Biomimetic transport and rational drug delivery.
Medicine and pharmaceutics are encountering critical needs and opportunities for transvascular drug delivery that improves site targeting and tissue permeation by mimicking natural tissue addressing and transport mechanisms. This is driven by the accelerated development of genomic agents requiring targeted controlled release. Although rationally designed for in vitro activity, such agents are not highly effective in vivo, due to opsonization and degradation by plasma constituents, and failure to transport across the local vascular endothelium and tissue matrix. A growing knowledge of the addresses of the body can be applied to engineer "Bio-Logically" staged delivery systems with sequential bioaddressins complementary to the discontinuous compartments encountered--termed discontinuum pharmaceutics. Effective tissue targeting is accomplished by leukocytes, bacteria, and viruses. We are increasingly able to mimic their bioaddressins by genomic means. Approaches described in this commentary include: (a) endothelial-directed adhesion mediated by oligosaccharides and carbohydrates (e.g. dermatan sulfate as a mimic of sulfated CD44) and peptidomimetics interacting with adhesins, selectins, integrins, hyaluronans, and locally induced growth factors (e.g. vascular endothelial growth factor, VEGF) and coagulation factors (e.g. factor VIII antigen); (b) improved tissue permeation conferred by hydrophilically "cloaked" carrier systems; (c) "uncloaking" by matrix dilution or selective triggering near the target cells; and (d) target binding-internalization by terminally exposed hydrophobic moieties, cationic polymers, and receptor-binding lectins, peptides, or carbohydrates. This commentary also describes intermediate technology solutions (e.g. "hybrid drugs"), and highlights the high-resolution, dynamic magnetic resonance imaging and radiopharmaceutical imaging technologies plus the groups and organizations capable of accelerating these important initiatives.
Ranney
D F
DF
Department of Radiology, University of Texas Southwestern Medical Center at Dallas 75235, USA. globemed@flash.net
D001693:Biological Transport, Active; D002241:Carbohydrates / Q000493:pharmacokinetics; D003871:Dermatan Sulfate / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D015195:Drug Design; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D018716:Molecular Mimicry; D009841:Oligonucleotides / Q000493:pharmacokinetics; D010539:Permeability; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics
D002241:Carbohydrates; D009841:Oligonucleotides; D019275:Radiopharmaceuticals; D003871:Dermatan Sulfate