Following its successful predecessor, this book covers the fundamentals, delivery routes and vehicles, and practical applications of Drug Delivery. In the 2nd edition, almost all chapters from the previous are retained and updated and several new chapters added to make a more complete resource and reference. * Helps readers understand progress in Drug Delivery research and applications * Updates and expands coverage to reflect advances in materials for delivery vehicles, Drug Delivery approaches, and therapeutics * Covers recent developments including transdermal and mucosal delivery, lymphatic system delivery, theranostics * Adds new chapters on nanoparticles, controlled drug release systems, theranostics, protein and peptide drugs, and biologics delivery
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LIST OF CONTRIBUTORS
1 FACTORS THAT IMPACT THE DEVELOPABILITY OF DRUG CANDIDATES
1.1 CHALLENGES FACING THE PHARMACEUTICAL INDUSTRY
1.2 FACTORS THAT IMPACT DEVELOPABILITY
1.3 REMARKS ON DEVELOPABILITY
1.4 DRUG DELIVERY FACTORS THAT IMPACT DEVELOPABILITY
2 PHYSIOLOGICAL, BIOCHEMICAL, AND CHEMICAL BARRIERS TO ORAL DRUG DELIVERY
2.2 PHYSIOLOGICAL BARRIERS TO DRUG DELIVERY
2.3 BIOCHEMICAL BARRIERS TO DRUG DELIVERY
2.4 CHEMICAL BARRIERS TO DRUG DELIVERY
2.5 DRUG MODIFICATIONS TO ENHANCE TRANSPORT ACROSS BIOLOGICAL BARRIERS
3 PHYSICOCHEMICAL PROPERTIES, FORMULATION, AND DRUG DELIVERY
3.2 PHYSICOCHEMICAL PROPERTIES
3.4 DRUG DELIVERY
4 TARGETED BIOAVAILABILITY
4.2 TARGET BIOAVAILABILITY
4.3 DRUG DELIVERY TRENDS AND TARGETS RELATED TO PK AND PD
4.4 PK–PD IN DRUG DISCOVERY AND DEVELOPMENT
4.5 SOURCE OF VARIABILITY OF DRUG RESPONSE
4.6 RECENT DEVELOPMENT AND ISSUES OF BIO-ANALYTICAL METHODOLOGY
4.7 MECHANISTIC PK–PD MODELS
5 THE ROLE OF TRANSPORTERS IN DRUG DELIVERY AND EXCRETION
5.2 DRUG TRANSPORT IN ABSORPTION AND EXCRETION
5.3 ABC (ATP-BINDING CASSETTE) TRANSPORTER FAMILY
5.4 SLC (SOLUTE CARRIER) TRANSPORTER FAMILY
6 INTRACELLULAR DELIVERY AND DISPOSITION OF SMALL-MOLECULAR-WEIGHT DRUGS
6.2 THE RELATIONSHIP BETWEEN THE INTRACELLULAR DISTRIBUTION OF A DRUG AND ITS ACTIVITY
6.3 THE RELATIONSHIP BETWEEN THE INTRACELLULAR DISTRIBUTION OF A DRUG AND ITS PHARMACOKINETIC PROPERTIES
6.4 OVERVIEW OF APPROACHES TO STUDY INTRACELLULAR DRUG DISPOSITION
6.5 THE ACCUMULATION OF DRUGS IN MITOCHONDRIA, LYSOSOMES, AND NUCLEI
6.6 SUMMARY AND FUTURE DIRECTIONS
7 CELL CULTURE MODELS FOR DRUG TRANSPORT STUDIES
7.2 GENERAL CONSIDERATIONS
7.3 INTESTINAL EPITHELIUM
7.4 THE BLOOD–BRAIN BARRIER
7.5 NASAL AND PULMONARY EPITHELIUM
7.6 THE OCULAR EPITHELIAL AND ENDOTHELIAL BARRIERS
7.7 THE PLACENTAL BARRIER
7.8 THE RENAL EPITHELIUM
8 INTELLECTUAL PROPERTY AND REGULATORY ISSUES IN DRUG DELIVERY RESEARCH
8.2 PHARMACEUTICAL PATENTS
8.3 STATUTORY REQUIREMENTS FOR OBTAINING A PATENT
8.4 PATENT PROCUREMENT STRATEGIES
8.5 REGULATORY REGIME
8.6 FDA MARKET EXCLUSIVITIES
8.7 REGULATORY AND PATENT LAW LINKAGE
9 PRESYSTEMIC AND FIRST-PASS METABOLISM
9.2 HEPATIC FIRST-PASS METABOLISM
9.3 INTESTINAL FIRST-PASS METABOLISM
9.4 PREDICTION OF FIRST-PASS METABOLISM
9.5 STRATEGIES FOR OPTIMIZATION OF ORAL BIOAVAILABILITY
10 PULMONARY DRUG DELIVERY
10.2 AEROSOL TECHNOLOGY
10.3 DISEASE THERAPY
10.4 FORMULATION VARIABLES
10.5 REGULATORY CONSIDERATIONS
10.6 FUTURE DEVELOPMENTS
11 TRANSDERMAL DELIVERY OF DRUGS USING PATCHES AND PATCHLESS DELIVERY SYSTEMS
11.2 TRANSDERMAL PATCH DELIVERY SYSTEMS
11.3 PATCHLESS TRANSDERMAL DRUG DELIVERY SYSTEMS
11.4 RECENT ADVANCES IN TRANSDERMAL DRUG DELIVERY
12 PRODRUG APPROACHES TO DRUG DELIVERY
12.2 BASIC CONCEPTS: DEFINITION AND APPLICATIONS
12.3 PRODRUG DESIGN CONSIDERATIONS
12.4 PRODRUGS OF VARIOUS FUNCTIONAL GROUPS
12.5 DRUG RELEASE AND ACTIVATION MECHANISMS
12.6 PRODRUGS AND INTELLECTUAL PROPERTY RIGHTS—TWO COURT CASES
13 LIPOSOMES AS DRUG DELIVERY VEHICLES
13.2 CURRENTLY APPROVED LIPOSOMAL DRUGS IN CLINICAL APPLICATIONS
13.3 CONVENTIONAL AND STEALTH LIPOSOMES
13.4 STIMULI-RESPONSIVE LIPOSOMES OR TRIGGERED-RELEASE LIPOSOMES
13.5 TARGETED LIPOSOMAL DELIVERY
13.6 HYBRID LIPOSOME DRUG DELIVERY SYSTEM
13.7 CONCLUSIONS AND FUTURE PERSPECTIVES
14 NANOPARTICLES AS DRUG DELIVERY VEHICLES
14.2 ORGANIC DDVs
14.3 INORGANIC DDVs: METAL- AND SILICA-BASED SYSTEMS
15 EVOLUTION OF CONTROLLED DRUG DELIVERY SYSTEMS
15.2 BIOPHARMACEUTICS AND PHARMACOKINETICS
15.3 MATERIAL SCIENCE
15.4 PROTEINS, PEPTIDES AND NUCLEIC ACIDS
15.5 DISCOVERY OF NEW MOLECULAR TARGETS—TARGETED DRUG DELIVERY
15.6 MICROELECTRONICS AND MICROFABRICATION TECHNOLOGIES
16 PATHWAYS FOR DRUG DELIVERY TO THE CENTRAL NERVOUS SYSTEM
16.2 CIRCUMVENTING THE CNS BARRIERS
16.3 TRANSIENT BBB DISRUPTION
16.4 TRANSCELLULAR DELIVERY ROUTES
17 METABOLIC ACTIVATION AND DRUG TARGETING
17.2 ANTICANCER PRODRUGS AND THEIR BIOCHEMICAL BASIS
17.3 ANTIBODY- AND GENE-DIRECTED ENZYME PRODRUG THERAPY
18 TARGETED DELIVERY OF DRUGS TO THE COLON
18.2 MICROBIALLY TRIGGERED RELEASE
18.3 pH-SENSITIVE POLYMERS FOR TIME-DEPENDENT RELEASE
18.4 OSMOTIC RELEASE
18.5 PRESSURE-CONTROLLED DELIVERY
18.6 NANOPARTICLE APPROACHES
19 RECEPTOR-MEDIATED DRUG DELIVERY
19.2 SELECTION OF A RECEPTOR FOR DRUG DELIVERY
19.3 DESIGN OF A LIGAND–DRUG CONJUGATE
19.4 FOLATE-MEDIATED DRUG DELIVERY
20 PROTEIN AND PEPTIDE CONJUGATES FOR TARGETING THERAPEUTICS AND DIAGNOSTICS TO SPECIFIC CELLS
20.2 RADIOLABELED ANTIBODIES FOR CANCER TREATMENT
20.3 ANTIBODY–DRUG CONJUGATE
20.4 NON-ANTIBODY-BASED PROTEIN–DRUG CONJUGATES
20.6 PROTEIN CONJUGATES FOR DIAGNOSTICS
20.7 PEPTIDE–DRUG CONJUGATES
20.8 CHALLENGES IN ANALYZING CONJUGATES
21 DRUG DELIVERY TO THE LYMPHATIC SYSTEM
21.2 ANATOMY AND PHYSIOLOGY OF THE LYMPHATIC SYSTEM
21.3 INFLUENCE OF PHYSICOCHEMICAL CHARACTERISTICS OF DRUG CARRIERS ON LYMPHATIC UPTAKE AND TRANSPORT
21.4 CARRIERS FOR LYMPHATIC DRUG DELIVERY
21.5 ADMINISTRATION ROUTES FOR LYMPHATIC DELIVERY
21.6 LYMPHATIC-TARGETING VACCINATION
22 THE DEVELOPMENT OF CANCER THERANOSTICS
22.2 IMAGING-GUIDED DRUG DELIVERY AND THERAPY
22.3 OPTICAL IMAGING-BASED THERANOSTICS
22.4 MRI-BASED THERANOSTICS
22.5 NUCLEAR IMAGING-BASED THERANOSTICS
22.6 ULTRASOUND-BASED THERANOSTIC PLATFORM
22.7 MULTIMODALITY IMAGING-BASED THERANOSTIC PLATFORM
22.8 CONCLUSION AND FUTURE PERSPECTIVES
23 INTRACELLULAR DELIVERY OF PROTEINS AND PEPTIDES
23.2 INTRACELLULAR DELIVERY STRATEGIES OF PEPTIDES AND PROTEINS
23.3 CONCEPTS IN INTRACELLULAR PEPTIDE AND PROTEIN DELIVERY
23.4 PEPTIDE AND PROTEIN DELIVERY TO LYSOSOMES
23.5 RECEPTOR-MEDIATED INTRACELLULAR DELIVERY OF PEPTIDES AND PROTEINS
23.6 TRANSMEMBRANE DELIVERY OF PEPTIDES AND PROTEINS
24 VACCINE DELIVERY
24.2 PARENTERAL ADMINISTRATION OF VACCINES
24.3 ORAL DELIVERY OF VACCINES
24.4 NASAL AND AEROSOL DELIVERY OF VACCINES
25 DELIVERY OF GENES AND OLIGONUCLEOTIDES
25.2 SYSTEMIC DELIVERY BARRIERS
25.3 CELLULAR DELIVERY BARRIERS
25.4 CURRENT AND FUTURE APPROACHES TO NUCLEIC ACID DELIVERY
25.5 SUMMARY AND FUTURE DIRECTIONS
END USER LICENSE AGREEMENT
Table 4.1 Summary of the Number of Clinical Trials Listed on ClinicalTrials.gov Organized as the Three Major Drug Delivery Categories (Updated on September 10, 2013)
Table 5.1 ABC Transporters
Table 5.2 Solute Carrier SLC Transporters
Table 9.1 Hepatic and Intestinal Expression of Major Human Xenobiotic-Metabolizing Enzymes
Table 11.1 Examples of Transdermal Patches Approved in the United States
Table 11.2 The Application of Coated and Dissolving Microneedle Techniques in Transdermal Vaccine Delivery
Table 12.1 Reversible Prodrug Forms for Various Functional Groups Present in Biologically Active Substances
Table 16.1 The Kinetic Parameters of Selected Transporter Proteins Expressed in the Brain Capillary Endothelial Cells (BBB) for Selected Endogenous/Exogenous Substrates
Table 18.1 List of Target Sites, Disease Condition, and Drug Used for Colon Targeting
Table 18.2 Different Delivery Methods for Achieving Colon Targeting
Table 18.3 pH-Sensitive Polymers Used in Colonic Drug Delivery
Table 19.1 Ligands Frequently Used for Receptor-Mediated Drug Delivery
Table 19.2 Autoimmune and Inflammatory Diseases That Can Be Targeted with Folate Conjugates
Table 21.1 Examples of Anticancer Drug-Loaded Nanoparticles That Have Demonstrated Enhanced Chemotherapeutic Efficacies in Tumor Models
Table 21.2 Approved and Emerging Liposome-Encapsulated Anticancer Drugs
Table 21.3 Targeting Ligands Frequently Used for Targeted Liposomes
Table 21.4 List of Lipids and Surfactants Typically Used for SMEDDS Formulations
Table 21.5 Summary of Primary Improvements of Drug-Carriers Administered via Alternative Routes Over Conventional Therapy
Table 21.6 Therapeutic Effect for Ovarian Cancer in F344 Rats Xenografts (Mean ± SD)
Table 23.1 Examples of Peptide and Protein Therapeutics on the Market
Table 23.2 Some of the Known CPPs and Their Sequences
Table 24.1 List of US-Approved Vaccines and Their Dose and Route of Administration
Table 24.2 Injection Site and Needle Size for Intramuscular and Subcutaneous Administration of Vaccines
Figure 1.1 A schematic illustration of the drug discovery and development process with the estimated number of compounds shown for each step.
Figure 1.2 The evaluation steps of various factors that impact the oral bioavailability of a drug candidate.
Figure 2.1 Several possible mechanisms of drug transport through the intestinal mucosa barrier. Pathway A is the passive transcellular route in which a drug permeates the cell passively by partitioning to cell membranes at both apical (AP) and basolateral (BL) sides. Pathway B is called the paracellular route where the drug passively diffuses between cells at the intercellular junctions. Pathway C is the active transport route where the drug is recognized by transporters, which shuttle the drug from the AP to BL sites. Pathway D is the route where the drug permeation is inhibited by efflux pumps; the efflux pumps expel the drug molecule from the cell membranes during the cell membrane partition process.
Figure 2.2 The intercellular junction is mediated by protein–protein interactions at different regions of intercellular junctions, including (a) tight junction (
), (b) adherens junction (
), and (c) desmosomes (
Figure 3.1 Schematic diagram showing the interdependence of physicochemical properties, formulation, and drug delivery.
Figure 3.2 Plot of percent prednisolone released versus time for different complexes of cyclodextrin and prednisolone. Prednisolone : (SBE)
-β-CD at a 1 : 1 molar ratio (), Prednisolone : (SBE)
-β-CD at a 1 : 2 molar ratio (), Prednisolone : HP-β-CD at a 1 : 2 molar ratio (), Prednisolone : sugar ().
Figure 3.3 Plot of drug concentration versus time for single- and multiple-dose therapy.
Figure 3.4 Plot of drug concentration versus time for nonimmediate release systems.
Figure 4.1 A schematic representation of the potential biological barriers that an orally administered compound must pass before reaching the site of action.
Figure 4.2 The drug action model in terms of basic components of pharmacokinetic and pharmacodynamic models.
Figure 4.3 Model-based drug development is a new paradigm that embraces all aspects of drug development from drug discovery to post-marketing.
Figure 4.4 Application of PBPK modeling and simulation to evaluate the effect of various extrinsic and intrinsic factors on drug exposure and response: (a) Intrinsic and extrinsic patient factors that can affect drug exposure and response and (b) components of PBPK modeling (drug-dependent component and drug-independent (system) component) .
Figure 4.5 Mechanism-based model of PK–PD for an anti-IgE monoclonal antibody.
Figure 4.6 Simulated probability between clinical response (Δ total symptom score) and dose for three different cases: (1) an optimistic response rate (70%), (2) a response rate similar to that expected for omalizumab (64%), and (3) a low response rate (50%).
Figure 5.1 Membrane transporters for drugs and endogenous substances. Localization of transporters on the plasma membrane of enterocytes, hepatocytes, and kidney proximal tubules are presented. (a) Intestinal transporters. On the apical (luminal) membrane of enterocytes, several solute carrier (SLC) transporters are presented. These include ileal apical sodium/bile acid cotransporter (ASBT), carnitine/organic cation transporters (OCTN1/2), concentrative nucleoside transporters (CNT1/2), peptide transporter 1 (PEPT1), monocarboxylate transporter 1 (MCT1), and organic anion transporting polypeptide transporters (OATP1A2 and 2B1). The apical ATP-binding cassette, ABC transporters, include multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp; MDR1), and ABC subfamily G members 5/8 (ABCG5/8). The transporters on the BLM of enterocytes consist of organic cation transporter 1 (OCT1), equilibrative nucleotide transporters (ENT1/2), MCT1, heteromeric organic solute transporters (OSTα-OSTβ), MRPs 1, 3, and 4. (b) Hepatic transporters. The uptake transporters on the basolateral (sinusoidal) membrane of hepatocytes include sodium/taurocholate cotransporting peptide (NTCP), OSTα-OSTβ, organic anion transporters (OAT1 and OAT2), OCT1/3, MCT1 and OATP1B1, 1B3, and 2B1. The efflux transporters present on the BLM of hepatocytes include MRP3 and 4. The efflux transport across canalicular membrane of hepatocytes includes BCRP, MRP2, MDR1 and 3, multidrug and toxin extrusion transporter (MATE1), ABCG5/8 and bile salt export pump (BSEP). (c) Renal transporters. The uptake transporters on the apical (brush-border) membrane of proximal tubules include CNT3, OCTN1/2, sodium-dependent monocarboxylate transporter 1 (SMCT1), OAT4, PEPT1/2 and urate transporter 1 (URAT1). The efflux transporters on the brush border membrane of proximal tubules contain MRP2 and 4, BCRP, P-gp, and MATE 1 and 2K. The transporters on the BLM of proximal tubules consist of ENT1/2, MCT1, OATP4C1, OCT2, and OAT1/3.
Figure 6.1 Diagram illustrating the accumulation of cationic drugs (D
) in the inner mitochondrial space. The Nernst equation that relates equilibrium concentrations (inside vs. outside) of the cation with membrane potential is shown.
Figure 6.2 Structures of common moieties that are covalently attached to drugs to promote mitochondrial accumulation.
Figure 6.3 Diagram illustrating the pH partitioning-based mechanism for accumulation of weakly basic drugs (B) in the acidic lysosomes. The equation at the bottom of the figure represents the lysosome to extracellular space steady-state concentration ratio for a base. The dissociation constant for the conjugate acid of the weak base is denoted as
] is the proton concentration (subscript E represents extracellular and L represents lysosomal). The ratio of permeabilities of the ionized base to that of the unionized base in the lysosomal lipid bilayer is denoted by the α term.
Figure 6.4 Theoretical relationship between weak base p
and the alpha permeability parameter. The relationships were derived using the equation shown in Figure 6.3, with indicated values for alpha.
Figure 6.5 Overview of intracellular distribution-based anticancer drug targeting platform.
Figure 6.6 Hypothetical example illustrating the potential influence of lysosomotropism on the apparent volume of distribution of a drug. See text for details.
Figure 6.7 Diagram illustrating the nuclear accumulation of drugs in the nucleus. Small-molecular-weight drugs can freely diffuse into the nucleus through nuclear pore complexes. Once bound to resident macromolecules (i.e., DNA), the complexed drug is too large to diffuse out.
Figure 7.1 General methods for establishing primary explant tissue cultures or primary cell culture models isolated from human or animal tissues.
Figure 7.2 Inserts with semipermeable membranes can be used to study directional drug transport across cell monolayers. Samples can be taken from both the apical and basolateral sides of the cells.
Figure 7.3 General mechanisms of drug transport across a cellular barrier. It should be noted that active, facilitative, and efflux transporter proteins may be present in both apical and basolateral membranes. Metabolizing enzymes within cells may in effect limit the transport of drugs by means of biotransformation to metabolites with altered or no pharmacological activity.
Figure 7.4 Cell types lining the respiratory system. Key: (1) ciliated columnar cells, (2) non-ciliated columnar cells, (3) basal cells, (4) goblet cells, (5) mucus, (6) basement membrane, (7) blood vessels, (8) lamina propria, (9) fibro-cartilaginous layer, (10) bone, (11) gland, (12) smooth muscle cells, (13) cartilage, (14) ciliated cuboidal cells, (15) Clara cells, (16) type I alveolar cells, (17) type II alveolar cells, (18) surfactant, (19) olfactory bulb, (20) cribriform plate, (21) receptor cell, (22) receptor cell cilia, (23) Bowman’s gland, (24) supporting cell.
model of the alveolar–capillary barrier. Cells representing the airway epithelium and pulmonary endothelium are grown on opposite sides of a flexible membrane. Vacuum is applied to the side chambers to mimic physiological breathing, causing mechanical stretching of the flexible membrane. Huh et al. , pp. 1662–1668.
Figure 9.1 Relative contribution of (a) CYP isoforms in human liver and (b) of CYP isoforms to the total CYP-mediated metabolism of marketed drugs.
Figure 9.2 Structure of irinotecan and its active metabolite SN-38.
Figure 9.3 Integrated ADME-based screen strategies during the candidate identification phase of drug discovery.
Figure 10.1 (a) Schematic diagram of a propellant-driven metered-dose inhaler. (b) Schematic diagram of a dry powder inhaler. (c) Schematic diagram of an air-jet nebulizer.
Figure 10.2 Mechanism of action of drugs for asthma therapy.
Figure 10.3 (a) Short-acting β-agonists and (b) long-acting β-agonists.
Figure 10.4 Anticholinergic.
Figure 10.5 Steroids.
Figure 10.6 Cromones.
Figure 10.7 Antimicrobials.
Figure 10.8 Fatty acid (oleic acid).
Figure 10.9 Lecithin.
Figure 10.10 Lactose.
Figure 11.1 Popular designs of transdermal patches.
Figure 11.2 Different designs of microneedle technology for vaccine delivery: (a) via a skin patch without using microneedles; (b) via a skin patch after treatment with solid microneedles; (c) via coated microneedles that were coated with the drug; (d) via dissolving microneedles in which the drug was loaded; (e) via hollow microneedles in combination with a skin patch.
Figure 11.3 Schematic diagram of PharmaDur Virtual Patch. (Shah et al. .)
Figure 11.4 Comparison of flux of caffeine with oleic acid formulations (controls) and with added 2% PharmaDur polymer. (Michniak et al. .)
Figure 11.5 Comparative diclofenac skin permeation profiles.
Scheme 12.1 Activation of balsalazide (25), ipsalazide (26), olsalazine (27), and sulfasalazine (28) to form mesalazine (29) by microbial azoreductases in the colon.
Scheme 12.2 Activation of the peptide doxorubicin conjugate 39 by PSA.
Scheme 12.3 Activation of the peptide-linked amino-cyclophosphamides (43a–c) by PSA to release 4-aminocylophosphamide (44).
Scheme 12.4 Activation of ester prodrugs by esterases.
Scheme 12.5 Design of cascade prodrugs containing double esters using α-acyloxyalkyl (62), carbonate (63), or alkoxycarbonyloxyalkyl (64) esters.
Scheme 12.6 Activation of candesartan cilexetil (67).
Scheme 12.7 Activation of adefovir dipivoxil (73).
Scheme 12.8 Sequential activation of
-α-acyloxyalkyl ether prodrugs of phenol-containing drugs.
Scheme 12.9 Metabolic activation of nabumetone (79).
Scheme 12.10 The formation and activation of Mannich base prodrugs.
Scheme 12.11 Sequential enzymatic and chemical activation of prodrugs in the form of
Scheme 12.12 Decomposition of
-α-acyloxyalkyl derivatives (93) of primary amides through an elimination–addition mechanism.
Scheme 12.13 Activation of capecitabine (102).
Scheme 12.14 Activation of loratidine (108).
Scheme 12.15 Activation of prodrugs of primary and secondary amines in the form of
-α-acyloxyalkoxycarbonyl derivatives (110).
Scheme 12.16 Activation of prodrugs in the form of a cyclized peptide via an α-acyloxyalkoxy promoiety.
Scheme 12.17 Enzyme-triggered activation of
-acyloxymethyl ether derivatives of salicylamide
-Mannich bases as prodrugs of amines.
Scheme 12.18 Activation of prontosil (125) to sulfanilamide (127).
Scheme 12.19 Proposed activation of an enone oxime prodrug to a catecholamine.
Scheme 12.20 Activation of an enol ester prodrug to form the positively charged coralyne in two steps.
Scheme 12.21 Stability and chemical activation of oxazolidines at pH 7.4 and 37°C.
Figure 12.1 Examples of drug-release/activation mechanisms.
Scheme 12.22 Reductive activation of cyclic and acyclic nitroaryl phosphoramides by nitroreductases (NTR) followed by 1,6-elimination.
Scheme 12.23 Activation of alkylaminoalkyl carbamates of phenolic drugs via cyclization.
Scheme 12.24 Two-step activation of
-nitrophenylalkanoate prodrugs via reduction and cyclization.
Scheme 12.25 Two-step activation of quinone propionic ester and amide prodrugs via reduction and cyclization.
Scheme 12.26 Two-step activation of a coumarin-based prodrug system.
Scheme 12.27 Activation of a pilocarpine prodrug via esterase-mediated hydrolysis and cyclization.
Scheme 12.28 Two-step activation of rilmazafone (172) via enzyme-mediated hydrolysis and cyclization.
Scheme 12.29 First-pass metabolism of terfenadine (175) to fexofenadine (176).
Figure 13.1 Schematic representations of unilamellar (a) and multilamellar (b) liposomes.
Figure 13.2 Chemical structures of some small molecule drugs that have been successfully formulated as liposomal drugs and approved by the FDA.
Figure 13.3 General structures of several phospholipids commonly used in liposomal drug delivery systems: distearoylphosphatidylcholine (DSPC) 1, distearoylphosphatidylethanolamine (DSPE) 2, dioleoylphosphatidylethanolamine (DOPE) 3, distearoylphosphatidylglycerol (DSPG) 4, egg PG (main component
-α-phosphatidylglycerol 5), cholesterol 6, PEGylated DSPE 7.
Figure 13.4 Representations of conventional liposome (a), stealth liposome (b), and targeted liposome (c) using antibody or ligand. The targeting components can be attached to the end of polyethylene glycol (PEG) or directly to the lipid head group.
Figure 13.5 The basic self-assembling properties of lipids. Depending on the structures of the lipids, they can form lamellar structures as in (a), micelles as in (b), or inverted hexagons (micelles) as in (c).
Figure 13.6 Structures of lipids utilized in thermo-sensitive liposomes.
Figure 13.7 Structures of lipids utilized in pH-sensitive liposomes.
Figure 13.8 Conversion of neutral malachite green carbinol base to the cationic form at low pHs.
Figure 13.9 Conformational conversion upon pH changes.
Figure 13.10 Structures of some representative acid-labile lipids.
Figure 13.11 The acid hydrolysis of the diorthoester 21.
Figure 13.12 The hydrolysis of a pH-sensitive PEG–phenyl-substituted vinyl ether (PIVE)-linked lipid conjugate.
Figure 13.13 Photo-isomerizations of azobenzene and spriropyran derivatives.
Figure 13.14 Structures and wavelengths of photo-cleavable groups and the photo-cleavage reactions.
Figure 13.15 Structures of lipids containing photo-triggerable functional groups.
Figure 13.16 A reduction-responsive liposomal system.
Figure 13.17 A prodrug that forms vesicle and can be activated by sPLA2.
Figure 13.18 Structures of PEGylated lipids that are useful for conjugation with ligands or antibodies, and the structures of two targeted lipids.
Figure 13.19 The conjugation of PPACK to PEG-DSPE-COOH.
Figure 14.1 Schematic representation of general DDV strategies. (a) Organic polymeric micelle.(b) Inorganic nanoparticle. Smith et al. , pp. 620–626.(c) Biological virus-based nanocarriers and their potential functionalization and cargo. Christie et al. , pp. 5174–5189.
Figure 14.2 DDV strategies for cellular targeting and penetration. The potential for DDV systems to correctly target, penetrate, and deliver its payload relies upon the selection of secondary targeting and its concomitant avidity. Without cell-surface targeting, therapeutic payloads suffer indiscriminant distribution. This figure offers a diverse summary of various potential approaches for cellular targeting, diagnosis, and therapeutic mechanisms .
Figure 14.3 Potential mechanisms for drug encapsulation and release. (a) Coordination with the backbone of the polymer through either hydrophobic (i), negatively charged moieties (ii), or positively charged systems (iii) affords the direct connectivity required to both stabilize the payload, but also the DDV core. Miyata et al. , pp. 227–234.(b) Fluorescent drugs or imaging agents undergo quenching upon encapsulation within the core, but their subsequent release restores their fluorescent properties. Bae and Kataoka , pp. 768–784. (c) A pH-sensitive micelle demonstrates its environmental sensitivity through the release of its fluorescent payload upon a decrease in intracellular pH.
Figure 14.4 Environmentally sensitive release characteristics and their corresponding functionalities. (a) A DDV with a thiol-crosslinked core and doxorubicin–hydrazine linkage demonstrate dual release functionalities: upon cellular internalization, the disulfides reduce due to the increase in glutathione, destabilizing the core. As the core destabilizes, the drop in pH severs the DOX–hydrazine linkage, releasing the drug payload . (b) The ability to maintain appropriate endosomal release, and therefore membrane destabilization, can be controlled by the number of mono and diprotonated moieties producing cationic charges . (c) A catch-and-release function whereby the target ligand catches its cell-surface receptor is then dethatched upon entering the endosomal compartment revealing the endosomal-escape component. Conversely, both functionalities are exposed to the milieu; however, the endosomal-disrupting function is protected until the proper pH is obtained within the endosome.
Figure 14.5 Effect of multivalency and DDV subcellular distribution. Introducing the cRGD peptide (Scheme 1), enhanced uptake and a broader subcellular distribution was observed.
Figure 14.6 Ligands and DDV multivalency. Multivalent binding mechanisms. (a) Effective concentration increases the chances of binding . (b) Statistical rebinding is higher for multivalent conjugates if the original interaction dissociates . (c) The chelate effect allows for multiple interactions through one conjugate. (a–c) van Dongen et al. , pp. 3215–3234, figure 7.(d) Binding avidity is also increased through multivalent displays. Lallana et al. , pp. 902–921, figure 4.
Figure 14.7 The enhanced penetration and retention (EPR) effect. The EPR effect is the primary point of tumor penetration for DDVs via passive targeting. Due to the irregular tumor vasculature and ineffective lymphatic drainage (RES), nanoparticles extravasate through the leaky system and enter the tumor environment. This resolves to expose the tumors cell surface and promote active DDV targeting (see
) and ultimately, payload distribution .
Figure 14.8 Schematic representation of organic-based DDVs and their attributes: (a) Polymeric drug or sequestrant, (b) polymer–protein conjugate, (c) polyplex: polymer–DNA complex, (d) polymer–drug conjugate, and (e) polymeric micelle.
Figure 14.9 Self-assembly block copolymer micelles and their potential payloads. Bae and Kataoka , pp. 768–784.
Figure 14.10 (a) The self-assembly of an environmentally sensitive polymeric micelle using hydrazine-linked doxorubicin tethered to an amphiphilic block copolymer. (b) A simple schematic illustrating the release of doxorubicin upon contact with an acidic environment.
Figure 14.11 Preparation of DACHPt/m. (a) Self-assembly of the metal-polymer complex DACHPt and PEG-P(Glu). (b) Pancreatic tumor activity as demonstrated by bioluminescence signal (PNAS is not responsible for the accuracy of this translation). Cabral et al. , pp. 11397–11402.
Figure 14.12 (a) An illustration demonstrating dendrimer topological architecture and hierarchical assembly. (b) Dendrimer passive targeting strategies and applications involving categories A, B, and Z. (c) Active targeting applications for dendrimer DDVs with all four divisions: A, B, C, and Z. (Z) A list of potential surface handles used to provide immune stealth or direct dendrimer-ligand bioconjugation. Menjoge et al. , pp. 171–185.
Figure 14.13 Representative dendrimers a, b, c, d, and e, with their respective generations (G). (a) Poly(glutamic acid) dendrimer (G-2), (b) polyamidoamine (PAMAM) dendrimer (G-2), (c) polypropyleneimine (PPI) dendrimer (G-3), (d) polymelamine dendrimer (G-3), and (e) polyester dendrimer (G-2).
Figure 14.14 (a) Divergent synthesis: Starting with the reactive initiator core, activated moiety Y produced the first-generation branched dendrimer. Iterative addition of the branched monomer produces additional generations, which are terminated with functional group Z. Reprinted (adapted) with permission from . Copyright 2009 American Chemical Society. (b) Convergent synthesis: The focal point Y of the branched monomer is chemically reactive to functional group Z. Iterative coupling of the branched monomer to another produced a parent dendron. The dendrimer is then assembled through addition of the reactive initiator core, which reacts with focal point Y of the parent dendron.
Figure 14.15 (a) Schematic illustration of the effect of pH upon dendrimer. As pH becomes weakly acidic, the PDEA chains become hydrophilic and extend, releasing the pyrimidine analog, 5-fluorouracil. (b) Surgically resected mouse tumors of the saline (negative control), 5-FU (positive control), PPD-5-FU, and PPD-empty groups. (c and d) Plots demonstrating the release characteristics of the 5-FU-PPD dendrimer at both physiological and endosomal pH of 7.4 and 6.5, respectively. Jin , pp. 378–384.
Figure 14.16 (a) Flow cytometry illustrating the rapid uptake of the 6-arm-PEG-FITC DDV. (b) Confocal image of negative control BV2 cells. (c) Confocal image of BV2 cells with 6-arm-PEG-FITC DDV. Navath et al. , pp. 447–456.
Figure 14.17 Mesoporous silica nanoparticles are a multifaceted DDV system capable of transporting NSAIDs (ibuprofen), anticancer therapeutics (doxorubicin), and therapeutic biopolymers such as pDNA and cytochrome C. Tang et al. , pp. 1504–1534.
Figure 14.18 Scheme showing the formation of mesoporous silica using structure-directing agents (SDAs): (a) the liquid-crystal template mechanism and (b) the cooperative liquid-crystal template mechanism. Tang et al. , pp. 1504–1534.
Figure 14.19 (a) Grafting: a post-synthesis chemical modification with organosilanes of type (R′O)
SiR (R = organic functional group). (b) The co-condensation of tetraalkoxysilanes [(RO)
Si (TEOS)] with terminal (R′O)
SiR groups and appropriate SDAs that project organic functionalities into the pore. (c) Periodic mesoporous organosilicas (PMOs): type (R′O)
precursors are used to generate a 3D lattice, which are homogeneously distributed throughout the MSN’s walls. Hoffmann et al. , pp. 3216–3251.
Figure 14.20 (Scheme 1) Synthesis of the trifunctional theranostic MSN incorporated with an NIR ATTO 647N contrast agent, cRGD targeting peptide, and palladium-based photosensitizer (Pd-TPP) for photodynamic therapy (PDT). (Scheme 2) Graphical representation of the trifunctional MSN binding to integrin receptors via the targeting cRGD peptide followed by cellular internalization, and Pd-TPP activation by PDT. (a) Flow cytometric analysis of positive control cells (U87-MG), which overexpress α
integrin receptors. (b) MCF-7 cells that are α
null for integrin receptors act as a negative control. (c and d) Immunofluorescent staining of α
integrin expression for U87-MG and MCF-7 cells, respectively.
Figure 14.21 Preparation of a monolayer-protected cluster (MPC) using the Brust–Schiffrin reaction. Rana et al. , pp. 200–216.
Figure 14.22 (Scheme 1) General schematic of the AuNP modified with Asp-PEG-FA with an acid-cleavable linker capable of releasing its fluorescent DOX payload at low pH. (a) Positive control: Free DOX in 4TI cells. (b) Au-P(LA-DOX)-
-PEG-OH in 4TI cells. (c) Au-P(LA-DOX)-
-PEG-FA in 4TI cells. Prabaharan et al. , pp. 6065–6075.
Figure 14.23 Fluorescence micrograph of HeLa cells transfected with FITC-β-Gal in (a) absence or (b) presence of NP_Pep. (c) ICP-MS measurements after NP_Pep/β-Gal treatment. (d–f) Confocal images of HeLa cells after protein transfection: (d) bright field, (e) fluorescence, and (f) merged.
Figure 15.1 Milestones in controlled and modified drug delivery systems.
Figure 16.1 (Panel a): Schematic representation of the cellular components of the blood–brain barrier (BBB). (Panel b): Blood–cerebrospinal fluid barrier (BCSFB). The BBB consists of continuous-type endothelial cells with complex tight junctions to limit paracellular diffusion. The astrocytes and pericytes located in close proximity to the brain endothelial cells release various endogenous factors that modulate endothelial cell permeability. In contrast, the choroid endothelial cells are fenestrated and the BCSFB properties are provided by the tight junctions formed between the choroid epithelial cells.
Figure 16.2 Potential mechanisms for drug () movement across the BBB. Routes of passage include passive diffusion through the brain capillary endothelial cells (a), utilization of inwardly directed transport or carrier systems expressed on the brain capillary endothelial cells (b), utilization of outwardly directed efflux transport systems (c), or utlization in various endocytic vesicular transport processes occurring within the brain capillary endothelial cells (d).
Figure 16.3 Effects of drug efflux transporters on the accumulation of various protein kinase inhibitors in the brain. Drug accumulation was examined in wild-type (wt) mice and triple knockout
Abcb1a/1b −/−; Abcg2 −
(KO) mice in the presence and absence of the drug efflux transport inhibitor, elacridar. All drugs were administered orally, and the dose of elacridar was (100 mg/kg). Data for this figure was based on previously published results [128–131].
Scheme 17.1 Bioactivation of prodrugs by a single-electron reductase.
Figure 17.1 Chemical structures of representative bioreductive prodrugs . AKR1C3, aldo-keto reductase 1C3; B5R, NADH-cytochrome
5 reductase; iNOS, inducible nitric oxide synthase; MTRR, methionine synthase reductase; NDOR1, NADPH-dependent diflavin oxidoreductase 1; NQO, NAD(P)H dehydrogenase; P450, cytochrome P450; P450R, NADPH-cytochrome P450 reductase.
Scheme 17.2 Bioreductive activation of mitomycin C, and its derivatives.
Scheme 17.3 Bioreductive activation of prodrug 4.
Scheme 17.4 Bioactivation of aromatic nitro–containing hypoxia-selective nitrogen mustard prodrugs.
Figure 17.2 Representative aromatic nitro–containing hypoxia-selective nitrogen mustard prodrugs.
Scheme 17.5 Bioreductive activation of prodrug 9.
Scheme 17.6 Bioreductive activation through a reduction of a nitro group followed by 1,6-elimination. *The nitrogen is part of the carbamate structure.
Scheme 17.7 Bioreductive activation of heteroaromatic prodrugs via reduction of a nitro group, followed by 1,5-elimination.
Scheme 17.8 Bioreductive activation of nitro or azido paclitaxel prodrug .
Scheme 17.9 Bioreductive activation of prodrug 22 to active drug 22a.
Scheme 17.10 Bioreductive activation of Tirapazamine (TPZ).
Scheme 17.11 Bioreductive activation of nitromin.
Scheme 17.12 Bioreductive activation of AQ4N.
Scheme 17.13 Bioreductive activation of sulfoxide-containing nitrogen mustard prodrugs.
Figure 17.3 Chemical structures of representative platinum-based anticancer drugs and bioreductive prodrugs .
Scheme 17.14 Bioreduction of platinum-based prodrugs. L, Ligand and can be another drug .
Scheme 17.15 Bioreduction activation of Ru(III) prodrugs to Ru(II) drugs. L, Ligands .
Figure 17.4 Chemical structures of Ru(III) anticancer prodrugs NAMI-A and KP1019.
Scheme 17.16 Bioreductive activation of Co(III) and Cu(II) nitrogen mustard prodrugs under hypoxic conditions [57, 58].
Figure 17.5 Chemical structures of representative acid labile anticancer prodrugs. X, carrier or linker.
Scheme 17.17 Activation of an acetal glycoside prodrug of aldophosphamide at acidic pH.
Scheme 17.18 Prodrugs with a drug directly connected to a peptide.
Scheme 17.19 Hydrolytic activation of prodrugs with a
-aminobenzyl alcohol as a spacer that contains a carbamate or carbonate bond. a, protease; b, 1,6 elimination.
Scheme 17.20 Hydrolytic activation of prodrugs with a
-aminobenzyl alcohol as a spacer that contains an ether bond. a, protease; b, 1,6 elimination.
Figure 17.6 Anticancer prodrugs activated by plasmin.
Figure 17.7 Prodrugs of doxorubicin and its derivatives with different number of spacers between the drug and a peptide.
Scheme 17.21 Hydrolytic bioactivation of prodrugs 39a and 39b.
Scheme 17.22 Hydrolytic bioactivation of prodrug 40 by plasmin.
Figure 17.8 Prodrug of paclitaxel with two
-aminobenzyl alcohol moieties.
Figure 17.9 Representative prodrugs activated by cathepsin B.
Scheme 17.23 Hydrolytic bioactivation of prodrugs by cathepsin B.
Scheme 17.24 The hydrolyzed prodrug (50a) fails to undergo 1,6-fragmentation to release
Figure 17.10 Chemical structures of representative MMP-activated prodrugs of Dox and paclitaxel.
Figure 17.11 Chemical structures of prolidase-activated prodrugs, and their corresponding anticancer drugs.
Scheme 17.25 Bioactivation of glucuronide prodrugs by β-glucuronidase.
Figure 17.12 Representative prodrugs bioactivated by β-glucuronidase.
Figure 17.13 Structure of a glucuronide prodrug of 9-aminocamptothecin.
Scheme 17.26 Activation of glucuronide nitrogen mustard prodrug 61.
Scheme 17.27 Glucuronidase-mediated bioactivation of prodrug 62.
Scheme 17.28 Bioactivation of prodrug 63 by β-glucuronidase.
Scheme 17.29 Bioactivation of prodrug 64a and 64b by β-glucuronidase.
Figure 17.14 Structures of glucuronide prodrugs 65a, 65b, and 66.
Figure 17.15 Structure of a glucuronide prodrug activated by prostate-specific antigen (PSA). Mu, morpholinocarbonyl.
Scheme 17.30 General structures of
-glutamyl amide nitrogen mustard prodrugs and activation of the prodrugs by CPG2.
Scheme 17.31 Bioactivation of prodrugs by β-lactamase.
Figure 17.16 Structures of some representative prodrugs that are activated by β-lactamase.
Scheme 17.32 Activation of monoglycosidic or diglycosidic prodrugs by β-
Scheme 17.33 Bioactivation of 5-FC by cytosine deaminase.
Scheme 17.34 Bioactivation of CB 1954 by reductases.
Figure 18.1 pH profile of a healthy GI tract.
Figure 18.2 Azo-linked prodrugs. (a) Prontosil, the prodrug of sulfanilamide; (b) sulfasalazine, the prodrug of mesalazine and sulfapyridine; and (c) olsalazine, the prodrug dimer of mesalazine.
Figure 18.3 Amino acid conjugate prodrugs.
Figure 18.4 Representation of a pressure-controlled release system.
Figure 18.5 Scanning electron microscopic images of nanoparticles prepared by (a) PLGA (mol. wt. 20,000) or (b) PLGA (mol. wt. 5,000).
Figure 18.6 Release profiles of rolipram nanoparticles in phosphate buffer, pH 7.4, at 37°C during 168 hour.
Figure 19.1 Receptor-mediated endocytosis. Exogenous ligands bind specifically to their cell surface receptors. The plasma membrane invaginates around the ligand–receptor complexes to form an intracellular vesicle (endosome). Intracellular trafficking of the ligand–drug conjugate may then involve passage of the conjugate through early endosome (EE) and late endosome (e.g., CURL), with ultimate translocation of the conjugate through a recycling endosome (RE) to the cell surface or directly to lysosomes (L).
Figure 19.2 Structural design of a ligand-targeted drug conjugate.
Figure 19.3 Structure of folic acid.
Figure 19.4 Folate receptor (FR) expression in various human cancers.
Figure 19.5 Anterior SPECT images of two patients receiving
In-DTPA-folate: (a) Image of a female patient without cancer and (b) image of a female patient with Stage IIIc ovarian carcinoma.
Figure 19.6 Survival of treated M109 tumor-bearing mice. Four days post inoculation, Balb/c mice bearing intraperitoneal M109 tumors were treated once daily with either the unmodified parent drug or the folate-derivatized drug. ILS, increased lifespan.
Figure 19.7 Folate-targeted immunotherapy strategy.
Figure 20.1 (a) The general structure of an antibody–drug conjugate (ADC) with the monoclonal antibody conjugated to the drug via a linker. (b) Adcetris (brentuximab vedotin) is a conjugate between anti-CD30 mAb and monomethyl auristatin E (MMAE) conjugated via a linker that can be cleaved by an enzyme. (c) Kadcyla (trastuzumab emtansine, T-DM1) is a conjugate between anti-CD33 mAb and merstansine (DM1) via a stable thioether linker. (d) Mylotarg (gemtuzumab ozogamicin) is a conjugate between anti-CD33 mAb and calicheamicin, which is connected via a hydrazone–disulfide linker. (e) BR96-doxorubicin (BR-96 DOX) is a conjugate between anti-Lewis Y mAb and DOX via a hydrazone–thioether linker. (f) The huC242-SPDB-DM4 compound is a conjugate between huC242 mAb and DM4.
Figure 20.2 The mechanism of targeting and uptake of the conjugate into the target cells. The carrier molecule binds to the target receptor on the cell surface followed by endocytosis into the cytoplasm inside the early endosomes. From the early endosomes, the receptors can move into recycling endosomes to carried back to the cell surface. The conjugates are released from the receptor and are trapped inside the late endosomes. Finally, the conjugates are degraded in the lysosomes to release the free drugs.
Figure 20.3 Examples of drug conjugates with various linkers to control the drug release. Compounds 1 and 2 contain a disulfide linker with monomethyl and gem-dimethyl group at the alpha-carbon of the disulfide bond, respectively. The drug release is faster in compound 1 than in compound 2. Compound 3 has a stable thioether linkage and the drug release in compound 3 is slower than in compound 2. Compound 4 contains a hydrazone–disulfide linker to control the drug release. The drug release from the hydrazone linker is acidic pH-sensitive as in the lysosomes.
Figure 20.4 Compounds 5–9 are conjugates of mAb and calicheamicin with different hydrazone linkers. The effect of different hydrazone derivatives on drug release at pH 7.4 and 4.5 to mimic the blood and lysosomes, respectively. The modified linkers affect the IC
and selectivity of the ADC in cell toxicity.
Figure 20.5 The structures of non-antibody protein conjugates including (a) MTX-HSA, (b) PLP-IDAC with the reactions to make the conjugate, (c) TPS-LZM, and (d) peptibody.
Figure 20.6 The mechanism of cancer cell detection using an antibody conjugated with TAMRA and QSY7 that binds to antigens on the surface of cancer cell. The antibody will be taken up by the cancer cells via receptor-mediated endocytosis and processed through early and late endosomes. In the early and late endosomes, the intact antibody with TAMRA and QSY7 has very low fluorescence intensity due to quenching of TAMRA fluorescence by QSY7. After degradation of the antibody in the lysosomes, the TAMRA is separated from the quencher QSY7 to produce fluorescence in the cancer cells.
Figure 20.7 The structures of drug–peptide conjugates including (a) DOX-r8, (b) DOX-RGDC4, and (c) MTX-cIBR.
Figure 20.8 The sequence of BPI molecule, which is a conjugate between an antigenic peptide (GAD, PLP, or CII peptide) and LABL peptide that are connected via a linker. GAD-BPI has been shown to suppress Type 1 diabetes in the non-obese diabetes mouse model. PLP-BPI suppresses the experimental autoimmune encephalomyelitis (EAE) in the mouse model as treatment, prophylactic, and vaccine. CII-BPI suppresses rheumatoid arthritis in collagen-induced rheumatoid arthritis.
, amino caproic acid;
Figure 20.9 The mutation residue in the monoclonal antibody-to-cysteine residue or unnatural amino acid for site-specific and homogeneous drug conjugation.
Figure 21.1 Microscopic view of the lymphatic capillary illustrating a closed intercellular junction (a) and an open intercellular junction (b) allowing luminal access to molecules along the pathway indicated by the arrow.
Figure 21.2 Initial lymphatic vessels, collecting lymphatic vessels, and the draining lymph node. (a) Schematic figure of lymphatic system, including initial lymphatic vessels, collecting lymphatic vessels, and the draining lymph node. (b) Initial lymphatic vessels and collecting lymphatic vessels. The initial lymphatic vessels have discontinuous cell junctions (Button pattern). Collecting lymphatics have continuous junction molecules and basement membrane and organized smooth muscle cell coverage. Organized smooth muscle coverage in collecting lymphatics allows phasic lymphatic contractions to propel lymph through lymphatic vessels.
Figure 21.3 Tumor-associated lymphatic vessels serve as a route for lymph node metastasis.
Figure 21.4 Comparison of nanoparticle uptake into the initial lymphatics. Fluorescence microlymphangiography of the lymphatic capillary network in mouse tail skin after 90 minutes infusion with fluorescent nanoparticles of: (a) 20, (b) 45 and (c) 100 nm diameter.
Figure 21.5 Influence of size on the pharmacokinetics and biodistribution of SC-administered liposomes. A single dose of liposomes of varying sizes was SC injected into the dorsal side of the foot of rats. Levels of radioactivity were determined 52 hours post injection. (a) Percentage of injected dose recovered from the SC injection site. (b) Percentage of the lymphatically absorbed fraction per gram recovered from the regional lymph nodes.
Figure 21.6 Lymph node retention of nanoparticles. Shown are sections from draining lymph nodes following the interstitial injections into the mouse tail with 20, 45, and 100 nm PPS nanoparticles. Nanoparticles were present at all time points for 20 and 45 nm nanoparticles, but 100 nm particles were not seen in the lymph nodes.
Figure 21.7 Effect of surface charges of liposomes on the lymphatic uptake and lymph nodal retention. Radiolabeled liposomes with negative, positive, or neutral charges were SC injected into rats footpad, and the percentage of the injected dose in both (a) primary lymph nodes and (b) secondary regional lymph nodes was calculated.
Figure 21.8 The axillary lymph nodal accumulation of plain liposomes (plain Gd Ls), dextran-modified liposomes (Dext Gd Ls), and PEG-modified liposomes (PEG Gd Ls).
Figure 21.9 The lymphatic trafficking of fluorescent liposomes after SC injection into forepaws of Balb/c mice. (a) The accumulation of different liposomes in draining lymph nodes (LNs) from 5 minutes to 48 hours post injection. (b) The fluorescent intensity of LN images measured with the maestro software. Data are shown as mean ± SE (
= 5), *
< 0.05; **
< 0.01. (c) The fluorescent image of draining LNs at 24 hours. White arrows indicate draining LNs.
Figure 21.10 Typical structure of liposomes. (a) Simple liposomes are vesicles that have a shell consisting of a lipid bilayer. A liposome can trap hydrophobic guest molecules a few nanometres in diameter (spheres) within the hydrophobic bilayer and hydrophilic guests up to several hundred nanometres (star) in its larger interior. (b) In “stealth” liposomes developed for drug-delivery applications, the lipid bilayer contains a small percentage of polymer lipids. Peptides (rectangle) that target specific biological targets may also be attached to the polymers. (c) Most cationic liposome–DNA complexes have an onion-like structure, with DNA (rods) sandwiched between cationic membranes. (d) Kubitschke et al. report liposomes in which the bilayer assembles from cavitands—vase-shaped molecules—to which the authors attached hydrophobic and hydrophilic chains. The cavitands can trap Angström-sized guest compounds (diamonds) in their hydrophobic cavities. These vesicles can therefore encapsulate guest molecules of different sizes in the cavitands, the bilayer and the liposome’s interior.
Figure 21.11 Representation of liposomes production by lipid hydration followed by size-reduction process.
Figure 21.12 Weight ratios of popliteal and iliac lymph nodes (LNs) on the left side (tumor inoculation and metastasis side) to the corresponding LNs at the right side of breast or lung tumor models after SC injection of normal saline (N.S.), doxorubicin (DOX) solution, untargeted PEG liposomes (P-LS/DOX), and LyP-1-PEG liposomes (L-P-LS/DOX). Compared with untargeted liposomes, LyP-1-PEG liposomes exhibited significantly enhanced inhibition of popliteal and iliac LNs metastases in breast tumor model but only iliac LN metastasis in lung tumor model (*
< 0.05, **
< 0.01, ***
Figure 21.13 Specific targeting of LyP-1-PEG liposomes to breast tumor lymphatics. Fluorescent LyP-1-PEG liposomes were colocalized with lymphatic vessel markers (shown for LYVE-1 and podoplanin arrows indicate the colocalization in metastatic LNs, indicating the specific binding ability of LyP-1-PEG liposomes to tumor lymphatics.
Figure 21.14 Pharmacokinetic profiles of fluorescein-loaded untargeted and LyP-1-PEG liposomes in metastatic popliteal lymph nodes (LNs) of MDA-MB-435 tumor models after the SC injection. The AUC of targeted liposomes (L-LS) in metastatic popliteal LNs was 53.9% higher than that of untargeted liposomes (LS) (
= 3, Mean ± SD), verifying the active targeting ability of LyP-1-PEG liposomes metastatic LNs.
Figure 21.15 Schematics of three types of lipid-based drug carriers.
lymphatic uptake of various formulations after oral administration of MTX PBS solution (MTX-Plain), MTX-loaded SLNs prepared from stearic acid (MTX-SA), monostearin (MTX-MS), tristearin (MTX-TS), and Compritol 888 (MTX-CA).
Figure 21.17 Structures of Dextran and Hyaluronan.
Figure 21.18 Self-assembly of polymeric micelles encapsulated with poorly water-soluble anticancer drugs.
Figure 21.19 The targeted delivery of LyP-1-PM to tumor lymphatics in MDA-MB-435S tumor-bearing nude mice by immunofluorescence technique. LyP-1-PM colocalized with the (a) lymphatic endothelial marker (LYVE-1), but not with (b) blood vessel markers (CD31). On the contrary, PM had good colocalization with (d) CD31, but not with (c) LYVE-1. Nuclei were counterstained with Hoechst 33258.
Figure 21.20 Drug absorption via the intestinal lymphatic system and portal vein. FA, fatty acid; LPs, lipoproteins; MG, monoglyceride; TG, triglyceride.
Figure 21.21 Rate of intestinal lymphatic uptake of lopinavir. Lo-MC, conventional lopinavir suspension; Lo-SLN, Lopinavir SLNs formulation (
Figure 21.22 (a) Visceral pleura lymphatics and peribronchial vascular lymphatic collectors of the right lung. (b) Visceral pleura lymphatics and peribronchial vascular lymphatic collectors of the left lung.
Figure 21.23 Gamma scintigraphy photographs of rats receiving
Tc-amikacin-loaded SLNs (a) IV after 0.5 hour, (b) IV after 6 hours, (c) pulmonary after 0.5 hour, and (d) pulmonary after 6 hours.
Figure 21.24 Aerosolized α-TEA, 9-NC, and combination treatments inhibited lung and lymph node metastasis. The number of fluorescent microscopic metastases (a) on the surface of the left lung lobe or (b) on the surface of individual lymph nodes were determined (
significantly different from control;
Figure 21.25 Diagrammatic representation of the subcutaneous injection site.
Figure 21.26 Tumor concentration of free
Tc-ETPL SLNs after injecting in Dalton’s lymphoma-bearing mice via different routes. Each value is the mean ± S.D. of three experiments. ET, etoposide; ETPL, etoposide SLNs.
Figure 21.27 Measurement of tumor size (a) and survival curves (b) of female Nu/Nu mice administered with IV saline, SC HA, equivalent doses of IV CDDP, SC HA–Pt, and IV HA–Pt (3.5 mg/kg on Pt basis, 5 ≤
≤ 7). Representative photographs of animals in (c) SC HA–Pt group at 12 weeks or (d) IV CDDP group at 8 weeks.
Figure 21.28 Paclitaxel lymph node (left) and tumor (right) distribution versus time after IP injection of 5 mg/kg paclitaxel (PTX) or Lipusu. Data represent the mean ± SD of three animals.
Figure 21.29 Comparison of paclitaxel concentration in all tissues collected at 48 hours after paclitaxel loading nanoparticle (PLA) and PTX IP administration at 5 mg/kg.
Figure 21.30 (a) Structure of albumin-binding molecular vaccine. (b and c) Tumor growth in C57BL/6 mice (
= 8 per group) inoculated with 3 × 10
TC-1 (b) or B16F10 (c) tumor cells and vaccinated with CpG plus E7 peptide or Trp2 peptide (10 µg prime, 20 µg boost), respectively, on days indicated by arrows. Statistically significant differences between soluble and amph-vaccines are indicated by asterisks: **
< 0.01, *
< 0.05 by one-way ANOVA with Bonferroni post-test. Data show mean ± s.e.m. of 2–4 independent experiments. NS, not significant.
Figure 22.1 Schematic representation of the highly interdisciplinary field of theranostics; the future of theranostics depends on multidisciplinary cooperation between medical scientists, molecular biologists, chemists, materials scientists, physicists, and imaging specialists.
Figure 22.2 Typical molecular imaging instruments and images representative of each modality: (a) MRI, (b) computed tomography, (c) positron emission tomography (PET), (d) single-photon emission computed tomography (SPECT), (e) optical imaging, and (f) ultrasound.
Figure 22.3 RGD peptide-labeled QD705 for NIR fluorescence imaging of tumor vasculature: (a) Schematic illustration of the peptide-labeled QDs (QD705-RGD), (b) AFM of QD705-RGD deposited on a silicon wafer and (c)
NIR fluorescence imaging of U87MG tumor-bearing mice injected with QD705-RGD (left) and QD705 (right), the tumor signal intensity reached its maximum at 6-hour postinjection with QD705-RGD (pointed by white arrows).
Figure 22.4 (a) Schematic representation of doxorubicin (Dox) and Fe
nanoparticle-loaded PEG-PLA micelles, with cRGD peptide conjugated on the micelle surface. (b) TEM image of cRGD-DOXO-SPIO-loaded polymeric micelles (scale bars: 20 nm). (c)
values of SLK cells treated with 16% cRGD-DOXO-SPIO micelles as a function of cell number. (d, e) Confocal laser scanning microscopy of SLK cells treated with 10 and 16% cRGD-DOXO-SPIO micelles.
Figure 22.5 (a) Schematic illustration of
-PEG-TRC105 nanoconjugate. (b) TEM image of NOTA-mSiO
-PEG-TRC105 in PBS solution. (c) Representative PET/CT and PET images of mice at 5 hours postinjection. Tumors are indicated by yellow arrowheads. (d) Fluorescence images of DOX-loaded nanocomposite in PBS solution and
optical image of major organs at 0.5 hour after intravenous injection of DOX-loaded nanocomposite.
Figure 22.6 (a) Schematic illustration for UC-[email protected] nanocomposite. (b) SEM image of UC-[email protected] (c) UCL (green) and FL (red) images of Squaraine (SQ) dye–loaded nanocomposites (UC-[email protected]-SQ) obtained by the Maestro
imaging system. (d)
-weighted MR images of mice before and post injection of UC-[email protected]-SQ.
Figure 22.7 (a) Illustration of the multifunctional cRGD-conjugated SPIO nanocarriers for combined tumor-targeting drug delivery and PET/MR imaging. (b)
relaxation rates (1/
) as a function of iron concentration (mM) for both cRGD-conjugated SPIO nanocarriers and commercial Feridex. (c) PET images of U87MG tumor-bearing mice at 0.5 hour post injection of
Cu-labeled SPIO nanocarriers (cRGD-conjugated, cRGD-free, and cRGD-conjugated with a blocking dose of cRGD).
Figure 23.1 Global sales of the peptide and protein therapeutics between 2007 and 2012. The center points of the circles represent the approximate global sales values, while the diameter of the circles (the percentage values) corresponds to the ratio in the wholesale therapeutics market. Even though the sales numbers of peptide and protein drugs are going higher every year, their percentage in the global pharmaceutics market remains similar, which indicates a stable share despite of the current developments.
Figure 23.2 Different pinocytosis pathways. Compared to the other endocytosis pathways, the vesicles of the macropinocytosis are significantly larger. Some clathrin- and caveolae-independent pathways also require dynamin.
Figure 23.3 The cellular uptake pathways of Tf and FA via their receptors. Holo-Tf binds to the TfR on the cell surface and complexes localize in clathrin-coated pits, which invaginate to initiate endocytosis. Acidification of the endosome results in a decrease in pH that stimulates a conformational change in Tf and its subsequent release of iron. The iron is then transported out of the endosome into the cytosol by DMT1. Apo-Tf remains bound to the TfR1 while in the endosome and is only released once the complex reaches the cell surface and neutral pH. Clathrin-independent endocytosis of FA differs according to the FA–FR interaction. Univalent complexes go through a different cycle and lower pH drop compared with the multivalent complexes, which reach lysosomes rapidly.
Figure 23.4 Possible cellular uptake pathways of CPPs. After the CPP (i.e., TATp)-enclosed macropinosomes enter the cytoplasm; the pH decrease stimulates the leakage of CPP-conjugated macromolecules from the vesicle. Structures are not proportional.
Figure 24.1 Intramuscular (IM), subcutaneous (SC), and intradermal (ID) delivery by traditional needle injection and newer needle-free delivery systems.
Figure 24.2 Devices for parenteral administration of vaccines. (a) Disposable needle and syringe for IM/SC delivery of a vaccine. (b) Prefilled syringe vaccine against human papilloma virus (Gardasil) for IM delivery. (c) Needle-free device Biojector® 2000 (Bioject Inc.) for IM/SC delivery.
Figure 24.3 Devices for intradermal delivery of vaccines. (a) BD SoluviaTM prefillable microinjection system currently marketed for use with influenza vaccine (Fluzone® Intradermal). (b) TheraJect VaxMat® dissolvable microneedle arrays currently under development.
Figure 24.4 Different dosage forms for oral administration of vaccines. (a) Liquid formulation in a plastic tube for oral delivery for RotaTeq®, a live, attenuated pentavalent rotavirus vaccine (Merck & Co., Inc.). (b) Enteric coated capsules containing lyophilized powder of live, attenuated bacteria for Vivotif®, a typhoid vaccine marketed by Crucell.
Figure 24.5 Devices for intranasal delivery. (a) Intranasal delivery of live attenuated influenza vaccine FluMist
. The vaccine is filled into a glass prefilled syringe with an attached nasal delivery device, Accuspray
(Becton, Dickinson and Company). (b) Nebulizer (AerovectRx, Inc.) utilizing battery powered piezoelectric energy to drive an aerosol from a disposable drug cartridge.
Figure 25.1 Characterization of ternary complexes for oligonucleotide delivery. (a) DNA accessibility in complexes of the cationic liposomes DOTAP with poly(propylacrylic acid) (PPAA) and oligodeoxynucleotide (ODN). A diluted solution of the single-stranded DNA-binding reagent OliGreen was added to the complexes, and the decrease of OliGreen fluorescence was measured at excitation and emission wavelengths of 485 and 530 nm, respectively. Means of three separate experiments ± SEM are shown. (b) Zeta potentials of DOTAP/PPAA/ODN complexes. Aliquots (120 µl) of complexes were diluted with 1.5 ml HBS before their zeta potentials were determined by phase analysis light scattering. Means of two separate experiments ± SEM are shown.
Figure 25.2 Heparin dissociation assay. The anionic polyelectrolyte heparin is added to polymer–nucleic acid complexes. The release of nucleic acid is a measure of the unpackaging capability of the complexes. In the example shown here, oligodeoxynucleotides (ODNs) with varying backbones—phosphodiester (PO), phosphorothioate (PS), or partially PS (with mod2, for example, indicating that two linkages on each end are phosphorothioate, and modALT, indicating alternating PO and PS linkages throughout)—were incubated with PEI of varying molecular weight. Results show that PS ODNs are resistant to heparin-induced dissociation compared to PO or mixed-backbone ODNs.
Figure 25.3 Active targeted delivery. Through a binding agent (shown) or via direct conjugation, a ligand is able to shuttle its nucleic acid cargo selectively to cells bearing the corresponding biological receptor, with comparatively less uptake in cells absent the receptor.
Figure 25.4 Intracellular delivery barriers. Nucleic acid vectors typically enter cells via endocytosis or via micropinocytosis leading eventually to fusion with the endosomal pathway. Escape from the endosomes before exocytosis or degradation in lysosomes is necessary for the nucleic acid to exert its biological activity, as is dissociation (unpackaging) from the carrier.
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