title: Real time, noninvasive imaging and quantitation of the accumulation of ligand-targeted drugs into receptor-expressing solid tumors.
abstract: Targeted therapies are emerging as a preferred strategy for treatment of cancer and other diseases. To evaluate the effect of high affinity receptors on the rate and extent of tumor penetration of receptor-targeted drugs, we have characterized the kinetics of folate-rhodamine uptake by folate receptor (FR)-expressing tumors in live mice. Folate-rhodamine was selected to model receptor-targeted drugs, because (i) it has high affinity (K(d) = 10(-9) M) for FR-rich tumors, (ii) its uptake can be monitored in vivo by multiphoton microscopy, and (iii) five folate-targeted drugs of similar size are currently undergoing clinical trials. We demonstrate that (1) folate-rhodamine saturates tumor FR in <5 min, <30 min, and <100 min following intravenous, paraorbital, and intraperitoneal injection, respectively; (2) complete clearance of folate-rhodamine from receptor-negative tissues requires > or =50 min, and (3) a "binding site barrier" may retard, but does not prevent, penetration of the ligand-targeted drug. We conclude that low molecular weight ligand-targeted drugs have appropriate pharmacokinetic properties for tumor-selective delivery.
authors.affiliation: Department of Chemistry and Bindley Bioscience Center, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Erina
authors.initials: E
authors.lastname: Vlashi
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Sturgis
authors.forename: Mini
authors.initials: M
authors.lastname: Thomas
authors.forename: Philip S
authors.initials: PS
authors.lastname: Low
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism / Q000493:pharmacokinetics*; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012235:Rhodamines / Q000378:metabolism / Q000493:pharmacokinetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D012235:Rhodamines; D005492:Folic Acid