Engineered Porous Beta-Cyclodextrin-Loaded Raloxifene Framework with Potential Anticancer Activity: Physicochemical Characterization, Drug Release, and Cytotoxicity Studies

Abstract

Background: Cancer ranks as the second most common cause of mortality as depicted by the World Health Organization, with one in six deaths being cancer-related mortality. Taking the lead in females, breast cancer is the most common neoplasm. Raloxifene, a selective estrogen receptor modulator, has been utilized as a chemotherapeutic agent for the treatment of breast cancer in postmenopausal women. However, its poor aqueous solubility hinders its clinical applications. Beta-cyclodextrin-based framework is a novel class of nano-vectors that used to potentiate the solubility and dissolution rate of poorly soluble drugs.

Aim: The present study investigates the solubility and dissolution rate enhancement as well as the potential cytotoxic activity of raloxifene-loaded nanosponges formulation.

Methods: The fabrication and optimization of cyclodextrin nanosponges crosslinked with diphenyl carbonate was portrayed through stoichiometric selection of cyclodextrin-to-crosslinker ratio. The complexation phenomenon and nanosponges formation were validated using FTIR, PXRD, TEM, and SEM examination.

Results: Raloxifene-loaded nanosponges exhibited a 440±8.5 nm particle size, a negative zeta potential of 25.18±2.3 mV and a partial drug incorporation. Moreover, the drug loaded nanosponges demonstrated an in-vitro significantly enhanced dissolution behavior. Furthermore, the in-vitro cytotoxicity of the raloxifene-loaded nanosponges on MCF-7 breast cancer cell lines was statistically significant compared to the complex-free raloxifene.

Conclusion: The cytotoxic behavior provided evidence that the incorporation of raloxifene within the nanosponges structure enhanced its anticancer activity and represents a potential nanocarrier for anticancer agent delivery.

Keywords: anticancer; beta-cyclodextrin; breast cancer; nanosponges; raloxifene.

Figure 1

Solubility of raloxifene in β-cyclodextrin based-nanosponges at various diphenyl carbonate crosslinker ratio and corresponding inclusion complexes.

Figure 2

FTIR spectra of raloxifene (A), unloaded nanosponges (B), raloxifene-loaded nanosponges (C), and their physical mixture (D).

Figure 3

XPRD spectra of raloxifene (A), unloaded nanosponges (B), raloxifene-loaded nanosponges (C), and their physical mixture (D).

Figure 4

Scanning electron microscopical images of raloxifene (A), ß-cyclodextrine (B), unloaded nanosponges (C), raloxifene-loaded nanosponges (D).

Figure 5

Photoelectromicroscopic image of raloxifene-loaded nanosponges using transmission electron microscope.

Figure 6

In vitro release of raloxifene from loaded nanosponges in comparison to free raloxifene, and their physical mixture in aqueous polysorbate 80 solution at 37 ± 0.5 °C.

Figure 7

Toxicity of raloxifene-loaded nanosponge to breast cells and their anticancer effect in human breast cancer cells in comparison to free raloxife and unloaded nanosponges. MTT assay showing the viability of MCF-7 breast cancer cell line. The cells were treated for 24 h with different concentrations of either raloxifene, or blank cubosomes or raloxifene-loaded nanosponge. Experiments were repeated three times, data are means ± SEM.