 Concluding Remarks
	5 Future Perspectives
	References
Chapter 8: The Lymphatic System in Kidney and Related Diseases
	1 Introduction
	2 Renal Anatomy
	3 Renal Vascular System
	4 Renal Lymphatics
	5 Lymphatic Anatomy
	6 Lymphatic Composition and Function
	7 Lymphatic Development
	8 Fluid Homeostasis
	9 Congestive Heart Failure (CHF)
	10 Acute Kidney Injury (AKI)
	11 Chronic Kidney Disease (CKD)
	12 Immune Regulation and Lymphatics
	13 Immune Function
	14 Neolymphangiogenesis
	15 Chronic Kidney Disease
	16 Transplant
	17 Autoimmune Conditions
	18 Nephrotoxic Nephritis
	19 Antiglomerular Basement Membrane Glomerulonephritis
	20 Systemic Lupus Erythematosus (SLE)
	21 Conclusions
	22 Future Perspectives
	References
Chapter 9: Lymphatic System in Lungs
	1 Introduction
	2 Cast Structure
	3 Pleural Surface
		3.1 Initial Lymphatics
		3.2 Conduit Lymphatics
	4 Lymphatic System Within the Lungs
	5 Markers
		5.1 Prox-1 (Prospero-Related Homeobox Gene)
		5.2 VEGFR-3 (Vascular Endothelial Growth Factor)
		5.3 Podoplanin
		5.4 LYVE-1 (Lymphatic Vessel Endothelial Hyaluronan Receptor-1)
		5.5 CCL21 (Chemokine Ligand 21)
	6 Lymphatic Expansion
	7 Lymph Flow
	8 Lymph Nodes and Immune Cell Trafficking
	9 Conclusion
	10 Future Perspectives
	References
Chapter 10: Lymphatic System and Dysfunctions in the Context of Male and Female
	1 Introduction
		1.1 Overview of the Lymphatic Vasculature
	2 Lymphatics: Anatomy, Physiology, and Development
		2.1 Lymphatic Growth Factors
		2.2 Structure and Function of Lymphatic Vessels
		2.3 Lymphatic Vasculature Development
		2.4 The Embryonic Origin of Lymphatic Endothelial Progenitor Cells
	3 Lymphatic Diseases
		3.1 Lymphatic-Associated Disease
			3.1.1 Lymphedema
				Primary Lymphedema
				Secondary Lymphedema
			3.1.2 Systemic Lupus Erythematosus and Dermatomyositis
			3.1.3 Blood Pressure and Lymphatics
			3.1.4 Cancer
			3.1.5 Cardiovascular Disease
	4 MicroRNAs and Lymphatics
	5 Junctional Proteins
	6 Estrogen Receptors (ERs) in Lymphatics
	7 X-Linked Factors
	8 Understudied Systems
		8.1 Female Reproduction
		8.2 Autoimmune Disease
	9 Conclusions
	References
Chapter 11: Physicochemical Properties of Carriers for Targeting Lymphatic System
	1 Introduction
	2 Drug Carriers and Their Properties for Lymphatic Targeting
		2.1 Solid Lipid Nanoparticles (SLNs)
		2.2 Nanostructured Lipid Carriers (NLCs)
		2.3 Nanoemulsion
		2.4 Liposomes
		2.5 Hydrogels and Nanogels
		2.6 Micelles
		2.7 Inorganic NPs
	3 Surface Modification of Drug Carriers for Improved Targeting of Lymphatic System
		3.1 Surfactants
		3.2 Biotin
		3.3 Folate
		3.4 Nanoparticles
		3.5 Polyethylene Glycol (PEG)
		3.6 Chitosan
		3.7 Liposomes
		3.8 Ligand
	4 Benefits and Limitations of Drug Delivery Targeting Lymphatic System
		4.1 Benefits
			4.1.1 Absorption of Long-Chain Fatty Acids
			4.1.2 Extended Circulation Time
			4.1.3 Reduced First-Pass Metabolism
			4.1.4 Targeting Specific Diseases
			4.1.5 Improving Drug Solubility
			4.1.6 Enhanced Immune Response
			4.1.7 Minimizing Systemic Side Effects
			4.1.8 Improved Therapeutic Index
			4.1.9 Long-Acting Formulations
			4.1.10 Innovative Drug Delivery Systems
		4.2 Limitations
			4.2.1 Complexity of Formulations
			4.2.2 Limited Understanding of Lymphatic Transport
			4.2.3 Risk of Immunogenicity
			4.2.4 Potential for Lymphatic System Overload
			4.2.5 Risk of Off-target Effects
			4.2.6 Variable Lymphatic Drainage
			4.2.7 Technical Challenges in Administration
			4.2.8 Cost of Development and Production
			4.2.9 Regulatory Challenges
	5 Conclusion
	6 Future Perspectives
	References
Chapter 12: Lipid-Based Carriers for Targeting Lymphatic System
	1 Introduction
	2 Liposomes
	3 Solid Lipid Nanoparticles
	4 Self-micro/Nanoemulsifying Systems
	5 Niosomes
	6 Lipid Polymer Hybrid Nanoparticles
	7 Lipidic Carriers Used for Imaging of Lymphatic System
	8 Toxicity Aspects
	9 Conclusions and Future Perspectives
	References
Chapter 13: Polymer-Based Carriers for Targeting Lymphatic System
	1 Introduction
	2 Methods of Preparation
		2.1 Solvent Evaporation
		2.2 Emulsification/Solvent Diffusion
		2.3 Emulsification/Reverse Salting Out
		2.4 Nanoprecipitation
	3 Various Approaches Used to Target the Lymphatic System
		3.1 Passive Targeting
		3.2 Active Targeting
	4 Polymer-Based Carriers Used for Various Diseases Related to Lymphatic System
		4.1 Natural
		4.2 Synthetic
	5 Polymer-Based Carriers Used for Imaging of Lymphatic System
		5.1 Natural
		5.2 Synthetic
	6 Toxicity Aspects
		6.1 Physiochemical Mechanisms
		6.2 Biochemical Mechanism
	7 Conclusion
	8 Future Perspective
	References
Chapter 14: Metal-Based Carriers for Targeting Lymphatic System
	1 Introduction
	2 Method of Preparation of Metal-Based Carriers for Lymphatic Targeting
	3 Classification of Metal-Based Carriers
		3.1 Metal-Based Nanomaterials
		3.2 Metal Oxide Nanoparticles
		3.3 Doped Metal/Metal Oxide Nanoparticle
		3.4 Metal Sulphide Nanoparticles
		3.5 Metal Organic Frameworks
	4 Physicochemical Properties of Carriers Considered for Lymphatic Targeting
		4.1 Size of the Carrier
		4.2 Surface Charge
		4.3 Lipophilicity
	5 Meatal-Based Carriers in Imaging Lymphatic System
	6 Approaches Used for Targeting Lymphatic System
	7 Metallic Carriers Used for Various Diseases Related to Lymphatic System
	References
Chapter 15: Routes of Administration for Carriers for Lymphatic Delivery
	1 Introduction
	2 Routes of Administrations for Lymphatic Delivery
	3 Subcutaneous Route for Lymphatic Delivery
	4 Pulmonary Route for Lymphatic Delivery
	5 Intraperitoneal Route for Lymphatic Delivery
	6 Intravenous Route for Lymphatic Delivery
	7 Enteral Route for Lymphatic Delivery
	8 Conclusion
	9 Future Perspectives
	References
Chapter 16: Nanoparticles for Imaging of Lymphatic System: Challenges and Future Perspective
	1 Introduction
	2 Principles of Lymphatic Imaging
	3 Lymphatic Imaging Strategies (Lymphatic Structure, Tracer Design, and Delivery)
		3.1 Lymphatic Structure
		3.2 Tracer Design
			3.2.1 MRI Contrast Agents
			3.2.2 Nuclear Imaging Tracers
			3.2.3 Fluorescent Dyes and Nanoparticles
			3.2.4 Tracer Delivery
			3.2.5 Subcutaneous Injection
			3.2.6 Intradermal Injection
			3.2.7 Intralymphatic Injection
			3.2.8 Intravenous Injection with Massage/Compression
	4 Nanoparticle-Based Imaging Agents in Preclinical for Imaging of Lymphatic System
		4.1 Exosomes
		4.2 Lipid-Based Nanocarriers
		4.3 Polymeric Nanoparticles
		4.4 Inorganic Nanoparticles
		4.5 Microneedles
		4.6 Others
	5 Challenges in Nanoparticle-Based Lymphatic Imaging
	6 Future Perspectives and Potential Applications
	7 Conclusion
	References
Chapter 17: Nanoparticles in Targeting Lymphatic System for Cancer Treatment
	1 Introduction
	2 Nanoparticles Targeting Lymphatic System
	3 Factors Influencing Effective Lymphatic System Targeting
	4 Strategies for Targeting Lymphatic Vessels
	5 Techniques for Focusing on Lymph Node Immunocytes
	6 Route of Administration for Targeting Lymphatic System
	7 In Vivo Lymphatic Imaging
	8 Conclusions
	9 Future Perspectives
	References
Chapter 18: Transdermal Application of Nanoparticles for Targeting Lymphatic System
	1 Introduction
	2 The Lymphatic System
	3 Nanocarriers for Targeting Lymphatic System Via Transdermal Route
	4 Transdermal Route Intended to Reach Lymphatic System
	5 The Lymphatic Reach
	6 Nanocarriers for Transdermal Lymphatic Targeting
	7 Strategies for Transdermal Lymphatic Targeting
	8 Biomedical Applications of Transdermal Lymphatic Targeting
		8.1 Cancer Therapy
		8.2 Lymphatic Filariasis
		8.3 Viral Infection
		8.4 Immunomodulation and Immunotherapy
		8.5 Biosensing and Bioimaging
	9 Conclusion
	References
Chapter 19: Lymphatic Tissue Engineering and Regeneration
	1 Introduction
	2 Tissue Engineering Approaches Based on Growth Factor
	3 Cellular Approach of Tissue Engineering
	4 Tissue Engineered Lymphatic Organs
	5 Approaches for Lymphatic Tissue Regeneration Using Stem Cells
	6 Pro-lymphangiogenic Factors
		6.1 VEGF-C
		6.2 TGF-β
		6.3 PDGF
		6.4 FGF
		6.5 Retinoic Acid
		6.6 Miscellaneous Factors
	7 Techniques Involved in Lymphatic Tissue Engineering
		7.1 Hydrogels
		7.2 Biochemical Stimuli
		7.3 Co-culture
		7.4 Scaffolds
			7.4.1 Nonbiodegradable Synthetic Scaffold
			7.4.2 Synthetic Biodegradable Scaffold
			7.4.3 Biocompatible Natural Polymer-Based Scaffold
			7.4.4 Scaffolding System Using Decellularization or Recellularization
			7.4.5 Cell Aggregation-Based Scaffold
			7.4.6 3D Bioprinting
		7.5 Interstitial Flow
		7.6 Extracorporeal Shockwave
		7.7 Combinatorial Techniques
	8 Challenges
	9 Current State of Lymphatic Tissue Engineering
	10 Conclusion
	References
Chapter 20: Lymphatic System and Immune Cell-Based Response
	1 Introduction
	2 Lymphatic Functions and Immune Regulation
		2.1 Innate Immunity
		2.2 Acquired Immunity
	3 Lymphatic System in Inflammation
	4 Lymphatic System in Cancer Regulation
		4.1 Brain Cancer
		4.2 Cervical Cancer
		4.3 Breast Cancer
		4.4 Colon Cancer
		4.5 Cancer Metastasis
			4.5.1 Primary Tumor Formation
			4.5.2 Invasion and Intravasation
			4.5.3 Circulation
			4.5.4 Arrest and Extravasation
			4.5.5 Formation of Microscopic Residual Disease
			4.5.6 Secondary Tumor Growth
			4.5.7 Metastatic Cascade
			4.5.8 Factors Influencing Metastasis
	5 Lymphatic System in Infectious Diseases
		5.1 Human Immunodeficiency Virus (HIV)
		5.2 Malaria
		5.3 Acute Respiratory Distress Syndrome (ARDS)
		5.4 Tuberculosis
		5.5 Dengue
	6 Conclusion
	7 Future Perspectives
	References
Chapter 21: Biomaterials for Neurotrauma Intervention
	1 Introduction of Neurotrauma
		1.1 What Causes Neurotrauma?
		1.2 Different Causes and Implications of Neurotrauma
		1.3 Pathophysiology of Neurotrauma
		1.4 Challenges of Current Neurotrauma Interventions
	2 Introduction to Lymphatic System
	3 Targeting Strategies
	4 Introduction to Biomaterials
		4.1 Properties and Characteristics of Biomaterials
		4.2 Importance of Biocompatibility
		4.3 Applications of Biomaterials
		4.4 Biomaterials in Neurotrauma
	5 Future Advancements and Innovation
	6 Conclusion
	References
Chapter 22: Challenges and Limitations of the Lymphatic Drug Delivery Systems
	1 Introduction
	2 Challenges in Drug Delivery to Lymph Node
		2.1 Drug Delivery to Lymphatic System
		2.2 Drug Routes of Administration
	3 Physicochemical Properties Governing Lymphatic Drug Delivery
		3.1 Size
			3.1.1 Challenges in Size of Nanoparticles
		3.2 Molecular Weight
		3.3 Surface Properties
			3.3.1 Challenges in Surface Properties of Nanomaterials
	4 Lymphatic Targeting
		4.1 Passive Lymphatic Targeting Delivery Pathway
			4.1.1 Challenges in Passive Lymphatic Targeting Pathway
		4.2 Active Lymphatic Targeting Delivery Pathway
			4.2.1 Challenges in Active Lymphatic Targeting Pathway
	5 Various Approaches for Delivery Systems Targeted to Lymph
		5.1 Lipid-Based Nano Drug Delivery Systems
			5.1.1 Types of Lipid-Based Nano Drug Delivery Systems
			5.1.2 Advantages of Lipid-Based Nano Drug Delivery Systems
			5.1.3 Applications of Lipid-Based Nano Drug Delivery Systems
			5.1.4 Challenges and Future Perspectives of Lipid-Based Nano Drug Delivery Systems
		5.2 Polymeric-Based Nano DDSs
			5.2.1 Advantages of Polymeric-Based Nano DDSs
		5.3 Polymeric Materials in DDSs
			5.3.1 Properties of Polymeric Materials in Drug Delivery Systems
			5.3.2 Types of Polymeric Nanoparticles Used in Drug Delivery Systems
			5.3.3 Common Methods for Polymer Nanofiber Fabrication
			5.3.4 Controlled Techniques for Drug Loading into and Release from Polymer Nanofibers
			5.3.5 Applications of Polymer Nanofibers in Drug Delivery
			5.3.6 Relation Between the Physicochemical Properties of Polymeric Nanofibers and Their Drug Delivery System Performance
		5.4 Metal-Based Nano DDSs
			5.4.1 Metal-Based Nano DDSs Advantages
			5.4.2 Use of MOFs in Drug Delivery Systems
				Properties of MOFs
			5.4.3 Types of Metal-Based Nano DDSs
			5.4.4 Fabrication Methods
			5.4.5 Controlled Techniques for Drug Loading into and Release from Metal Nanoparticles
			5.4.6 Applications of Metal Nanoparticles in Drug Delivery
			5.4.7 Relation Between the Physicochemical Properties of Metal Nanoparticles and Their Drug Delivery System Performance
		5.5 Inorganic-Based Nano DDSs
			5.5.1 Use of Inorganic Nanoparticles in Drug Delivery Systems
			5.5.2 Properties of Inorganic Nanoparticles
			5.5.3 Types of Inorganic Nano DDSs
			5.5.4 Controlled Techniques for Drug Loading into and Release from Inorganic Nanoparticles
			5.5.5 Applications of Inorganic Nanoparticles in Drug Delivery
			5.5.6 Relation Between the Physicochemical Properties of Inorganic Nanoparticles and Their DDS Performance
	6 Microneedles in Lymph Drug Delivery
		6.1 The Combination of Microneedles with Nanomedicines in Lymphatic Targeting
		6.2 Advantages and Disadvantages of Using Microneedles for Lymph Drug Delivery
			6.2.1 Benefits of Microneedles in Lymph Drug Delivery
			6.2.2 Disadvantages of Microneedles in Lymph Drug Delivery
		6.3 Challenges, Limitations, and Future Directions of Microneedles in Lymph Drug Delivery
			6.3.1 Challenges and Limitations
			6.3.2 Future Directions
		6.4 Dendrimers in Lymph Drug Delivery
			6.4.1 Advantages and Disadvantages of Using Dendrimers for Lymph Drug Delivery
			6.4.2 Challenges, Limitations, and Future Directions of Dendrimers in Lymph Drug Delivery
				Challenges and Limitations
				Future Directions
		6.5 Miscellaneous Nano Drug Delivery Systems in Lymph Drug Delivery
			6.5.1 Exosomes in Lymph Drug Delivery
			6.5.2 Advantages and Disadvantages of Using Exosomes for Lymph Drug Delivery
				Advantages of Using Exosomes as Drug Carriers in Cancer Therapy
				Disadvantages of Using Exosomes as Drug Carriers in Cancer Therapy
			6.5.3 6.5.3 Challenges, Limitations, and Future Directions of Using Exosomes as Drug Carriers in Cancer Therapy
				Challenges and Limitations
				Future Directions
		6.6 Antibodies in Lymph Drug Delivery
			6.6.1 Advantages and Disadvantages of Using Antibodies for Lymph Drug Delivery
				Advantages of Using Antibodies in Lymphatic Targeted Therapy
				Disadvantages of Using Antibodies in Lymphatic Targeted Therapy
			6.6.2 Challenges and Limitations
			6.6.3 Future Directions
	7 Niosomes
	8 Nanosuspensions
	References
Index