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Vol. 53, Issue 2, 283-318, June 2001
Molecular Targeting and Polymer Toxicology Group, School of
Pharmacy and Biomolecular Sciences, University of Brighton, Brighton,
United Kingdom (S.M.M., A.C.H.); and Laboratory of Molecular Oncology,
CRC Department of Clinical Oncology, City Hospital, University of
Nottingham, Nottingham, United Kingdom (J.C.M.)
I. Introduction
II. Theoretical Applications of Long-Circulating Particulate
Carriers in Experimental and Clinical Medicine
A. Circulating Drug Reservoir in the Blood Compartment
B. Artificial Oxygen Delivery Systems
C. Blood-Pool Imaging
D. Passive Targeting
E. Active Targeting
III. Rational Approaches in the Design of Long-Circulating
Particles
A. The First Few Steps
1. Physicochemical Characteristics of Nanoparticles and Their
Effect on Protein Adsorption and Opsonization.
2. Macrophage Heterogeneity, Physiological Status, and Species
Differences.
3. Splenic Filtration.
4. Confinement to Vasculature.
IV. Translation of Microbial and Related Mammalian Technologies to
Nanoparticle Engineering
V. Synthetic Polymers in Colloid Engineering
A. Polymeric Nanospheres
B. Micelles (Self-Assembly Constructs)
C. Liposomes
D. Oil-in-Water Emulsions
VI. Essential Thoughts on Using Polymers in Nanoparticle
Engineering
A. The Concept of Polymer Polydispersity: Does Size Matter?
B. Sources of Chemical Contamination in Polymers
C. Interspecies and Intraspecies Response(s) to Polymeric Systems
D. Biodegradable Polymers
VII. Why Are Polymer-Coated Long-Circulating Particles Eventually
Cleared by Macrophages?
VIII. Experimental and Clinical Trials with Parenterally
Administered Long-Circulating Particles: Achievements and Pitfalls
A. Circulating Drug Reservoir in the Blood Compartment
B. Blood-Pool Imaging
C. Passive Targeting
1. Pathologies with Leaky Vasculature: Solid Tumors.
2. Pathologies with Leaky Vasculature: Inflammatory and Infectious
Sites.
3. Spleen.
4. Lymph Nodes.
D. Active Targeting
1. Ligand Coupling.
2. Demonstration of Longevity and Target Binding.
3. Antibody-Mediated in Vivo Targeting (the Cart in Front of the
Horse?).
4. Folate-Mediated Targeting.
E. Passive or Active Targeting?
IX. Conclusions
References
The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.
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