title: Quantity and accessibility for specific targeting of receptors in tumours.
abstract: Synaphic (ligand-directed) targeting of drugs is an important potential new approach to drug delivery, particularly in oncology. Considerable success with this approach has been achieved in the treatment of blood-borne cancers, but the advances with solid tumours have been modest. Here, we have studied the number and availability for ligand binding of the receptors for two targeting ligands. The results show that both paucity of total receptors and their poor availability are major bottlenecks in drug targeting. A tumour-penetrating peptide greatly increases the availability of receptors by promoting transport of the drug to the extravascular tumour tissue, but the number of available receptors still remains low, severely limiting the utility of the approach. Our results emphasize the importance of using drugs with high specific activity to avoid exceeding receptor capacity because any excess drug conjugate would lose the targeting advantage. The mathematical models we describe make it possible to focus on those aspects of the targeting mechanism that are most likely to have a substantial effect on the overall efficacy of the targeting.
authors.affiliation: 1] Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA [2] Center for Nanomedicine, and Department of Cell, Molecular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106-9610, USA.
authors.forename: Sajid
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA 93106-5080, US.
authors.forename: Maria
authors.initials: M
authors.lastname: Rodriguez-Fernandez
authors.affiliation: 1] Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA [2] Center for Nanomedicine, and Department of Cell, Molecular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106-9610, USA.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Braun
authors.affiliation: Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA 93106-5080, US.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Doyle
authors.affiliation: 1] Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA [2] Center for Nanomedicine, and Department of Cell, Molecular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106-9610, USA.
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D008024:Ligands; D055641:Mathematical Concepts; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D010455:Peptides; D011956:Receptors, Cell Surface