Targeting of follicle stimulating hormone peptide-conjugated dendrimers to ovarian cancer cells

Dimple A. Modi, Suhair Sunoqrot, Jason Bugno, Daniel D. Lantvit, Seungpyo Hong, Joanna E. Burdette

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34 Citations (Scopus)

Abstract

Ovarian cancer is the most lethal gynecological malignancy. Current treatment modalities include a combination of surgery and chemotherapy, which often lead to loss of fertility in premenopausal women and a myriad of systemic side effects. To address these issues, we have designed poly(amidoamine) (PAMAM) dendrimers to selectively target the follicle stimulating hormone receptor (FSHR), which is overexpressed by tumorigenic ovarian cancer cells but not by immature primordial follicles and other non-tumorigenic cells. Fluorescein-labeled generation 5 (G5) PAMAM dendrimers were conjugated with the binding peptide domain of FSH (FSH33) that has a high affinity to FSHR. The targeted dendrimers exhibited high receptor selectivity to FSHR-expressing OVCAR-3 cells, resulting in significant uptake and downregulation of an anti-apoptotic protein survivin, while showing minimal interactions with SKOV-3 cells that do not express FSHR. The selectivity of the FSH33-targeted dendrimers was further validated in 3D organ cultures of normal mouse ovaries. Immunostaining of the conjugates revealed their selective binding and uptake by ovarian surface epithelium (OSE) cells that express FSHR, while sparing the immature primordial follicles. In addition, an in vivo study monitoring tissue accumulation following a single intraperitoneal (i.p.) injection of the conjugates showed significantly higher accumulation of FSH33-targeted dendrimers in the ovary and oviduct compared to the non-targeted conjugates. These proof-of-concept findings highlight the potential of these FSH33-targeted dendrimers to serve as a delivery platform for anti-ovarian cancer drugs, while reducing their systemic side effects by preventing nonspecific uptake by the primordial follicles.

Original languageEnglish
Pages (from-to)2812-2820
Number of pages9
JournalNanoscale
Volume6
Issue number5
DOIs
Publication statusPublished - 2014 Mar 7

All Science Journal Classification (ASJC) codes

  • Materials Science(all)

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    Modi, D. A., Sunoqrot, S., Bugno, J., Lantvit, D. D., Hong, S., & Burdette, J. E. (2014). Targeting of follicle stimulating hormone peptide-conjugated dendrimers to ovarian cancer cells. Nanoscale, 6(5), 2812-2820. https://doi.org/10.1039/c3nr05042d