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

Mol Pharm. Nov-Dec 2009;6(6):1868-75. doi: 10.1021/mp900158d.


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.

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Folate Receptors, GPI-Anchored
  • Folic Acid / metabolism
  • Folic Acid / pharmacokinetics*
  • Kinetics
  • Mice
  • Mice, Nude
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Rhodamines / metabolism
  • Rhodamines / pharmacokinetics*
  • Xenograft Model Antitumor Assays


  • Carrier Proteins
  • Folate Receptors, GPI-Anchored
  • Receptors, Cell Surface
  • Rhodamines
  • Folic Acid