Real time, noninvasive imaging and quantitation of the accumulation of ligand-targeted drugs into receptor-expressing solid tumors

Erina Vlashi, Jennifer E. Sturgis, Mini Thomas, Philip Low

Research output: Contribution to journalArticle

20 Scopus citations

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 (Kd = 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 ≥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.

Original languageEnglish (US)
Pages (from-to)1868-1875
Number of pages8
JournalMolecular pharmaceutics
Volume6
Issue number6
DOIs
StatePublished - Dec 7 2009

Keywords

  • Folic acid
  • Real time imaging
  • Targeted cancer therapy
  • Tumor uptake

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

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