Targeted Drug Delivery

Juliano, Rudolph L. (EDT); Audus, K. L. (CON); Bodor, N. (CON); Borchardt, R. T. (CON); Brewster, M. E. (CON)

ISBN 10: 3642758649 / ISBN 13: 9783642758645

Editore: Springer, 2011

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Dati bibliografici

• Titolo: Targeted Drug Delivery
• Editore: Springer
• Data di pubblicazione: 2011
• Lingua: Inglese
• ISBN 10: 3642758649
• ISBN 13: 9783642758645
• Rilegatura: Brossura
• Condizione: As New

Descrizione articolo

Riassunto

The chapters in this volume describe a powerful emerging approach for the therapy of disease. Targeted drug delivery, that is control of the kinetic behavior, tissue distribution, and subcellular localization of pharmaco­ logically active agents, offers an important means for improving the efficacy of a wide variety of drug therapies. This is particularly true for therapeutic approaches based on newer agents which are the products of recombinant DNA research. These agents, be they peptides, proteins, or oligonucleotides, tend to be larger, more complex, and less stable than traditional drugs. Thus they stand to benefit most from drug delivery systems which can protect them from premature degradation and which can carry them to critical target sites in the body. This volume examines several important aspects of the current state of drug delivery research; it also attempts to project future directions for this field. Successful approaches to drug targeting are based, first of all, on a sophisticated understanding of the biological barriers encountered by the drug-carrier complex as it moves from the portal of administration to the ultimate target site. A second aspect of successful drug delivery is appro­ priate matching of the disease entity with the pharmacologically active substance and with the delivery system. Thus it is important to be aware of the variety of delivery technologies which currently exist and to be sensitive to their strengths and limitations.

Contenuti

1 A New Perspective for Drug Delivery Research.- A. Promises Realized: A Recent History of Controlled Drug Delivery.- I. Sustained Delivery Systems: A Clinical and Commercial Success.- 1. Implantable Systems.- 2. Transdermal Systems.- II. Microparticulate Delivery Systems.- 1. Solving Old Problems.- 2. Clinical Evaluation.- B. The Opening Door: Molecular Biology Generates New Opportunities and Challenges for Drug Delivery Research.- I. Using the Body’s Own Pharmaceuticals.- II. Endocrine Vs Paracrine: A Drug Targeting Problem.- C. An Overview of this Volume: Building on the Past and Looking Toward the Future.- D. Drug Targeting Research in the Twenty-First Century: A New Perspective.- References.- 2 Internalization and Sorting of Macromolecules: Endocytosis.- A. Introduction.- B. Pathways of Endocytosis in Nonpolarized Cells.- I. Endosomes.- II. Properties of Endosomes.- 1. Acidification.- 2. Endosome Fusion and Sorting.- 3. Maturation of Endosomes.- C. Molecular Basis of Endocytosis.- I. Internalization.- 1. Required Receptor Sequences.- 2. Clathrin-Coated Pit Clustering Proteins.- 3. Formation of Endocytic Vesicles.- II. Intracellular Routing.- D. Noncoated Pit Internalization.- E. Endocytosis in Polarized Cells.- F. Summary.- References.- 3 Transport of Macromolecules Across the Capillary Endothelium.- A. Introduction.- B. Pathways for the Passage of Macromolecules Across Capillary Endothelium.- I. Capillary Endothelium.- II. Fenestrations.- III. Large Pores.- IV. Intercellular Junctions.- V. Endocytosis and Phagocytosis.- C. The Blood-Brain Barrier.- D. Experimental Model Systems.- I. Brain Perfusion Model.- II. Isolated Capillaries.- III. Tissue Culture Systems.- E. Applications of Tissue Culture Models in the Study of Capillary Endothelial Cell Transport of Macromolecules.- I. Kinetics of Marker Molecules.- 1. Lucifer Yellow.- 2. Lectins.- II. Large Peptides.- 1. Transferrin.- 2. Insulin and Insulin-Like Growth Factor.- 3. Atrial Natriuretic Factor.- 4. Modified Albumins.- III. Small Peptides.- IV. Regulation of the Permeability of Capillary Endothelium.- 1. Astrocytes.- 2. Vasoactive Peptides.- F. Summary.- References.- 4 Pharmacokinetics of Drug Targeting: Specific Implications for Targeting via Prodrugs.- A. Introduction.- B. Pharmacokinetic Models and Drug Targeting.- I. Defining Drug Targeting.- II. Testing Targeting Hypotheses Using Classical or Compartmental Pharmacokinetic Models.- III. Testing Targeting Hypotheses Using Physiological Pharmacokinetic Models.- 1. Perfusion Models.- 2. Trafficking and Cellular Uptake Limitations.- 3. Specific Examples of Models Used to Evaluate and Predict Targeting Strategies.- C. Prodrug-Mediated Targeted Drug Delivery.- I. Prodrugs in General.- II. Site-Specific Drug Delivery via Prodrugs.- 1. Indirect Drug Targeting via Prodrugs.- 2. Direct Drug Targeting via Prodrugs.- References.- 5 Soluble Polymers as Targetable Drug Carriers.- A. Introduction.- B. Consequences of Drug Binding to Macromolecular Carriers: Cellular Level.- I. Pinocytosis.- 1. Receptor-Mediated Endocytosis.- II. Endosomes.- III. Lysosomes.- C. Fate of Macromolecular Carriers In Vivo.- I. Principles of Biodegradability.- II. Influence of Substitution on the Degradability of Natural Polymers.- 1. Polysaccharides.- 2. Polyamino Acids.- III. Elimination of Macromolecular Carriers from the Organism.- 1. Structural Factors Influencing the Fate of Macromolecules.- D. Release of Drugs.- I. Release of Drugs by Hydrolysis.- II. Disulfide Spacers.- III. Release of Drugs by Enzymes.- 1. Release of Drug Models from HPMA Copolymers by Chymotrypsin.- 2. Cleavage by Lysosomal Enzymes.- IV. Relationship Between Susceptibility to Enzymatically Catalyzed Hydrolysis and Biological Activity.- E. Targeting.- I. Principles of Targeting.- II. Obstacles to Targeted Drug Delivery.- 1. Multidrug Resistance.- III. Targeting Lysosomes with Carbohydrate Moieties.- 1. Asialoglycoproteins.- 2. Lysosomal Hydrolases.- 3. Glycoconjugates.- 4. Synthetic and Natural Polymers.- IV. Antibodies.- 1. Antibody-Drug Conjugates.- 2. Antibody-Synthetic Polymer-Drug Conjugates.- 3. Antibody-Natural Polymer-Drug Conjugates.- V. Hormones.- VI. Other Targeting Systems.- F. Photosensitization: Activation by Light.- I. Photodynamic Therapy.- 1. Double Targeting.- 2. Uptake of Photosensitizer Conjugates.- G. Decreased Toxicity and Immunogenicity of Drug-Polymer Conjugates.- I. Toxicity of Drug-Polymer Conjugates.- II. Immunogenicity of Polymer-Drug Conjugates.- H. Soluble Polymers for Site Specific Oral Drug Delivery.- I. Enzyme Controlled Site Specific Drug Release.- II. Bioadhesion of Polymeric Carriers.- III. Two Fold Specificity in Oral Drug Delivery.- I. Concluding Remarks.- References.- 6 Systemic Delivery of Pharmacologically Active Molecules Across the Skin.- A. Biomedical Logic of Transdermal Drug Delivery.- I. Introduction.- II. The Skin Site for Percutaneous or Transdermal Drug Delivery.- III. Mechanisms and Kinetics of TDD.- B. Historic Development of TDD.- C. Transdermal Delivery of Pharmacologically Active Organic Molecules.- I. Nitroglycerin-Releasing TDD System.- 1. Membrane Permeation-Controlled Drug Delivery.- 2. Matrix Diffusion-Controlled Drug Delivery.- 3. Interfacial Partitioning-Controlled Drug Delivery.- II. Scopolamine-Releasing TDD System.- III. Clonidine-Releasing TDD System.- IV. Estradiol-Releasing TDD System.- V. Determination of TDD Kinetics.- 1. In Vitro Drug Release Kinetics.- 2. In Vitro Transdermal Permeation Kinetics.- 3. In Vivo Transdermal Permeation Kinetics.- 4. In Vitro and In Vivo Correlations of Transdermal Permeation Kinetics.- VI. Optimization of Transdermal Controlled Drug Delivery.- D. Transdermal Delivery of Pharmacologically Active Peptide/Protein Molecules.- E. Conclusion.- References.- 7 Chemical Delivery Systems.- A. Introduction.- B. Site and Stereospecific Drug Delivery to the Eye.- C. Brain-Targeting Drug Delivery.- I. Background.- II. Dihydronicotinate CDSs.- 1. Brain-Targeting of Neurotransmitters and Amino Acids.- 2. Brain-Enhanced Delivery of Antiviral Agents.- 3. Application of the Brain-Targeting CDS to Estrogens.- 4. Conclusion.- References.- 8 In Vivo Behavior of Liposomes: Interactions with the Mononuclear Phagocyte System and Implications for Drug Targeting.- A. Introduction.- B. Interactions with Body Fluids.- C. Interactions with Cells.- D. Anatomical Barriers.- E. Factors Influencing Liposome Uptake by Cells.- I. Liposome Size.- II. Liposome Composition.- III. Cholesterol and Opsonization.- IV. Prolonged Circulation Time.- F. Surface Modification.- G. Intracellular Processing of Liposomes.- H. Implications for Drug Targeting.- I. Concluding Remarks.- References.- 9 Antisense Oligonucleotides as Pharmacological Modulators of Gene Expression.- A. General Principles and Historical Background.- B. Artificial Control of Gene Expression by Synthetic Oligonucleotides: An Overview of Problems and Potential.- C. Oligonucleotide Chemistry and Modifications.- I. Modifications of the Phosphodiester Backbone.- 1. Nonionic Oligonucleotides.- 2. Isoelectric Oligonucleotides.- 3. Phosphoramidate Oligonucleotides.- II. Modifications of the Sugar Moiety.- 1. Sugar-Modified Oligonucleotides.- 2. Oligoribonucleotide Analogues.- III. Functionalization of Oligonucleotide Ends.- D. Internalization Pathway of Antisense Oligonucleotides and Alternative Methods to Increased Cellular Uptake.- I. Mechanism of Uptake of Oligonucleotides in Cells.- II. Modifications of Oligonucleotides to Increase Cell Uptake.- E. Mechanism of Action of Antisense Oligonucleotides.- F. Biological Potential of Synthetic Oligonucleotides.- G. Prospectives of In Vivo Utilization of Antisense Oligonucleotides.- References.