Targeting integrins with RGD-conjugated gold nanoparticles in radiotherapy decreases the invasive activity of breast cancer cells

Abstract

Gold nanoparticles (AuNPs) have recently attracted attention as clinical agents for enhancing the effect of radiotherapy in various cancers. Although radiotherapy is a standard treatment for cancers, invasive recurrence and metastasis are significant clinical problems. Several studies have suggested that radiation promotes the invasion of cancer cells by activating molecular mechanisms involving integrin and fibronectin (FN). In this study, polyethylene-glycolylated AuNPs (P-AuNPs) were conjugated with Arg–Gly–Asp (RGD) peptides (RGD/P-AuNPs) to target cancer cells expressing RGD-binding integrins such as α5- and αv-integrins. RGD/P-AuNPs were internalized more efficiently and colocalized with integrins in the late endosomes and lysosomes of MDA-MB-231 cells. A combination of RGD/P-AuNPs and radiation reduced cancer cell viability and increased DNA damage compared to radiation alone in MDA-MB-231 cells. Moreover, the invasive activity of breast cancer cell lines after radiation treatment was significantly inhibited in the presence of RGD/P-AuNPs. Microarray analyses revealed that the expression of FN in irradiated cells was suppressed by combined use of RGD/P-AuNPs. Reduction of FN and downstream signaling may be involved in suppressing radiation-induced invasive activity by RGD/P-AuNPs. Our study suggests that RGD/P-AuNPs can target integrin-overexpressing cancer cells to improve radiation therapy by suppressing invasive activity in addition to sensitization. Thus, these findings provide a possible clinical strategy for using AuNPs to treat invasive breast cancer following radiotherapy.

Targeting Integrins in Cancer Nanomedicine: Applications in Cancer Diagnosis and Therapy

“…Another problem is the localization of AuNPs in cells. As described above, integrin-targeted NPs mainly accumulate in late endosomes and lysosomes [78]. This localization suggests that NPs appear to work in lysosomes, but in some situations, the function of the lysosomes might decrease NP efficacy.…”

“…These characteristics have inspired individuals to conjugate integrin-targeted ligands to the surface of AuNPs, which illustrates the concept of "targeted radiosensitizers". We have reported the radiosensitizing effects of RGD-conjugated polyethylene-glycosylated AuNPs (RGD/P-AuNPs) on integrin-overexpressing breast cancer cells [78]. Our study showed that RGD/P-AuNPs are efficaciously internalized into integrin-overexpressing cancer cells subjected to an increase in radiation-induced DNA damage.…”

“…Interestingly, some of the artificial integrin-targeted peptide mimics act as antagonists that can inhibit integrin-mediated functions [76,77]. Through modification with integrin-targeted peptides, these NPs have been shown to exhibit not only high affinity to integrin-overexpressing cancer cells but also potential efficacy to suppress cancer progression through the inhibition of integrin-mediated functions [78,79].…”

“…Incidentally, the required factors for regulating the recycling of integrins back to the plasma membrane are specifically upregulated in cancer cells and thus related to cancer progression [80,82]. Due to these characteristics (endocytosis and recycling of integrins), the integrin-targeted NPs are able to interact with integrins on the cell surface and are effectively internalized by the cancer cells together with the ligand [83], and some of these NPs accumulate in late endosomes and lysosomes [78].…”

“…Our study showed that RGD/P-AuNPs are efficaciously internalized into integrin-overexpressing cancer cells subjected to an increase in radiation-induced DNA damage. Interestingly, the IR-induced invasiveness [180] was also suppressed by the RGD/P-AuNPs [78]. Several studies have revealed that some cancer cells that survive radiotherapy might exhibit enhanced invasiveness (IR-enhanced invasiveness) [181,182] or acquire an invasive phenotype [183], which might lead to a higher proportion of distal recurrences after radiotherapy.…”