Synergistic anticancer effects of co-delivery of linc-RoR siRNA and curcumin using polyamidoamine dendrimers against breast cancer.

Breast cancer resistance to chemotherapy necessitates novel combination therapeutic approaches. Linc-RoR is a long intergenic noncoding RNA that regulates stem cell differentiation and promotes metastasis and invasion in breast cancer. Herein, we report a dual delivery system employing polyamidoamine dendrimers to co-administer the natural compound curcumin and linc-RoR siRNA for breast cancer treatment. Polyamidoamine dendrimers efficiently encapsulated curcumin and formed complexes with linc-RoR siRNA at an optimal N/P ratio. In MCF-7 breast cancer cells, the dendriplexes were effectively internalized and the combination treatment synergistically enhanced cytotoxicity, arresting the cell cycle at the G1 phase and inducing apoptosis. Linc-RoR gene expression was also significantly downregulated. Individual treatments showed lower efficacy, indicating synergism between components. Mechanistic studies are warranted to define the molecular underpinnings of this synergistic interaction. Our findings suggest dual delivery of linc-RoR siRNA and curcumin via dendrimers merits further exploration as a personalized therapeutic approach for overcoming breast cancer resistance.

Niosomal Curcumin Suppresses IL17/IL23 Immunopathogenic Axis in Skin Lesions of Psoriatic Patients: A Pilot Randomized Controlled Trial.

Psoriasis (PS) is characterized by hyperplasia of epidermis and infiltration of immune cells in the dermis. A negligible susceptibility of hypodermic permeation for local anti-inflammatory remedies is one of the major causes of medication failures. Although curcumin (CUR) has indicated effectiveness in treatment of inflammation, its successful permeation through the stratum corneum is yet a challenging issue. Therefore, niosome (NIO) nanoparticles were used as curcumin carriers to enhance its delivery and anti-inflammatory effects. Curcumin-niosome (CUR-NIO) formulations were constructed by the thin-film-hydration (TFH) technique and were added to hyaluronic acid and Marine-collagen gel-based formulation. Five mild-to-moderate PS patients (18-60 years) with PASI scores < 30 with symmetrical and similar lesions were included in the study. The prepared formulation (CUR 15 µM) was topically administered for 4 weeks on the skin lesions, in comparison to the placebo. Clinical skin manifestations were monitored and skin punches were obtained for further gene expression analyses. There was a significant reduction in redness, scaling, and an apparent improvement in CUR-NIO-treated group in comparison to the placebo-treated counterpart. The gene expression analyses resulted in significantly downregulation of IL17, IL23, IL22, and TNFα, S100A7, S100A12, and Ki67 in CUR-NIO-treated lesions. Consequently, CUR-NIO could provide therapeutic approaches for the patients with mild-to-moderate PS by suppressing the IL17/IL23 immunopathogenic axis.

Curcumin inhibits the replication of rotavirus in vitro.

Rotavirus is the most important etiological agent of infectious diarrhea in children under 5 years of age with more than 125,000 deaths occurring annually worldwide. The present study aims to determine the effect of curcumin, a natural polyphenol compound, on rotavirus in a cell culture model. The anti-viral activity of curcumin was evaluated by reverse-transcriptase quantitative PCR (RT-qPCR), TCID50, and western blot techniques to assess CC50 in curcumin-treated MA104 cells as well as EC50 and SI within the infected MA104 cell line. Our findings supported that curcumin exerted an inhibitory influence against rotavirus in a dose-dependent manner and decreased the viral titer and VP6 expression by ~99% at a concentration of 30 µM (p Keywords: curcumin; rotavirus; RT-qPCR; in vitro; anti-rotavirus agent.

WDR7 up-regulation upon knocking down of neighboring non-coding RNA using siRNAs encapsulated in polyamidoamine dendrimers.

OBJECTIVES: Breast cancer is the second leading cause of cancer death in females. Understanding molecular mechanisms in cancer cells compared with normal cells is crucial for diagnostic and therapeutic strategies. Long intergenic non-protein coding RNA, a regulator of reprogramming (lincRNA-RoR) is a noncoding RNA which initially was detected in induced pluripotent stem cells, and it has an important role in cell reprogramming and highly expressed in breast cancer cells. A key point in successful gene silencing is the usage of siRNA delivery system that is safe and efficient. MATERIALS AND METHODS: In this study, the fifth-generation of PAMAM dendrimer is used as a nanocarrier for entering siRNA molecules for gene silencing of lincRNA-RoR. WDR7 is the gene encoding adjacent of lincRNA-RoR, which has an important role in apoptosis and cell cycle. Gel retardation assay was used to find the best Negative/Positive (N/P) molar charge ratio of siRNA- PAMAM transfected into MDA-MB 231 cells. MTT assay was performed 24 hr after transfection revealed the IC50 value (half maximal inhibitory concentrations) about 100 nanomolar for lincRNA-ROR siRNA. RESULTS: The lincRNA-RoR and WDR7 gene expression changes were evaluated by real-time PCR after siRNA treatment and showed an increase in the gene expression of WDR7. CONCLUSION: This study showed that PAMAM dendrimer G5/ siRNA could be a useful system delivery for future gene therapy approaches.

Cationic vesicles for efficient shRNA transfection in the MCF-7 breast cancer cell line.

INTRODUCTION: Novel and safe delivery solutions for RNAi therapeutics are essential to obtain the full potential of cancer gene therapy. METHODS: In this study, cationic vesicular nanocarrier was applied for delivering lnc urothelial carcinoma-associated 1 (lnc UCA1) shRNA expression vector to MCF-7 cells. The physicochemical characteristics, cytotoxicity, and transfection efficiency of cationic vesicles prepared from various molar ratios of amphiphilic surfactant Tween 80 (T), squalene (S), cationic charge lipid didodecyldimethylammonium bromide, and polyethylenimine were investigated. The particle sizes of the vesicles in the nanosize range were determined by dynamic light scattering and transmission electron microscopy. RESULTS: Gel protection assay with agarose gel electrophoresis showed cationic vesicles can protect the shRNA plasmid from DNase 1 enzyme. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium, inner salt result showed no significant cytotoxicity was caused in MCF-7 cancer cell line by (T:S):polyethylenimine cationic vesicles. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium, inner salt assay, fluorescence microscope images, and flow cytometry analyses confirmed that (T:S)1,040 µM with 4.3 µg/mL of PEI vesicles provided effective transfection without significant cytotoxicity. Furthermore, we found efficient UCA1 shRNA transfection and significant (P<0.05) cell cycle arrest and apoptosis in MCF-7 cancer cells. CONCLUSION: The novel nonviral vesicular nanocarrier, (T:S)1,040 µM with 4.3 µg/mL of PEI, might be safe and efficient for cancer gene therapy and can be used in further in vitro and in vivo studies.

Serine adsorption through different functionalities on the B12N12 and Pt-B12N12 nanocages.

The present work reports the adsorption of serine in the neutral and zwitterionic forms on the pure and Pt-decorated B12N12 fullerenes by means of density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations. The binding energy of serine over the fullerene has been studied through its hydroxyl (-OH), carboxyl (-COOH), and amine (-NH2) functional groups. Based on our analysis, the binding energy of serine in zwitterionic form (F: -1.52 eV) on B12N12 fullerene is less stable than that of the neutral form (C: -1.61 eV) using the M06-2X functional. Our results indicated that the most stable chemisorption state for serine is through its amine group (I: -2.49 eV) interacting with the Pt-decorated B12N12 fullerene in comparison with the carbonyl group (J: -1.92 eV). The conductivity of the B12N12 and Pt-decorated B12N12 fullerenes is influenced by the energy band gap variation when serine is adsorbed upon the outer surface of fullerenes. Understanding the adsorption of serine on B12N12 and Pt-decorated B12N12 fullerenes provide fundamental knowledge for future applications in biomolecules and metal surfaces.

Use of single chain antibody derivatives for targeted drug delivery.

Single chain antibodies (scFvs), which contain only the variable domains of full-length antibodies, are relatively small molecules that can be used for selective drug delivery. In this review, we display how scFv antibodies help improve the specificity and efficiency of drugs. Small interfering RNA (siRNA) delivery using scFv-drug fusion peptides, siRNA delivery using scFv-conjugated nanoparticles, targeted delivery using scFv-viral peptide- fusion proteins, use of scFv in fusion with cell penetrating peptides for effective targeted drug delivery, scFv-mediated targeted delivery of inorganic nanoparticles, scFv-mediated increase of tumor killing activity of granulocytes, use of scFv for tumor imaging, site-directed conjugation of scFv molecules to drug carrier systems, use of scFv to relieve pain, use of scFv for increasing drug loading efficiency are among the topics that are discussed here.

Encapsulation of curcumin in diblock copolymer micelles for cancer therapy.

Application of nanoparticles has recently promising results for water insoluble agents like curcumin. In this study, we synthesized polymeric nanoparticle-curcumin (PNPC) and then showed its efficiency, drug loading, stability, and safety. Therapeutic effects of PNPC were also assessed on two cell lines and in an animal model of breast cancer. PNPC remarkably suppressed mammary and hepatocellular carcinoma cells proliferation (P < 0.05). Under the dosing procedure, PNPC was safe at 31.25 mg/kg and lower doses. Higher doses demonstrated minimal hepatocellular and renal toxicity in paraclinical and histopathological examinations. Tumor take rate in PNPC-treated group was 37.5% compared with 87.5% in control (P < 0.05). Average tumor size and weight were significantly lower in PNPC group than control (P < 0.05). PNPC increased proapoptotic Bax protein expression (P < 0.05). Antiapoptotic Bcl-2 protein expression, however, was lower in PNPC-treated animals than the control ones (P < 0.05). In addition, proliferative and angiogenic parameters were statistically decreased in PNPC-treated animals (P < 0.05). These results highlight the suppressing role for PNPC in in vitro and in vivo tumor growth models. Our findings provide credible evidence for superior biocompatibility of the polymeric nanocarrier in pharmacological arena together with an excellent tumor-suppressing response.

A novel diblock of copolymer of (monomethoxy poly [ethylene glycol]-oleate) with a small hydrophobic fraction to make stable micelles/polymersomes for curcumin delivery to cancer cells.

Curcumin is a potent natural anticancer agent, but its effectiveness is limited by properties such as very low solubility, high rate of degradation, and low rate of absorption of its hydrophobic molecules in vivo. To date, various nanocarriers have been used to improve the bioavailability of this hydrophobic biomaterial. This study investigates the encapsulation of curcumin in a novel nanostructure of monomethoxy poly(ethylene glycol)-oleate (mPEG-OA) and its anticancer effect. Tests were done to determine the critical micelle concentration (CMC), encapsulation efficiency, drug-loading efficiency, and cytotoxicity (against U87MG brain carcinoma cells and HFSF-PI3 cells as normal human fibroblasts) of some nanodevice preparations. The results of fluorescence microscopy and cell-cycle analyses indicated that the in vitro bioavailability of the encapsulated curcumin was significantly greater than that of free curcumin. Cytotoxicity evaluations showed that half maximal inhibitory concentrations of free curcumin and curcumin-loaded mPEG-OA for the U87MG cancer cell line were 48 µM and 24 µM, respectively. The Annexin-V-FLUOS assay was used to quantify the apoptotic effect of the prepared nanostructures. Apoptosis induction was observed in a dose-dependent manner after curcumin-loaded mPEG-OA treatments. Two common self-assembling structures, micelles and polymersomes, were observed by atomic force microscopy and dynamic light scattering, and the abundance of each structure was dependent on the concentration of the diblock copolymer. The mPEG-OA micelles had a very low CMC (13.24 µM or 0.03 g/L). Moreover, atomic force microscopy and dynamic light scattering showed that the curcumin-loaded mPEG-OA polymersomes had very stable structures, and at concentrations 1,000 times less than the CMC, at which the micelles disappear, polymersomes were the dominant structures in the dispersion with a reduced size distribution below 150 nm. Overall, the results from these tests revealed that this nanocarrier can be considered as an appropriate drug delivery system for delivering curcumin to cancer cells.