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Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase signaling inhibits angiogenesis

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Abstract

Objective

Dysregulation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a hallmark of human cancer, occurring in a majority of tumors. Activation of this pathway is critical for transformation and also for the angiogenic switch, which is a key step for tumor progression. The objective of this study was to engineer a PI3K inhibitor-loaded biodegradable nanoparticle and to evaluate its efficacy.

Methods and results

Here we report that a nanoparticle-enabled targeting of the PI3K pathway results in inhibition of downstream Akt phosphorylation, leading to inhibition of proliferation and induction of apoptosis of B16/F10 melanoma. It, however, failed to exert a similar activity on MDA-MB-231 breast cancer cells, resulting from reduced internalization and processing of nanoparticles in this cell line. Excitingly, the nanoparticle-enabled targeting of the PI3K pathway resulted in inhibition of endothelial cell proliferation and tubulogenesis, two key steps in tumor angiogenesis. Furthermore, it inhibited both B16/F10- and MDA-MB-231-induced angiogenesis in a zebrafish tumor xenotransplant model.

Conclusion

Our study, for the first time, shows that targeting of the PI3K pathway using nanoparticles can offer an attractive strategy for inhibiting tumor angiogenesis.

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Acknowledgments

This work was supported by a Department of Defense BCRP Era of Hope Scholar award [W81XWH-07-1-0482] and Mary Kay Ash Charitable Foundation Grant to SS. DH is supported by an AHA Fellow to Faculty Transition Grant and RH is supported by a CIHR Fellowship. We thank Prof. Joseph Bonventre for access to his laboratory and Nicki Watson, Imaging Facility at Whitehead Institute for Biomedical, for the electron microscopy studies.

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Authors and Affiliations

  1. Harvard-MIT Division of Health Sciences and Technology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Rania Harfouche, Sudipta Basu, Shivani Soni, Raghunath A. Mashelkar & Shiladitya Sengupta

  2. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Rania Harfouche, Sudipta Basu, Shivani Soni, Dirk M. Hentschel & Shiladitya Sengupta

  3. Harvard Medical School, Brigham and Women’s Hospital, Room 317, 65 Landsdowne street, Cambridge, MA, 02139, USA

    Shiladitya Sengupta

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  1. Rania Harfouche
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  2. Sudipta Basu
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  3. Shivani Soni
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Correspondence to Shiladitya Sengupta.

Additional information

Rania Harfouche and Sudipta Basu have contributed equally to this work.

Electronic supplementary material

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10456_2009_9154_MOESM1_ESM.pdf

Supplementary Fig. 1 Concentration–Effect of NP-LY on viability of cancer cells. a–c Breast adenocarcinoma (MDA-MB-231), Lewis lung carcinoma (LLC) and melanoma (B16-F10) cells were plated on 96-well plates in the presence or absence of either free drug (LY) or LY-encapsulated nanoparticles (NP-LY). Cells were subjected to incubation with the drugs in a time- and concentration-dependent manner. At 24 and 72 h, the viability of cells was quantified using the MTS assay. Data represents mean ± SEM from independent triplicates. *P < 0.05 compared with vehicle-treated control cells (ANOVA) (PDF 54 kb)

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Harfouche, R., Basu, S., Soni, S. et al. Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase signaling inhibits angiogenesis. Angiogenesis 12, 325–338 (2009). https://doi.org/10.1007/s10456-009-9154-4

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  • DOI: https://doi.org/10.1007/s10456-009-9154-4

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