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

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

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 3H–RGD2–PTX was compared with that of 3H–PTX. The treatment effect of RGD2–PTX and RGD2+PTX was measured by tumor size, 18F-FDG/PET, 18F-FLT/PET, and postmortem histopathology.

Results

By comparing the biodistribution of 3H–RGD2–PTX and 3H–PTX, we found that 3H–RGD2–PTX had higher initial tumor exposure dose and prolonged tumor retention than 3H–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 18F-FLT/PET imaging and ex vivo Ki67 staining indicated little effect of the PTX-based drug on cell proliferation, 18F-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.

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Acknowledgment

We would like to thank the cyclotron team at the Stanford University for 18F-FDG and 18F-FLT production. Grant support was from the National Cancer Institute (NCI; R01 120188, R01 CA119053, R21 CA121842, R21 CA102123, P50 CA114747, U54 CA119367, and R24 CA93862) and the Department of Defense (DOD; W81XWH-07-1-0374, W81XWH-04-1-0697, W81XWH-06-1-0665, W81XWH-06-1-0042, and DAMD17-03-1-0143).

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Authors and Affiliations

  1. The Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Biophysics, and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd, Stanford P095, CA, 94305-5484, USA

    Qizhen Cao, Zi-Bo Li, Kai Chen, Zhanhong Wu, Lina He & Xiaoyuan Chen

  2. Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA, USA

    Nouri Neamati

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  1. Qizhen Cao
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  2. Zi-Bo Li
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  3. Kai Chen
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  4. Zhanhong Wu
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  5. Lina He
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  6. Nouri Neamati
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  7. Xiaoyuan Chen
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Correspondence to Xiaoyuan Chen.

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Cao, Q., Li, ZB., Chen, K. et al. 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 35, 1489–1498 (2008). https://doi.org/10.1007/s00259-008-0744-y

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  • DOI: https://doi.org/10.1007/s00259-008-0744-y

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