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RGD-conjugated solid lipid nanoparticles inhibit adhesion and invasion of αvβ3 integrin-overexpressing breast cancer cells

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Abstract

αvβ3 integrin receptors expressed on cancer cell surfaces play a crucial role in promoting tumor angiogenesis and cancer cell metastasis. Thus, cyclic arginyl-glycyl-aspartic acid (cRGD) peptides have been explored as a αvβ3 integrin receptor-specific targeting moiety for the targeted delivery of nanoparticle-loaded therapeutics. However, our previous study showed that cyclic RGD could act as a double-edged sword that, on one hand, extended the retention of cRGD-modified solid lipid nanoparticles (RGD-SLNs) at αvβ3 integrin receptor overexpressing breast carcinoma, and yet on the other hand, decreased the amount of tumor accumulation of RGD-SLNs attributable to the greater uptake by the mononuclear phagocyte system (MPS). Therefore, we aimed to optimize the RGD-decorated nanoparticle systems for (1) inhibiting αvβ3 integrin receptor overexpressing tumor cell metastasis and (2) increasing nanoparticle accumulation to tumor site. SLNs with cRGD content ranging from 0 to 10 % mol of total polyethyleneglycol (PEG) chains were synthesized. The binding of RGD-SLNs with αvβ3 integrin receptors increased with increasing cRGD concentration on the nanoparticles. RGD-SLNs were demonstrated to inhibit MDA-MB-231 cell adhesion to fibronectin and invasion through Matrigel. In vivo whole-body fluorescence imaging revealed that 1 % cRGD on the SLNs’ surface had maximum tumor accumulation with extended tumor retention among all formulations tested in an orthotopic MDA-MB-231/EGFP breast tumor model. This work has laid a foundation for further development of anticancer drug-loaded optimized cRGD nanoparticle formulations for the treatment of breast cancer metastasis.

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Acknowledgments

This work was funded by the Canadian Breast Cancer Foundation-Ontario Region. The authors also acknowledge the scholarships from the National Science and Engineering Research Council of Canada to D. Shan and J. Li, the University of Toronto Fellowships to D. Shan and P. Prasad, and the University of Toronto Nanotechnology Network Award and Anna and Alex Beverly Fellowship to D. Shan.

Animal studies

All institutional and national guidelines for the care and use of laboratory animals were followed

Conflict of interest

D. Shan, P. Cai, J. Li, P. Prasad, F. Liu, A.M. Rauth, and X.Y. Wu declare that they have no conflict of interest.

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Authors and Affiliations

  1. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada

    Dan Shan, Jason Li, Ping Cai, Preethy Prasad, Franky Liu & Xiao Yu Wu

  2. Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada

    Andrew Michael Rauth

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  1. Dan Shan
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Correspondence to Xiao Yu Wu.

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Shan, D., Li, J., Cai, P. et al. RGD-conjugated solid lipid nanoparticles inhibit adhesion and invasion of αvβ3 integrin-overexpressing breast cancer cells. Drug Deliv. and Transl. Res. 5, 15–26 (2015). https://doi.org/10.1007/s13346-014-0210-2

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