Breast cancer is a leading cause of cancer deaths among women in the US, with 40 % chance of relapse after treatment. Recent studies outline the role of cancer stem cells (CSCs) in tumor initiation, propagation, and regeneration of cancer. Moreover, it has been established that breast CSCs reside in a quiescent state that makes them more resistant to conventional cancer therapies than bulk cancer cells resulting in tumor relapse. In this study, we establish that CSCs are associated with the overexpression of vasoactive intestinal peptide (VIP) receptors which can be used to actively target these cells. We investigated the potential of using a novel curcumin nanomedicine (C-SSM) surface conjugated with VIP to target and hinder breast cancer with CSCs. Here, we formulated, characterized, and evaluated the feasibility of C-SSM nanomedicine in vitro. We investigated the cytotoxicity of C-SSM on breast cancer cells and CSCs by tumorsphere formation assay. Our results suggest that curcumin can be encapsulated in SSM up to 200 μg/ml with 1 mM lipid concentration. C-SSM nanomedicine is easy to prepare and maintains its original physicochemical properties after lyophilization, with an IC50 that is significantly improved from that of free curcumin (14.2±1.2 vs. 26.1±3.0 μM). Furthermore, C-SSM-VIP resulted in up to 20 % inhibition of tumorsphere formation at a dose of 5 μM. To this end, our findings demonstrate the feasibility of employing our actively targeted nanomedicine as a potential therapy for CSCs-enriched breast cancer.
Purpose: Despite recent advances in breast cancer therapy, many patients still experience relapse. Evidence suggests that a sub-population of treatment-resistant “cancer stem cells” (CSCs) may be responsible for recurrence of the disease. Recently, we have shown that nanotechnology-based delivery of curcumin in sterically stabilized phospholipid micelles (C-SSM) significantly improved the anti-cancer stem cell (anti-CSC) activity of free curcumin (C-DMSO) in a tumorsphere formation assay using MCF-7 human breast cancer cells (Gulcur et al. AAPS annual meeting, 2011). Here, we investigate 1) the expression of vasoactive intestinal peptide (VIP) receptors on MCF-7 CSCs, and 2) the efficacy of a novel VIP-grafted C-SSM formulation (C-SSM-VIP) to eliminate CSCs, with the aim of further improving the anti-CSC activity of C-SSM. Methods: VIP receptor expression of MCF-7 CSCs was determined using a fluorescence-based ligand binding assay. Cells, previously sorted into CD44+/CD24−/low CSC and CD44+/CD24+ normal cancer cell populations using flow cytometry, were cytospun to glass slides and stained with fluorescence-labeled VIP. Mean fluorescence intensities (MFIs) were quantified from confocal microscope images of the slides. The C-SSM nanomedicine and VIP conjugation to activated distearoyl phosphatidylethanolamine - polyethylene glycol 3400-NHS (VIP-DSPE-PEG) were prepared as previously described (Thaqi et al. CRS annual meeting, 2011; S. Dagar et al. J. Ctrl. Rel. (2001) 74:129-134). VIP-DSPE-PEG constructs were incorporated into C-SSM by incubation to form C-SSM-VIP. Anti-CSC activity of C-SSM-VIP was evaluated using a tumorsphere formation assay, where MCF-7 cells were seeded in ultralow attachment plates as a single cell suspension in serum-free media. C-DMSO, C-SSM and C-SSM-VIP at 5 μM curcumin concentrations, and control treatments were then added to the culture. Sphere formation was evaluated under microscope after 7 days. Results: Analysis of the MFIs from confocal images showed ∼3-fold higher expression of VIP receptors on the CSC population of MCF-7 cells compared to normal cancer cells (P<0.05). Furthermore, targeting the VIP receptors on CSCs with C-SSM-VIP had a significantly higher efficacy for inhibition of sphere formation compared to both C-SSM and C-DMSO (66.9% ± 2.7 vs. 58.9% ± 2.9 and 57.5% ± 4.3, respectively; P<0.05). Conclusion: These findings demonstrate for the first time that improved elimination of breast CSCs can be achieved with the C-SSM-VIP nanomedicine that employs a dual targeting strategy by 1) delivering curcumin in an effective way to target CSC pathways, and 2) actively targeting CSCs through internalizing VIP receptors. Therefore, we suggest that C-SSM-VIP should be further developed as a novel and safe nanomedicine with a high potential to provide a relapse-free cure of breast cancer. Funded by NIH grant CA121797. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1944. doi:1538-7445.AM2012-1944
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