Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells

Abstract

Glioblastoma is an invasive tumor of the central nervous system. Tumor recurrence resulting from ineffective current treatments, mainly due to the blood–brain barrier, highlights the need for innovative therapeutic alternatives. The recent availability of nanotechnology represents a novel targeted strategy in cancer therapy. Natural products have received considerable attention for cancer therapy because of general lower side effects. Curcumin is a new candidate for anticancer treatment, but its low bioavailability and water solubility represent the main disadvantages of its use. Here, curcumin was efficiently encapsulated in a nontoxic nanocarrier, termed dendrosome, to overcome these problems. Dendrosomal curcumin was prepared as 142 nm spherical structures with constant physical and chemical stability. The inhibitory role of dendrosomal curcumin on the proliferation of U87MG cells, a cellular model of glioblastoma, was evaluated by considering master genes of pluripotency and regulatory miRNA (microribonucleic acid). Methylthiazol tetrazolium assay and flow cytometry were used to detect the antiproliferative effects of dendrosomal curcumin. Annexin-V-FLUOS and caspase assay were used to quantify apoptosis. Real-time polymerase chain reaction was used to analyze the expression of OCT4 (octamer binding protein 4) gene variants ( OCT4A , OCT4B , and OCT4B1 ), SOX-2 (SRY [sex determining region Y]-box 2) , Nanog , and miR-145 . Dendrosomal curcumin efficiently suppresses U87MG cells growth with no cytotoxicity related to dendrosome. Additionally, the accumulation of cells in the SubG 1 phase was observed in a time- and dose-dependent manner as well as higher rates of apoptosis after dendrosomal curcumin treatment. Conversely, nonneoplastic cells were not affected by this formulation. Dendrosomal curcumin significantly decreased the relative expression of OCT4A , OCT4B1 , SOX-2 , and Nanog along with noticeable overexpression of miR-145 as the upstream regulator. This suggests that dendrosomal curcumin reduces the proliferation of U87MG cells through the downregulation of OCT4 (octamer binding protein 4) variants and SOX-2 (SRY [sex determining region Y]-box 2) in an miR-145 -dependent manner.

Therapeutic Potential of Curcumin for the Treatment of Brain Tumors

“…These vesicles, or polymersomes, can be made of one or more different high-molecular weight amphiphilic block copolymers such as oleic acid and PEG 400 as a diblock nanostructure. This combination has been shown effective in delivering curcumin and reducing tumor burden in mouse models [75, 76]. Monomethoxy PEG has a higher molecular weight of 2 kDa versus 400 Da and has also been tested in attempt to obtain a better thermodynamic profile [77].…”

“…Dendrosome carriers, comprised of esterified oleoyl chloride and polyethylene glycol 400, have recently been published as effective means of delivery curcumin [75, 76]. In vitro data treating U87MG GBM cells with curcumin, dendrosomal curcumin, and empty dendrosome found that dendrosomal curcumin had superior efficacy at 24, 48, and 72 hours.…”

“…During cellular differentiation, miR-145 expression suppresses these pluripotent genes. The authors reported that dendrosomal curcumin was able to exert its effects by inciting an approximately 35-fold elevation of miR-145 [75]. Treatment of A431 (epidermoid carcinoma) and WEHI-164 (mouse fibrosarcoma) cell lines with dendrosomal curcumin resulted in IC 50 values of 14.3 and 7.5  μ M at 48 hours, respectively, compared to 37  μ M for curcumin alone against WEKI-164 cells [76].…”

Application of a novel pH-responsive gemini surfactant for delivery of curcumin molecules

“…Tahmasebi Mirgani et al have reported curcumin nano-formulation based on dendrosomes (branchedpolymeric micelles) that can down-regulate pluripotency genes in U87MG glioblastoma cells [12]. Furthermore, Erfani et al [13] have revealed that diblock copolymer-based micelles can be considered for delivery of curcumin molecules to the cancer cells [13].…”

“…This is mainly due to its low aqueous solubility, poor absorption, low bioavailability, extensive metabolism and rapid elimination [5,6,8,9].The employment of nano-drug delivery systems has allured the attention of many researchers to conquer the physiochemical limitations of curcumin [10]. Lipid-based and polymer-based nanocarriers are among the most favoured nano-systems approved as carriers of anti-cancer drugs to be implemented in clinical trials [6,11].Tahmasebi Mirgani et al have reported curcumin nano-formulation based on dendrosomes (branchedpolymeric micelles) that can down-regulate pluripotency genes in U87MG glioblastoma cells [12]. Furthermore, Erfani et al [13] have revealed that diblock copolymer-based micelles can be considered for delivery of curcumin molecules to the cancer cells [13].Here, an mPEG urethane gemini surfactant was synthesised and its viability as a curcumin delivery vehicle was examined.…”