Pioglitazone enhances cisplatin's impact on triple-negative breast cancer: Role of PPARγ in cell apoptosis.

Peroxisome proliferator-activated receptor-gamma (PPARγ) has been recently shown to play a role in many cancers. The breast tissue of triple-negative breast cancer (TNBC) patients were found to have a significantly lower expression of PPARγ than the other subtypes. Furthermore, PPARγ activation was found to exert anti-tumor effects by inhibiting cell proliferation, differentiation, cell growth, cell cycle, and inducing apoptosis. To start with, we performed a bioinformatic analysis of data from OncoDB, which showed a lower expression pattern of PPARγ in different cancer types. In addition, high expression of PPARγ was associated with better breast cancer patient survival. Therefore, we tested the impact of pioglitazone, a PPARγ ligand, on the cytotoxic activity of cisplatin in the TNBC cell line. MDA-MB-231 cells were treated with either cisplatin (40 µM) with or without pioglitazone (30 or 60 µM) for 72 h. The MTT results showed a significant dose-dependent decrease in cell viability as a result of using cisplatin and pioglitazone combination compared with cisplatin alone. In addition, the protein expression of Bcl-2, a known antiapoptotic marker, decreased in the cells treated with cisplatin and pioglitazone combination at doses of 40 and 30 µM, respectively. On the other hand, cleaved- poly-ADP ribose polymerase (PARP) and -caspase-9, which are known as pro-apoptotic markers, were upregulated in the combination group compared with the solo treatments. Taken together, the addition of pioglitazone to cisplatin further reduced the viability of MDA-MB-231 cells and enhanced apoptosis compared with chemotherapy alone.

MicroRNA-219 loaded chitosan nanoparticles for treatment of glioblastoma.

Recent evidence has implicated microRNA-219 (miR-219) in regulation of gene contributed in glioblastoma (GBM) pathogenesis. This study aimed to prepare miR-219 in chitosan (CS) nanoparticles (NPs), characterize and investigate their efficacy on human GBM cell line (U87 MG). NPs were prepared using ionic gelation method. The influence of process parameters on physicochemical characteristics of NPs was investigated. Apoptotic effect of miR-219 was examined on U87 MG cells. Formulated NPs showed particle size of 109 ± 2.18 nm, with poly dispersity index equal to 0.2 ± 0.05, and zeta potential of +20.5 ± 0.7 mV. Entrapment efficiency of miR-219 in loaded NP has reached 95%. The in vitro release study demonstrated sustained release pattern of miR-219 from CS-NPs. Gel retardation assay has confirmed the integrity of miR-219 after production process. The fabricated NPs reduced the survival of U87 MG cells to 78% after 24 h of post-transfection, and into 67.5% after 48 h. However, fibroblasts were not affected by the NPs, revealing their specificity for GBM cells. Given the tumour suppressing function of miR-219, and advantage of CS-NPs for gene delivery to the central nervous system, the presented NPs have a great potential for treatment of GBM.

MicroRNA-539-5p-Loaded PLGA Nanoparticles Grafted with iRGD as a Targeting Treatment for Choroidal Neovascularization.

Choroidal neovascularization (CNV) is a major cause of visual impairment that results from excessive growth of blood vessels in the eye's choroid. The limited clinical efficacy of the current therapy for this condition requires the emergence of new treatment modalities such as microRNA (miRNAs). A recent study identified microRNA-539-5p (miR-539) as an angiogenic suppressor in a CNV animal model; however, its therapeutic delivery is limited. Therefore, this study aims to formulate miR-539 in targeted nanoparticles (NPs) prepared from polylactic-co-glycolic acid (PLGA). The NPs were decorated with internalizing arginylglycylaspartic (RGD) peptide (iRGD), which specifically targets the alpha-v-beta-3 (αvß3) integrin receptor that is overexpressed in blood vessels of ocular tissue in CNV patients. The 1H NMR spectra results revealed successful conjugation of iRGD peptide into PLGA NPs. The miR-539-PLGA.NPs and miR-539-iRGD-PLGA.NPs were prepared and showed a particle size of 300 ± 3 and 306.40 ± 4 nm, respectively. A reduction in human retinal microvascular endothelial cell (HRMEC) viability was shown 48 and 72 h post transfection with miR-539 incorporated in PLGA NPs and iRGD-PLGA.NPs. iRGD-functionalized PLGA NPs caused further significant reduction in cell viability when compared with plain ones, revealing an enhancement in the NP uptake with iRGD-grafted NPs. The current study showed that miR-539-PLGA.NPs and miR-539-iRGD-PLGA.NPs are promising approaches that reduced the viability of HRMECs, suggesting their therapeutic potential in the treatment of CNV.

Trastuzumab Targeted Neratinib Loaded Poly-Amidoamine Dendrimer Nanocapsules for Breast Cancer Therapy.

BACKGROUND: Human epidermal growth factor receptor2 (Her2) positive breast cancer represents 25% of breast cancer cases. Targeted therapy with Her2 monoclonal antibody, trastuzumab (TZ), represents the first-line treatment for this type of breast cancer. In addition, neratinib, an irreversible inhibitor of the HER-2 receptor tyrosine kinase, has recently been approved as adjuvant therapy to TZ. This study aims to formulate (TZ)-grafted dendrimers loaded with neratinib, allowing a dual treatment alongside reducing the associated resistance as well as targeted therapy. METHODS: TZ was conjugated on the surface of dendrimer using hetero-cross linker, MAL-PEG-NHS, and the zeta potential, and in vitro release of neratinib from dendrimers was characterized. Formulated dendrimers were also fluorescently conjugated with fluorescein isothiocyanate to visualize and quantify their SKBR-3 cellular uptake. RESULTS: The G4 PAMAM dendrimer showed successful encapsulation of neratinib and a sustained release profile. Comparative in vitro studies revealed that these TZ-targeted dendrimers loaded with neratinib were more selective and have higher antiproliferation activity against SKBR-3 cells compared to neratinib alone and neratinib loaded dendrimer. CONCLUSION: In the current study, neratinib loaded in plain and trastuzumab-grafted dendrimer were successfully prepared. Enhanced cellular uptake of trastuzumab conjugated dendrimers was shown, together with a higher cytotoxic effect than plain neratinib dendrimers. These findings suggest the potential of TZ-conjugated dendrimers as targeting carrier for cytotoxic drugs, including neratinib.