Evaluation of biodistribution and anti-tumor effect of a dimeric RGD peptide-paclitaxel conjugate in mice with breast cancer

Eur J Nucl Med Mol Imaging. 2008 Aug;35(8):1489-98. doi: 10.1007/s00259-008-0744-y. Epub 2008 Mar 29.


Purpose: Targeting drugs to receptors involved in tumor angiogenesis has been demonstrated as a novel and promising approach to improve cancer treatment. In this study, we evaluated the anti-tumor efficacy of a dimeric RGD peptide-paclitaxel conjugate (RGD2-PTX) in an orthotopic MDA-MB-435 breast cancer model.

Methods: To assess the effect of conjugation and the presence of drug moiety on the MDA-MB-435 tumor and normal tissue uptake, the biodistribution of (3)H-RGD2-PTX was compared with that of (3)H-PTX. The treatment effect of RGD2-PTX and RGD2+PTX was measured by tumor size, (18)F-FDG/PET, (18)F-FLT/PET, and postmortem histopathology.

Results: By comparing the biodistribution of (3)H-RGD2-PTX and (3)H-PTX, we found that (3)H-RGD2-PTX had higher initial tumor exposure dose and prolonged tumor retention than (3)H-PTX. Metronomic low-dose treatment of breast cancer indicated that RGD2-PTX is significantly more effective than PTX+RGD2 combination and solvent control. Although in vivo (18)F-FLT/PET imaging and ex vivo Ki67 staining indicated little effect of the PTX-based drug on cell proliferation, (18)F-FDG/PET imaging showed significantly reduced tumor metabolism in the RGD2-PTX-treated mice versus those treated with RGD2+PTX and solvent control. Terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining also showed that RGD2-PTX treatment also had significantly higher cell apoptosis ratio than the other two groups. Moreover, the microvessel density was significantly reduced after RGD2-PTX treatment as determined by CD31 staining.

Conclusion: Our results demonstrate that integrin-targeted delivery of paclitaxel allows preferential cytotoxicity to integrin-expressing tumor cells and tumor vasculature. The targeted delivery strategies developed in this study may also be applied to other chemotherapeutics for selective tumor killing.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics
  • Breast Neoplasms / diagnostic imaging
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Drug Delivery Systems / methods
  • Female
  • Metabolic Clearance Rate
  • Mice
  • Mice, Nude
  • Oligopeptides / administration & dosage*
  • Oligopeptides / pharmacokinetics*
  • Organ Specificity
  • Paclitaxel / administration & dosage*
  • Paclitaxel / pharmacokinetics*
  • Radionuclide Imaging
  • Tissue Distribution


  • Antineoplastic Agents
  • Oligopeptides
  • arginyl-glycyl-aspartic acid
  • Paclitaxel