Original Article
Lipid–polymer nanoparticles encapsulating curcumin for modulating the vascular deposition of breast cancer cells

https://doi.org/10.1016/j.nano.2014.02.004Get rights and content

Abstract

Vascular adhesion and endothelial transmigration are critical steps in the establishment of distant metastasis by circulating tumor cells (CTCs). Also, vascular inflammation plays a pivotal role in steering CTCs out of the blood stream. Here, long circulating lipid–polymer nanoparticles encapsulating curcumin (NANOCurc) are proposed for modulating the vascular deposition of CTCs. Upon treatment with NANOCurc, the adhesion propensity of highly metastatic breast cancer cells (MDA-MB-231) onto TNF-α stimulated endothelial cells (HUVECs) reduces by ~ 70%, in a capillary flow. Remarkably, the CTCs vascular deposition already reduces up to ~ 50% by treating solely the inflamed HUVECs. The CTCs arrest is mediated by the interaction between ICAM-1 on HUVECs and MUC-1 on cancer cells, and moderate doses of curcumin down-regulate the expression of both molecules. This suggests that NANOCurc could prevent metastasis and limit the progression of the disease by modulating vascular inflammation and impairing the CTCs arrest.

From the Clinical Editor

In this novel study, lipid nanoparticles encapsulating curcumin were able to prevent metastasis formation and limited the progression of the disease by modulating vascular inflammation and impairing the circulating tumor cells' arrest as a result of down-regulation of ICAM1 and MUC1 in a highly metastatic breast cancer cell line model.

Graphical Abstract

Tumor cells adhere to the vessel walls and migrate across the endothelium to colonize distant sites. Vascular adhesion molecules, such as ICAM-1 and E-selectin, support the interaction of circulating tumor cells with the inflamed endothelium facilitating cell extravasation. Long circulating nanoparticles loaded with curcumin, a potent anti-inflammatory natural product, can modulate the expression of adhesion molecules on both the circulating tumor cells and the inflamed endothelium thus reducing the likelihood of metastasis formation.

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Section snippets

Materials and chemicals

Human Fibronectin was obtained from Sigma Aldrich (St. Louis, MO, USA). Curcumin (mixture of curcumin, demethoxycurcumin, and bisdemethoxycurcumin, 98+%) was obtained from Fisher Scientific. XTT kit was obtained from Trevigen (Gaithersburg, Maryland 20877). Anti-human CD54 Purified, Anti-human CD227 (Mucin 1) eFluor615 (clone SM3), Anti-mouse IgG1 APC, and mouse IgG1 K Isotype control PE antibodies were obtained from e-biosciences; Anti-MUC1 purified (clone SM3) was obtained from abcam.

Synthesis and physico-chemical characterization of nanoparticles encapsulating curcumin

Nanoparticles encapsulating curcumin molecules (NANOCurc) were synthesized using an emulsion/solvent evaporation technique, as detailed in the Materials and Methods. NANOCurc comprise a polymeric core, made of poly(lactic-co-glycolic acid) (PLGA); and an external layer, composed of a mixture of natural lipids and poly(ethylene glycol) (PEG) chains, as schematically depicted in the insets of Figure 1, B. The curcumin molecules are dispersed within the hydrophobic PLGA core; whereas the outer

Discussion

It is becoming clearer that systemic inflammation may influence the dissemination of tumor cells by facilitating the vascular arrest of CTCs and their proliferation at distant sites. In vivo studies document that the intravenous injection of LPS into mice may increase by over 40% the vascular deposition of lung carcinoma cells in hepatic sinusoids.16 Also, pulmonary inflammation was shown to enhance the formation of melanoma metastasis in the lungs by over 3 times.17 Furthermore, in obese

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      NSAIDs inhibit the growth of a number of tumors by blocking COX activity and modulating the NF-κB pathway, among other key inflammatory pathways [196]. Curcumin loaded in lipid-polymer NPs called NANOCurc curbs the vascular accumulation of circulating tumor cells [197]. In a different study, researchers loaded docetaxel (DTXL) and curcumin together in curcumin-conjugated cholesteryl-hyaluronic acid nanogels (CHA-CUR) as well as spherical polymeric nano constructs (SPNs), which resulted in a 13-fold tumor suppression [198].

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    Grants and Conflict of Interests: This work was partially supported by the Cancer Prevention Research Institute of Texas through grant CPRIT RP110262; the National Institutes of Health (NIH, USA) through grants U54CA143837 and U54CA151668. Anna L. Palange and Daniele Di Mascolo acknowledge the Doctoral School of The University of Magna Graecia (Italy) for travel support. Daniele Di Mascolo also acknowledges the support of the EU Commission, the European Social Fund and the department 11 “Culture-Education-University-Research-Technological Innovation-Higher Education” of Calabria Region (POR Calabria FSE 2007/2013).

    The authors declare no competing interests.

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