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Effective targeting and delivery of large amounts of medications into the cancer cells enhance their therapeutic efficacy through saturation of cellular defensive mechanisms, which is the most privilege of nano drug delivery systems (NDDS) compared to traditional approaches. Herein, we designed dual-pH/redox responsive DTX-loaded poly (β-amino ester) (PBAS) micelles decorated with a chimeric peptide and TA1 aptamer. In vitro and in vivo results demonstrated that the designed nanoplatform possessed an undetectable nature in the blood circulation, but after exposure to the tumor microenvironment (TME) of 4T1 breast cancer, it suddenly changed into dual targeting nanoparticles (NPs) (containing two ligands, SRL-2 and TA1 aptamer). The dual targeting NPs destruction in the high GSH and low pH conditions of the cancer cells led to amplified DTX release (around 70% at 24 h). The IC50 value of DTX-loaded MMP-9 sensitive heptapeptide/TA1 aptamer-modified poly (β-amino ester) (MST@PBAS) micelles and free DTX after 48 h of exposure was determined to be 1.5 µg/ml and 7.5 µg/ml, respectively. The nano-formulated DTX exhibited cytotoxicity that was 5-fold stronger than free DTX (Pvalue˂0.001). Cell cycle assay test results showed that following exposure to MST@PBAS micelles, a considerable rise in the sub G1 population (48%) suggested that apoptosis by cell cycle arrest had occurred. DTX-loaded MST@PBAS micelles revealed significantly higher (Pvalue ˂ 0.001) levels of early apoptosis (59.8%) than free DTX (44.7%). Interestingly, in vitro uptake studies showed a significantly higher TME accumulation of dual targeted NPs (6-fold) compared to single targeted NPs (Pvalue < 0.001) which further confirmed by in vivo biodistribution and fluorescent TUNEL assay experiments. NPs treated groups demonstrated notable tumor growth inhibition in 4T1 tumor bearing Balb/c mice by only 1/10th of the DTX therapeutic dose (TD) as a drug model. In conclusion, cleverly designed nanostructures here demonstrated improved anticancer effects by enhancing tumor targeting, delivering chemotherapeutic agents more accurately, promoting drug release, reducing the therapeutic dosage, and lowering side effects of anticancer drugs. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) incidence and mortality rates continue to escalate globally. Early detection of OC is challenging due to extensive metastases and the ambiguity of biomarkers in advanced High-Grade Primary Tumors (HGPTs). In the present study, we conducted an in-depth in silico analysis in OC cell lines using the Gene Expression Omnibus (GEO) microarray dataset with 53 HGPT and 10 normal samples. Differentially-Expressed Genes (DEGs) were also identified by GEO2r. A variety of analyses, including gene set enrichment analysis (GSEA), ChIP enrichment analysis (ChEA), eXpression2Kinases (X2K) and Human Protein Atlas (HPA), elucidated signaling pathways, transcription factors (TFs), kinases, and proteome, respectively. Protein–Protein Interaction (PPI) networks were generated using STRING and Cytoscape, in which co-expression and hub genes were pinpointed by the cytoHubba plug-in. Validity of DEG analysis was achieved via Gene Expression Profiling Interactive Analysis (GEPIA). Of note, KIAA0101, RAD51AP1, FAM83D, CEP55, PRC1, CKS2, CDCA5, NUSAP1, ECT2, and TRIP13 were found as top 10 hub genes; SIN3A, VDR, TCF7L2, NFYA, and FOXM1 were detected as predominant TFs in HGPTs; CEP55, PRC1, CKS2, CDCA5, and NUSAP1 were identified as potential biomarkers from hub gene clustering. Further analysis indicated hsa-miR-215-5p, hsa-miR-193b-3p, and hsa-miR-192-5p as key miRNAs targeting HGPT genes. Collectively, our findings spotlighted HGPT-associated genes, TFs, miRNAs, and pathways as prospective biomarkers, offering new avenues for OC diagnostic and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Over 70 million people worldwide are suffering from different forms of epilepsy. Despite significant advances in the past few decades, between 20 and 40% of these patients would develop medically intractable epilepsy. Technological advances are essential in the identification of novel reliable diagnostic and therapeutic approaches and in improving the quality of health services for patients with epilepsy. Nanotechnology-based approaches offer potential effective methods to improve seizure detection and treatment. Nanomedicine-based nanoparticles can promote anti-convulsant therapy through improving pharmacokinetics and biodistribution of drugs as well as providing more efficient drugs and active molecule delivery systems. Furthermore, nanotechnology-based approaches can tackle barriers to a better diagnosis of epilepsy via the improvement of bioelectrical recording approaches as well as the development of novel biomarkers and imaging systems. In the present review, we summarized the current nanotechnology-based advances in the diagnosis and treatment of epilepsy and discussed how the knowledge of these achievements could convey a better treatment outcome in epilepsy. [ABSTRACT FROM AUTHOR]

Here, we investigated the photothermal effect of gold nanorods (GNRs) on human neuroblastoma CD133+ cancer stem cells (CSCs) via autophagic cell death. GNRs were synthesized using Cetyltrimethylammonium bromide (CTAB), covered with bovine serum albumin (BSA). CD133+ CSCs were enriched from human neuroblastoma using the magnetic-activated cell sorting (MACS) technique. Cells were incubated with GNRs coated with BSA and exposed to 808-nm near-infrared laser irradiation for 8 min to yield low (43 °C), medium (46 °C), and high (49 °C) temperatures. After 24 h, the survival rate and the percent of apoptotic and necrotic CSCs were measured using MTT assay and flow cytometry. The expression of different autophagy-related genes was measured using polymerase chain reaction (PCR) array analysis. Protein levels of P62 and LC3 were detected using an enzyme-linked immunosorbent assay (ELISA). The viability of CSC was reduced in GNR-exposed cells compared to the control group (p < 0.05). At higher temperatures (49 °C), the percent of apoptotic CSCs, but not necrotic cells, increased compared to the lower temperatures. Levels of intracellular LC3 and P62 were reduced and increased respectively when the temperature increased to 49 °C (p < 0.05). These effects were non-significant at low and medium temperatures (43 and 46 °C) related to the control CSCs (p > 0.05). The clonogenic capacity of CSC was also inhibited after photothermal therapy (p < 0.05). Despite these changes, no statistically significant differences were found in terms of CSC colony number at different temperatures regardless of the presence or absence of HCQ. Based on the data, the combination of photothermal therapy with HCQ at 49 °C can significantly abort the CSC clonogenic capacity compared to the control-matched group without HCQ (p < 0.0001). PCR array showed photothermal modulation of CSCs led to alteration of autophagy-related genes and promotion of co-regulator of apoptosis and autophagy signaling pathways. Factors related to autophagic vacuole formation and intracellular transport were significantly induced at a temperature of 49 °C (p < 0.05). We also note the expression of common genes belonging to autophagy and apoptosis signaling pathways at higher temperatures. Data showed tumoricidal effects of laser-irradiated GNRs by the alteration of autophagic response and apoptosis. [ABSTRACT FROM AUTHOR]

Unraveling unwanted side effects of nanotechnology-based therapies like photothermal therapy (PTT) is vital in translational nanomedicine. Herein, we monitored the relationship between autophagic response at the transcriptional level by using a PCR array and tumor formation ability by colony formation assay in the human neuroblastoma cell line, SH-SY5Y, 48 h after being exposed to two different mild hyperthermia (43 and 48 °C) induced by PTT. In this regard, the promotion of apoptosis and autophagy were evaluated using immunofluorescence imaging and flow cytometry analyses. Protein levels of Ki-67, P62, and LC3 were measured using ELISA. Our results showed that of 86 genes associated with autophagy, the expression of 54 genes was changed in response to PTT. Also, we showed that chaperone-mediated autophagy (CMA) and macroautophagy are stimulated in PTT. Importantly, the results of this study also showed significant changes in genes related to the crosstalk between autophagy, dormancy, and metastatic activity of treated cells. Our findings illustrated that PTT enhances the aggressiveness of cancer cells at 43 °C, in contrast to 48 °C by the regulation of autophagy-dependent manner. [ABSTRACT FROM AUTHOR]

Adjuvant-aided combination chemotherapy is one of the most effective ways of cancer treatment by overcoming the multidrug resistance (MDR) and reducing the side-effects of anticancer drugs. In this study, Conferone (Conf) was used as an adjuvant in combination with Doxorubicin (Dox) for inducing apoptosis to MDA-MB-231 cells. Herein, the novel biodegradable amphiphilic β-cyclodextrin grafted poly maleate-co-PLGA was synthesized by thiol-ene addition and ring-opening process. Micelles obtained from the novel copolymer showed exceptional properties such as small size of around 34.5 nm, CMC of 0.1 μg/mL, and cell internalization of around 100% at 30 min. These novel engineered micelles were used for combination delivery of doxorubicin-conferone with high encapsulation efficiency of near 100% for both drugs. Our results show that combination delivery of Dox and Conf to MDA-MB-231 cells had synergistic effects (CI < 1). According to cell cycle and Annexin-V apoptosis analysis, Dox-Conf loaded micelle significantly induce tumor cell apoptosis (more than 98% of cells population showed apoptosis at IC50 = 0.259 μg/mL). RT-PCR and western-blot tests show that Dox-Conf loaded βCD-g-PMA-co-PLGA micelle induced apoptosis via intrinsic pathway. Therefore, the unique design of multi-functional pH-sensitive micelles open a new perspective for the development of nanomedicine for combination chemo-adjuvant therapy against malignant cancer. [ABSTRACT FROM AUTHOR]

Chemotherapy is still one of the routine methods for cancer therapy, but due to its poor specificity to the target site and a lot of side effects, it is not considered as a harmless approach for cancer therapy. For improving cancer-targeted drug delivery, in the present experiment, we synthesized chitosan-coated silica (SiO2@CS) nanoparticles and attached them to epigallocatechin gallate (EGCG). The functional amine groups of chitosan in SiO2@CS-EGCG nanoparticles (NPs) were attached to AS1411 aptamer electrostatically. Our developed nanoparticles showed spherical core-shell morphology with a size of around 100 nm in TEM images. Also, the internalization efficiency of SiO2@CS-EGCG-aptamer nanoparticles (51%) was higher than SiO2@CS-EGCG nanoparticles (29%) in the SKOV-3 cell line, which proved the successful recognition of nucleolin by attached AS1411 aptamer. Besides, DAPI staining and Annexin V analyses showed that SiO2@CS-EGCG-aptamer nanoparticles meritoriously improved the cytotoxic effect of the EGCG (with around 93% of cells showed late apoptosis). Additionally, cell cycle results showed that SiO2@CS-EGCG-aptamer nanoparticles resulted in a decrease in S and G2/M and increase G0/G1 and arrested cells in the G1 cell cycle. Moreover, the expression level of ERK2 and hTERT downregulated in SiO2@CS-EGCG-aptamer nanoparticles was treated SKOV-3 cells in comparison with the groups that were treated with free EGCG and SiO2@CS-EGCG. These results suggested that SiO2@CS-EGCG-aptamer had great potential for targeted delivery of different therapeutic agents like EGCG to the SKOV-3 cell line. [ABSTRACT FROM AUTHOR]

The field of tissue engineering (TE) experiences its most exciting time in the current decade. Recent progresses in TE have made it able to translate into clinical applications. To regenerate damaged tissues, TE uses biomaterial scaffolds to prepare a suitable backbone for tissue regeneration. It is well proven that the cell–biomaterial crosstalk impacts tremendously on cell biological activities such as differentiation, proliferation, migration, and others. Clarification of exact biological effects and mechanisms of a certain material on various cell types promises to have a profound impact on clinical applications of TE. Chitosan (CS) is one of the most commonly used biomaterials with many promising characteristics such as biocompatibility, antibacterial activity, biodegradability, and others. In this review, we discuss crosstalk between CS and various cell types to provide a roadmap for more effective applications of this polymer for future uses in tissue engineering and regenerative medicine. [ABSTRACT FROM AUTHOR]

Magnetic nanoparticles such as Fe3O4 and γ-Fe2O3 are extensively used in medical application, i.e. drug delivery, MRI, etc. Chemical toxicity and side-effect behaviors always play an important role in such applications. Thus, synthesis of such less-toxic compounds with green technology is privilege. In this study, the extract prepared from mango leaves was used for the preparation of iron oxide nanoparticles (γ-Fe2O3) using FeSO4 as iron source with the green-assisted route. The X-ray diffraction pattern indicated single-phase formation with the average crystallite size of 7 ± 2 nm. HRTEM micrographs indicated a dot-cloud-surrounded like particles ranging from 1 to 12 nm. Fourier Transform Infrared (FT-IR) spectroscopy showed two absorption bands at 457 and 634 cm−1, which are attributed to octahedral and tetrahedral sites of Fe-O band, respectively. A vibrating sample magnetometer (VSM) indicated a saturation magnetization (Ms) value about 53 emu/g with negligible coercivity (Hc), suggesting superparamagnetic behavior of the synthesized nanoparticles. The cytotoxicity was evaluated by exposing the breast cancer cell type (MCF7) to different concentrations of the γ-Fe2O3 nanoparticles. MTT assay results revealed that the growth and survival of MCF7 cells directly depend on the concentration of synthesized iron oxide nanoparticles. It was found that up to concentration of 200 µg/mL, cell survival has not yet reached 50%, which indicates the safety of nanoparticles and lack of toxicity. [ABSTRACT FROM AUTHOR]

Chronic morphine leads to dependence, tolerance, and neural apoptosis. Vitamin C inhibits the withdrawal syndrome in morphine-dependent subjects and prevents apoptosis in experimental models. Sodium-dependent vitamin C transporter (SVCT) type-2 is the main transporter for carrying vitamin C into the brain and neural cells. The mechanism(s) by which vitamin C inhibits morphine dependence in not understood. SVCT activity determines the vitamin C availably within the nervous system. We have examined the alterations in the expression of SVCT1, SVCT2, and its splice variants in morphine-tolerant rats. Morphine (20 mg/kg) was injected twice/day to male rats for either 7 or 14 days. The development of analgesic tolerance was assessed using tail-flick test. Lumbar spinal cord and the hippocampus were isolated for RNA extraction. Semiquantitative reverse transcriptase-polymerase chain reaction method was used to assess the levels of gene expression. Administration of morphine for 7 or 14 days reduced the expression level of SVCT2 in both hippocampus and dorsal lumbar spinal cord of rats. SVCT2 expression was reduced in vitamin C-, and vitamin C combined with morphine-treated animals. Results did not show SVCT2 splice variation. SVCT1 did not express in control or morphine-treated rats. It seems that reduced expression level of SVCT2 might be involved in the development of morphine side effects such as tolerance and dependency. [ABSTRACT FROM AUTHOR]