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. 2017 Apr 18;9(2):15.
doi: 10.3390/pharmaceutics9020015.

Folate Decorated Nanomicelles Loaded with a Potent Curcumin Analogue for Targeting Retinoblastoma

Hashem Alsaab  1   2 , Rami M Alzhrani  3   4 , Prashant Kesharwani  5   6 , Samaresh Sau  7 , Sai Hs Boddu  8 , Arun K Iyer  9   10
Affiliations

Folate Decorated Nanomicelles Loaded with a Potent Curcumin Analogue for Targeting Retinoblastoma

Hashem Alsaab et al. Pharmaceutics. .

Abstract

The aim of this study was to develop a novel folate receptor-targeted drug delivery system for retinoblastoma cells using a promising anticancer agent, curcumin-difluorinated (CDF), loaded in polymeric micelles. Folic acid was used as a targeting moiety to enhance the targeting and bioavailability of CDF. For this purpose, amphiphilic poly(styrene-co-maleic acid)-conjugated-folic acid (SMA-FA) was synthesized and utilized to improve the aqueous solubility of a highly hydrophobic, but very potent anticancer compound, CDF, and its targeted delivery to folate overexpressing cancers. The SMA-FA conjugate was first synthesized and characterized by ¹H NMR, FTIR and DSC. Furthermore, the chromatographic condition (HPLC) for estimating CDF was determined and validated. The formulation was optimized to achieve maximum entrapment of CDF. The particle size of the micelles was measured and confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cytotoxicity studies were conducted on (Y-79 and WERI-RB) retinoblastoma cells. Results showed that the solubility of CDF could be increased with the newly-synthesized polymer, and the entrapment efficiency was >85%. The drug-loaded nanomicelles exhibited an appropriate size of <200 nm and a narrow size distribution. The formulation did not show any adverse cytotoxicity on a human retinal pigment epithelial cell (ARPE-19), indicating its safety. However, it showed significant cell killing activity in both Y-79 and WERI-RB retinoblastoma cell lines, indicating its potency in killing cancer cells. In conclusion, the folic acid-conjugated SMA loaded with CDF showed promising potential with high safety and pronounced anticancer activity on the tested retinoblastoma cell lines. The newly-formulated targeted nanomicelles thus could be a viable option as an alternative approach to current retinoblastoma therapies.

Keywords: 3,4-difluorobenzylidene curcumin (CDF); WERI-RB; Y-79; fluorocurcumin; folate-receptor targeting; nanomicelles; retinoblastoma; targeted drug delivery.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Accumulation of targeted formulation (synthesized amphiphilic poly(styrene-co-maleic acid)-conjugated-folic acid (SMA-FA)-CDF) at the tumor via folate receptor-mediated endocytosis due to the specific binding of FA to folate receptors overexpressed on retinoblastoma cells (Y-79).
Figure 2
Figure 2
Up: 1H NMR was performed for (a) folic acid, (b) FA-SMA and FA-SMA-CDF; Bottom: FTIR and characterization of CDF, FA, SMA and the FA-SMA conjugate.
Figure 2
Figure 2
Up: 1H NMR was performed for (a) folic acid, (b) FA-SMA and FA-SMA-CDF; Bottom: FTIR and characterization of CDF, FA, SMA and the FA-SMA conjugate.
Figure 3
Figure 3
(a) Particle size characterization of SMA-CDF and FA-SMA-CDF using the dynamic light scattering (DLS) technique; (b) surface morphology of SMA-CDF and FA-SMA-CDF by transmission electron microscopy (TEM); (c) differential scanning calorimetry (DSC) of pure drug (CDF), FA-SMA, and FA-SMA-CDF nanoformulations.
Figure 4
Figure 4
In vitro cell viability assay showing the percentage of cell viability observed at 24 h after treating ARPE-19 cells with the pure drug (CDF), FA-SMA and FA-SMA-CDF. Data are expressed as the percentage of control cells and the mean ± SEM.
Figure 5
Figure 5
(a) In vitro cell viability assay showing the percentage of cell viability observed at 48 h after treating Y-79 cells with various formulations is shown (n = 8); (b) MTT assay observed at a 48-h treatment of WERI-RB1 cells with SMA-CDF and FA-SMA-CDF as compared to the same treatment is shown (n = 8).
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