title: Design of target-seeking antifibrotic compounds.
abstract: Selective delivery of drugs and biotherapeutics to the site of disease (synaphic targeting) has a number of advantages. First, the enhanced accumulation of the therapeutic compound at the target tissue increases drug efficacy without increasing side effects. Alternatively, the dose of the drug can be lowered to reduce the side effects. On the practical level, when a drug is difficult or expensive to make, being able to lower the dose may be the key to commercial viability. Certain targeting systems can change the distribution of the drug in a beneficial way. Examples include wider distribution and deeper penetration of the drug in the target tissue, active intracellular targeting when desirable, and even targeting to a particular subcellular organelle. In this chapter, we illustrate these principles by describing the development of a targeting system for an antifibrotic biotherapeutic, decorin. The system is based on vascular homing peptide (sequence: CARSKNKDC; referred to as CAR) that specifically recognizes angiogenic blood vessels in injured (regenerating) and inflammatory tissues and can deliver a payload to such tissues with high selectivity. So far, the CAR-targeted decorin has been shown to promote tissue repair with reduced scarring in a skin wound model, but this biotherapeutic can potentially be used in other injuries and in various fibrotic diseases.
authors.affiliation: Vascular Mapping Laboratory, Center for Nanomedicine, Sanford-Burnham Medical Research Institute at UCSB, University of California, Santa Barbara, California, USA.
authors.forename: Tero A H
authors.initials: TA
authors.lastname: Järvinen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003001:Cloning, Molecular; D058575:Decorin / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D005355:Fibrosis; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D019151:Peptide Library; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D058575:Decorin; D006497:Heparan Sulfate; D010446:Peptide Fragments; D019151:Peptide Library; D011993:Recombinant Fusion Proteins; C546878:DCN protein, human