Hyaluronated nanoparticles deliver raloxifene to CD44-expressed colon cancer cells and regulate lncRNAs/miRNAs epigenetic cascade

Abstract

Background: Colorectal malignant cells (CRC) are one of the world’s main causes of cancer mortality and morbidity. Notwithstanding the plenty of anti-CRC therapeutics, its prognosis remains not selective owing to cancer resistance to these therapeutics. Raloxifene (RX), a medication firstly used to treat osteoporosis, was recently licenced for the prevention of CRC. Unfortunately, due to medication resistance, many RX-based therapies are likely to become ineffective. Recently, we identified a novel method of administration to lengthen the half-life of RX by mixing it with chitosan (CS) and hyaluronic acid (HA). Thus, the rationale of the current study was to investigate how colon cancer cells were affected by RX-HA-CS nanoparticles (RX NPs) in terms of targetability, cytotoxicity, and epigenetic cascade alteration. Results: RX NP had an entrapment efficiency (EE%) of 90.0 ± 8.12%. Compared to HCT 116 cells, Caco-2 cells were more susceptible to the cytotoxic effects of RX and its NP as well as they had a higher binding affinity to CD44 receptors compared to normal WI-38 cells. In comparison to the free RX, the RX NP’s cytotoxic fold changes in HCT 116 and Caco-2 cells were 2.16 and 2.52, respectively. Furthermore, the epigenetic cascade of some noncoding RNAs was examined. Moreover, particular protein concentrations were investigated in all tested cells after application of the proposed therapies. Our results showed that the RX NP recorded higher remarkable cytotoxic impact on CRC cells compared to the free RX. Intriguingly, it was hypothesized that RX nanoparticles attacked colon cancerous cells by up-regulating miR-944 and E-cadherin (ECN) expressions, while down-regulating the expressions of PPARγ, YKL-40, VEGF, H-19, LINC00641, HULC, HOTTIP, miR-92a, miR-200, and miR-21. Conclusions: We may conclude that the RX NP effectively targets CRC cells in vitro via altering lncRNAs and miRNAs epigenetic cascade as well as cellular uptake through CD44-expressed CRC cells.