Smart Polymeric Nano-Constructs in Drug Delivery: Concept, Design and Therapeutic Applications

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Smart Polymeric Nano-Constructs in Drug Delivery: Concept, Design and Therapeutic Applications
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Contents
Contributors
Chapter 1: Introduction to smart polymers and their application
	1. Introduction
		1.1. History
		1.2. Concept and design
		1.3. Why smart polymers?
	2. Types of smart polymers
		2.1. Stimulus-responsive polymers
			2.1.1. Temperature-responsive polymers
				LCST polymers
				UCST polymers
			2.1.2. pH-responsive polymers
				Polyanions/polyacids
				Polycations/polybasic
			2.1.3. Photoresponsive polymers
				Reversible photoresponsive polymers
				Irreversible photoresponsive polymers
			2.1.4. Field-responsive polymers
				Electric field-responsive polymers
				Magnetic field-responsive polymers
			2.1.5. Ultrasound-responsive polymers
		2.2. Bioresponsive polymers
			2.2.1. Glucose-responsive polymers
				Based on the Gox-induced glucose oxidation
				Based on binding with lectins
				Based on a covalent bond with boronic acid and analogs
			2.2.2. Enzyme-responsive polymers
		2.3. Shape memory polymers
			2.3.1. Thermally induced shape memory polymers
			2.3.2. Light-induced shape memory polymers
			2.3.3. Reversible bonds-based shape memory polymers
			2.3.4. Reversible shape memory polymers
		2.4. Self-healing polymers
			2.4.1. Extrinsic self-healing polymers
			2.4.2. Intrinsic self-healing polymers
		2.5. Hydrogels
			2.5.1. Temperature-responsive hydrogel
			2.5.2. pH-responsive hydrogel
			2.5.3. Photoresponsive hydrogel
			2.5.4. Electric field-responsive hydrogel
			2.5.5. Magnetic field-responsive hydrogel
	3. Application of smart polymers
		3.1. Tissue engineering
		3.2. Drug delivery system
		3.3. Biomedical devices
		3.4. Biosensors or actuators
	4. Conclusions
	Acknowledgments
	References
Chapter 2: Thermoresponsive polymers: Phase behavior, drug delivery, and biomedical applications
	1. Introduction
	2. Thermoresponsive polymers
		2.1. Phase transition behaviors of thermoresponsive polymers
	3. Applications of thermoresponsive polymers in biomedical and drug delivery
		3.1. Thermoresponsive polymeric micelles
		3.2. Thermoresponsive nanoparticles
		3.3. Thermoresponsive liposomes
		3.4. Thermoresponsive hydrogels
	4. Conclusion and future prospects
	References
	Further reading
Chapter 3: pH-sensitive polymeric nanocarriers for enhanced intracellular drug delivery
	1. Introduction
	2. pH-dependent cellular microenvironments
	3. Different strategies for the development of pH-sensitive polymeric nanocarriers
		3.1. pH-responsive linkages
		3.2. pH-sensitive nanomaterials
			3.2.1. Polymeric micelles
			3.2.2. Polymeric nanogels
			3.2.3. Polymer-drug conjugates
			3.2.4. Core-shell nanocarriers
			3.2.5. Inorganic nanocarriers
	4. Mechanism of drug release from pH-sensitive nanocarriers
	5. pH-responsive nanocarriers for drug delivery and targeting
		5.1. Small molecule drug delivery
		5.2. Gene delivery
		5.3. Dual drug delivery
		5.4. Combination with photothermal/photodynamic therapy
	6. pH-responsive nanocarriers for disease diagnosis
	7. Challenges in the design of pH-sensitive nanocarriers
	8. Future perspectives
	9. Concluding remarks
	References
Chapter 4: Photoresponsive nanocarriers for the delivery of bioactives
	1. Introduction
	2. Photoresponsiveness: Light as source for triggering drug release
		2.1. Photoresponsive biomaterials
		2.2. Response of chemical structure to the light sources
	3. Development of photosensitive nanocarriers
	4. Mechanisms of photoresponsive nanoparticles for drug release
		4.1. Drug release by NIR light
		4.2. Photothermal responsive
	5. Photoresponsive drug delivery nanocarriers
		5.1. Gold nanoparticles
		5.2. Polymeric nanobioconjugates
		5.3. Polymeric nanoparticles
		5.4. Polymeric micelle
		5.5. Liposomes
		5.6. Polymersomes
		5.7. Mesoporous silica nanoparticles
		5.8. Hydrogels
		5.9. Nanogels
	6. Conclusions and future prospects
	Acknowledgment
	References
Chapter 5: Magnetically responsive polymeric gels and elastomeric system(s) for drug delivery
	1. Introduction
	2. Polymer gels and elastomers
	3. Magnetic modulation of polymer gels and elastomers
	4. Transport phenomenon in magnetic drug delivery
		4.1. Convective transport in magnetic drug delivery
			4.1.1. Applications
	5. For disease therapy
		5.1. Delivery of chemotherapeutic drugs to liver tumors
		5.2. Magnetic targeting of radioactivity
		5.3. Treatment of tumors with magnetically induced hyperthermia
		5.4. Magnetically enhanced gene therapy
		5.5. Magnetically responsive systems for the diagnosis of diseases
	6. Concluding remarks and future prognosis
	References
Chapter 6: Bioadhesive and phase change polymers for drug delivery
	1. Introduction
	2. Bioadhesive polymers in drug delivery
	3. Advantages of bioadhesive polymers in drug delivery
	4. Theories of bioadhesion
		4.1. The electrostatic theory
		4.2. The wettability theory
		4.3. The diffusion interpenetration theory
		4.4. The adsorption theory
		4.5. The fracture theory
		4.6. Mechanical theory
	5. Requirements for an ideal bioadhesive polymer
	6. Factors affecting the bioadhesive polymers
		6.1. Polymer-related factors
			6.1.1. Molecular weight
			6.1.2. Cross-linking
			6.1.3. Functional group
			6.1.4. Chain length
			6.1.5. Polymer concentration
			6.1.6. Spatial conformation
		6.2. Environmental factors
			6.2.1. pH
			6.2.2. Degree of hydration
			6.2.3. Initial contact time
			6.2.4. Applied pressure
			6.2.5. Ionic strength
			6.2.6. Mucus gel viscosity
		6.3. Physiological factors
			6.3.1. Mucin turnover
			6.3.2. Disease states
	7. Classification of bioadhesive polymers
		7.1. Classification based on polymer origin
			7.1.1. Natural polymers
			7.1.2. Synthetic polymers
		7.2. Classification based on solubility
			7.2.1. Water-soluble polymers
			7.2.2. Water-insoluble polymers
		7.3. Classification based on polymer charge
			7.3.1. Cationic polymers
			7.3.2. Anionic polymers
			7.3.3. Nonionic polymers
	8. Commonly employed bioadhesive polymers in drug delivery
		8.1. Chitosan
		8.2. Starch
		8.3. Alginates
		8.4. Hyaluronic acid
		8.5. Carbopol
		8.6. Sodium carboxymethyl cellulose
		8.7. Polyethylene glycol
		8.8. Polyacrylates
	9. Phase change polymers
		9.1. pH-responsive polymers
		9.2. Temperature/thermoresponsive polymers
		9.3. Light-responsive polymers
		9.4. Metabolite-responsive polymers
		9.5. Electric current-responsive polymers
		9.6. Ultrasound-responsive polymers
		9.7. Magnetic-responsive polymers
		9.8. Osmotic-responsive polymers
		9.9. Dual-/multiresponsive polymers
	10. Application of bioadhesive and phase change polymers in drug delivery
		10.1. Buccal drug delivery
		10.2. Ocular drug delivery
		10.3. Nasal drug delivery
		10.4. Gastrointestinal drug delivery
		10.5. Vaginal drug delivery
		10.6. Rectal drug delivery
	11. Conclusions
	References
Chapter 7: Block copolymer micelles as long-circulating drug vehicles
	1. Introduction
	2. Design criteria of block copolymers for self-assembly of polymeric micelles
		2.1. Molecular weight
		2.2. Critical micelle concentration
		2.3. Hydrophilic (corona-forming) blocks
		2.4. Hydrophobic (core forming) blocks
		2.5. Crystallinity of the core-forming blocks
	3. Micelle preparation method
		3.1. Dialysis method
		3.2. Thin film hydration method
		3.3. Oil-in-water emulsion method
		3.4. Solid dispersion method
	4. General considerations and characteristics of micelles
		4.1. Drug partition coefficient
		4.2. Core-drug compatibility
		4.3. Drug/polymer ratio
		4.4. Micellar dimensions
	5. Synthesis of amphiphilic block copolymers possessing PEG chain for stealth effect
	6. Fate of polymeric systems upon systemic delivery
		6.1. Role of physical barriers
		6.2. Role of biological barriers
	7. Avoiding rapid clearance from systemic circulation
		7.1. Manipulating physical properties
		7.2. Manipulating chemical properties
	8. Future trends
	9. Conclusions
	References
Chapter 8: Polymer-drug conjugates: Origins, progress to date, and future directions
	1. Introduction
	2. Advantages of polymer-drug conjugates
	3. Origins of polymer-drug conjugates
	4. Types of polymer-drug conjugates for drug targeting
		4.1. End group system
		4.2. Pendant group system
	5. Targeted vs nontargeted conjugates
	6. Approaches for designing the polymer-drug conjugates
	7. Gap between the current studies and clinical application for polymeric-drug conjugates
	8. Approaches for the enhancing the transportation of polymer-drug conjugates
	9. Clinical status of polymer-drug conjugates
	10. Future prospects of polymer-drug conjugates
	References
Chapter 9: Molecularly imprinted polymers for drug delivery and biomedical applications
	1. Introduction
	2. Concept behind the molecularly imprinted polymers
	3. Designing MIPs for drug delivery
		3.1. MIP designing
		3.2. Production limitations
		3.3. Template expulsion
			3.3.1. Solvent-based extraction
			3.3.2. Physical assistance based-extraction
			3.3.3. Subcritical or supercritical solvent-based extraction
	4. MIP-based drug delivery systems
	5. Stimuli-responsive molecularly imprinted polymers
	6. MIPs for drug delivery and biomedical applications
		6.1. Targeted drug release
		6.2. Cell recognition
		6.3. Gastrointestinal disorders
		6.4. Ophthalmic disorders
		6.5. Chemotherapy
		6.6. Gene therapy
		6.7. Biomedical application
		6.8. Molecular imaging and disease diagnosis
	7. Conclusions
	References
Chapter 10: Dendritic polymer macromolecular carriers for drug delivery
	1. Introduction
	2. Properties of dendritic polymer macromolecular carriers
	3. Synthesis of dendrimers
		3.1. Divergent approach
		3.2. Convergent approach
		3.3. Other approaches
			3.3.1. Hypercores and branched monomer growth method
			3.3.2. Double exponential growth method
			3.3.3. Lego chemistry
	4. Toxicity of dendritic polymer macromolecules
		4.1. Cytotoxicity
		4.2. Hematological toxicity
		4.3. Immunogenicity
		4.4. In vivo toxicity
	5. Types of dendritic polymer macromolecular carriers
		5.1. Functionality-based dendrimers
			5.1.1. Polypropylene imine (PPI) dendrimers
			5.1.2. Poly(amidoamine) (PAMAM) dendrimers
			5.1.3. PAMAMOS dendrimers
			5.1.4. Frechet-type dendrimers
			5.1.5. Coro-shell tecto dendrimers
			5.1.6. Chiral dendrimers
			5.1.7. Liquid crystalline dendrimers
			5.1.8. Peptide dendrimers
			5.1.9. Multiple antigen peptide (MAP) dendrimers
			5.1.10. Glycodendrimers
			5.1.11. Hybrid dendrimers
			5.1.12. Janus dendrimers
			5.1.13. Polylysine dendrimers
		5.2. Biodegradable dendrimers
			5.2.1. Monomers based on bis-HMPA
			5.2.2. Other aliphatic ester monomers
			5.2.3. Alternating polyester dendrimers
			5.2.4. Degradable dendrimers not based on ester bonds
		5.3. Stimuli-responsive dendrimers
			5.3.1. pH-responsive systems
			5.3.2. Redox microenvironment
			5.3.3. Enzymatic stimuli dendrimers
			5.3.4. Photosensitive dendrimers
			5.3.5. Thermo-responsive dendrimers
	6. Drug delivery strategies
		6.1. Encapsulation
		6.2. Conjugation
		6.3. Electrostatic interaction
	7. Applications of dendritic macromolecules
		7.1. Dendrimers in the delivery of anticancer agents
		7.2. Dendrimers in gene delivery
		7.3. Dendrimers in the delivery of antimicrobial agents
		7.4. Dendrimers in neurodegenerative diseases
		7.5. Miscellaneous drug delivery applications
			7.5.1. Cardiovascular diseases
			7.5.2. Diabetes mellitus
	8. Conclusions
	References
Chapter 11: Advances in hydrogel-based controlled drug-delivery systems
	1. Introduction
	2. Hydrogels
	3. Structure of hydrogels
	4. Classification of hydrogels
	5. Preparation of hydrogels
	6. Characterization of hydrogels
		6.1. Physicochemical characterization
			6.1.1. Solubility
			6.1.2. Swelling measurement
			6.1.3. Sol-gel analysis
			6.1.4. pH sensitivity
			6.1.5. Rheology
			6.1.6. UV spectroscopy
			6.1.7. Infrared spectroscopy
			6.1.8. Mass spectroscopy
			6.1.9. Nuclear magnetic resonance
			6.1.10. Dynamic light scattering
			6.1.11. X-ray diffraction analysis
		6.2. Morphological and structural characterization
			6.2.1. Transmission electron microscopy (TEM)
			6.2.2. Scanning electron microscopy (SEM)
			6.2.3. Atomic force microscopy (AFM)
			6.2.4. Confocal microscopy
		6.3. Thermal characterization
			6.3.1. Differential scanning calorimetry (DSC)
			6.3.2. Thermal gravimetric analysis (TGA)
			6.3.3. Dynamic mechanical thermal analysis (DMTA)
	7. Therapeutic application of hydrogels
		7.1. Hydrogels for the vision system
		7.2. Hydrogels for the small intestine
		7.3. Hydrogels for the skin
		7.4. Hydrogels for the colon
		7.5. Hydrogels for the respiratory system
		7.6. Hydrogels for drug-delivery to brain
		7.7. Advanced use of hydrogels for tissue engineering and tissue imaging
			7.7.1. Naturally derived materials
			7.7.2. Synthetically derived materials
	8. Current research and future prospects
	References
Chapter 12: Stimuli-responsive protein fibers for advanced applications
	1. Introduction
	2. Synthesis
	3. Various responsive systems
		3.1. pH-responsive systems
		3.2. Thermo-responsive systems
		3.3. Enzyme-responsive systems
		3.4. Light-responsive systems
		3.5. Ultrasound-responsive systems
	4. Preclinical studies
		4.1. RATEA-16 nanofibrillar hydrogel in the treatment of hyperglycemia
		4.2. IGF-1 functionalized peptide nanofibers for treatment of myocardial infarction
		4.3. PVNFKFLSH-hemopressin peptide for the treatment of atherosclerosis
		4.4. RATEA-16 polypeptide employed for wound healing
		4.5. RADA 16-I and RADA 16-mix in neuron repair and regeneration
		4.6. FDPC polypeptide for enhanced drug delivery in tumor therapy
		4.7. NF/PDGF-BB in myocardial protection
		4.8. PEG-Pep-TPE (FFKY) in synergistic chemotherapy
		4.9. Using BP-KLVFF-SWTLYTPSGQSK (BFS) to prevent tumor metastasis
		4.10. (Fbp-GDFDFDYD (E, S, or K)-ss-ERGD) as immune adjuvant in anticancer therapy
	5. Clinical trial studies
		5.1. Silk/elastin/collagen-based polymers
			5.1.1. Silk fibroin coated with a bioactive layer
			5.1.2. SilkBridge-A biocompatible silk fibroin-based scaffold
			5.1.3. Matriderm-Collagen/elastin carrier
		5.2. Polymeric micellar systems in clinical trials
			5.2.1. NK911
			5.2.2. NK105
			5.2.3. NC-6004
	6. Applications of self-assembled peptide nanofibers
		6.1. Regenerative and reparative medicines
		6.2. Vaccine and immunotherapeutic
		6.3. Drug delivery systems
		6.4. Stimuli-responsive drug delivery
		6.5. 4D printing
		6.6. Tissue engineering
		6.7. Biosensors and biomaterials
		6.8. Actuators
		6.9. Disease-specific study-Diagnosis and treatment
	7. Marketed preparations
		7.1. BD PuraMatrix
		7.2. D-Fibroheal Ag foam
	8. Conclusion and future prospects
	References
Chapter 13: Smart drug delivery systems and their clinical potential
	1. Introduction
	2. Potential stimuli-responsive nanocarriers
		2.1. Liposomes
		2.2. Micelles
		2.3. Polymeric nanoparticles
		2.4. Nanogels
		2.5. Dendrimers
		2.6. Mesoporous silica nanoparticles
		2.7. Gold nanocarriers
		2.8. Carbon nanotubes
		2.9. Iron oxide nanoparticles
	3. Stimuli-responsive DDSs: Design, rationale, and types
		3.1. Endogenous/internal stimuli-responsive DDS
			3.1.1. Redox-responsive DDS
			3.1.2. pH-responsive DDS
			3.1.3. Enzyme-responsive DDSs
		3.2. Exogenous/external stimuli-responsive SDDs
			3.2.1. Temperature-responsive DDSs
			3.2.2. Magneto-responsive DDSs
			3.2.3. Ultrasound-responsive DDSs
			3.2.4. Light-responsive DDS
	4. Dual/multistimuli-responsive DDSs
	5. Clinical scenario of stimuli-responsive DDS
	6. Conclusions
	Conflict of interests
	References
Chapter 14: Novel biomimetic polymersomes as polymer therapeutics for drug delivery
	1. Introduction
		1.1. Self-assembly and fabrication of polymersomes from amphiphilic block copolymers
	2. Background
	3. Need and importance
	4. Variants of polymersomes
		4.1. Peptide-based polymersomes
			4.1.1. Peptosomes
			4.1.2. Polyion complex vesicles (PICsomes)
		4.2. Protein-based polymersomes
		4.3. Multicompartmentalized polymersomes
			4.3.1. Double emulsion method for preparing multicompartments
			4.3.2. Self-assembly method for preparing multicompartments
		4.4. Synthesis of photoresponsive block copolymers
	5. Chemistry and preparation of polymersomes
		5.1. Rehydration
		5.2. Electroformation
		5.3. Polymerization-induced self-assembly (PISA)
		5.4. Direct injection
		5.5. Emulsion phase transfer
		5.6. Microfluidics
	6. Therapeutic applications
		6.1. Polymersomes as nanoreactors
		6.2. Polymersomes for medical applications
			6.2.1. Cancer drug delivery
		6.3. Vaccine delivery
		6.4. Nucleic acid delivery
	7. Beyond polymersomes
	8. Conclusions
	References
Chapter 15: Bioinspired and biomimetic conjugated drug delivery system(s): A biohybrid concept combining cell(s) and dr
	1. Bioinspired systems: An insight
	2. Methods for active drug delivery of bioconjugates
	3. Virus-inspired bioactive delivery systems
		3.1. Virosomes
		3.2. Virus-mimicking particles
	4. Mammalian cell-based bioactive delivery systems
		4.1. Erythrocytes
		4.2. Immune cells
	5. Cell-inspired bioactive delivery systems
		5.1. Exosomes
		5.2. Cancer cell membrane
	6. Polymer-based bioactive delivery systems
		6.1. Chitosan
	7. Bioactive(s) delivery via biomacromolecular systems
		7.1. Albumins
		7.2. Nucleic acid
		7.3. Lipoprotein
	Acknowledgment
	References
Chapter 16: Conductive polymers and composite-based systems: A quantum leap in the drug delivery arena and ther
	1. Introduction
	2. Conductive polymers
		2.1. Historical perspective
		2.2. Importance in drug delivery
	3. Synthesis of conductive polymers (CPs)
		3.1. Electrochemical synthesis
		3.2. Chemical synthesis
	4. Types of CPs
		4.1. Polypyrrole (PPy)
		4.2. Polyaniline (PAni)
		4.3. Polythiophene and derivatives
	5. CP composites
	6. Synthesis of CP composites
		6.1. Melt processing
		6.2. Mixing
		6.3. Latex technology
		6.4. In situ polymerization
	7. Types of CP composites
		7.1. Composites based on conjugated CPs
		7.2. Composites based on nonconjugated CPs
	8. Applications of CPs and composites
		8.1. CP architects for drug targeting and drug delivery
			8.1.1. Polymeric films
			8.1.2. Polymeric nanoparticles
			8.1.3. Polymeric nanowires, fibers, and nanotubes
			8.1.4. Polymeric nonporous films and nanosponges
			8.1.5. Hybrid 3D structures
		8.2. For tissue engineering and regenerative medicine
		8.3. As sensors for biologically important molecules
		8.4. For neural interfacing
	9. Conclusions
	10. Future prospects
	Acknowledgments
	References
Chapter 17: Nanomedicine: Principles, properties, and regulatory issues
	1. Introduction
	2. Dynamic behavior of polymeric nanomedicine
	3. Preparation methods of polymeric nanomedicines
		3.1. Polymer precipitation methods
			3.1.1. Emulsification solvent evaporation method
			3.1.2. Solvent displacement (nanoprecipitation)
			3.1.3. Salting out
		3.2. Polymerization-based methods
			3.2.1. Emulsion polymerization
			3.2.2. Interfacial Polycondensation combined with spontaneous emulsification
		3.3. Amphiphilic macromolecule cross-linking
			3.3.1. Heat cross-linking
			3.3.2. Chemical cross-linking
		3.4. Ionic gelation
		3.5. Supercritical fluid
		3.6. High-pressure homogenization
	4. Characterization of polymeric nanomedicines
		4.1. Particle size distribution
		4.2. Shape
		4.3. Surface charge
		4.4. Elasticity
		4.5. Surface area
		4.6. Agglomeration
		4.7. Small angle X-ray diffraction (SAXS) and X-ray diffraction (XRD)
		4.8. Differential scanning calorimetry (DSC)
		4.9. Drug entrapment and drug loading
		4.10. In vitro release studies
	5. Sterility and pyrogenicity
	6. Pharmacokinetics and pharmacodynamics
	7. Nanotoxicity and risk assessment
	8. Challenges in the manufacturing scale-up and reproducibility
	9. Regulatory issues
		9.1. Need for nanomedicine regulations
		9.2. Regulatory challenges
		9.3. Regulatory perspective on the development of nanomedicines
		9.4. Regulatory development of next-gen nanomedicines
		9.5. Global trends on regulatory of nanomedicines
			9.5.1. Canada
			9.5.2. Asia
			9.5.3. International pharmaceutical regulators program
			9.5.4. USFDA
			9.5.5. European Union
	10. Example and list of currently approved polymeric nanomedicines released into the market
	Consent for publication
	References
Chapter 18: Polymer-matrix nanocomposites and its potential applications
	1. Introduction
	2. Processing methods of polymer-matrix nanocomposites
		2.1. Polymer employed for the fabrication of nanocomposites
			2.1.1. Cellulose
			2.1.2. Hyaluronic acid
			2.1.3. Chitosan
			2.1.4. Keratin
			2.1.5. Collagen
			2.1.6. Fibrin
			2.1.7. Silk fibroin
			2.1.8. Gelatin
		2.2. Potential applications of polymer nanocomposite in health care
			2.2.1. Bone tissue engineering
			2.2.2. Wound healing
			2.2.3. Diabetes management
			2.2.4. Cancer therapy
			2.2.5. Drug delivery
	3. Conclusions
	References
Index
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