A comprehensive review on novel targeted therapy methods and nanotechnology-based gene delivery systems in melanoma.

Melanoma, a malignant form of skin cancer, has been swiftly increasing in recent years. Although there have been significant advancements in clinical treatment underlying a well-understanding of melanoma-susceptible genes and the molecular basis of melanoma pathogenesis, the permanency of response to therapy is frequently constrained by the emergence of acquired resistance and systemic toxicity. Conventional therapies, including surgical resection, chemotherapy, radiotherapy, and immunotherapy, have already been used to treat melanoma and are dependent on the cancer stage. Nevertheless, ineffective side effects and the heterogeneity of tumors pose major obstacles to the therapeutic treatment of malignant melanoma through such strategies. In light of this, advanced therapies including nucleic acid therapies (ncRNA, aptamers), suicide gene therapies, and gene therapy using tumor suppressor genes, have lately gained immense attention in the field of cancer treatment. Furthermore, nanomedicine and targeted therapy based on gene editing tools have been applied to the treatment of melanoma as potential cancer treatment approaches nowadays. Indeed, nanovectors enable delivery of the therapeutic agents into the tumor sites by passive or active targeting, improving therapeutic efficiency and minimizing adverse effects. Accordingly, in this review, we summarized the recent findings related to novel targeted therapy methods as well as nanotechnology-based gene systems in melanoma. We also discussed current issues along with potential directions for future research, paving the way for the next-generation of melanoma treatments.

Carbon dot incorporated mesoporous silica nanoparticles for targeted cancer therapy and fluorescence imaging.

A new and efficient theranostic nanoplatform was developed via a green approach for targeted cancer therapy and fluorescence imaging, without the use of any anticancer chemotherapeutic drugs. Toward this aim, monodisperse and spherical mesoporous silica nanoparticles (MSNs) of approximately 50 nm diameter were first synthesized using the sol-gel method and loaded with hydrothermally synthesized anticancer carbon dots (CDs). The resulting MSNs-CDs were then functionalized with chitosan and targeted by an anti-MUC1 aptamer, using the glutaraldehyde cross-linker, and fully characterized by TEM, FE-SEM, EDS, FTIR, TGA, XRD, and BET analysis. Potent and selective anticancer activity was obtained against MCF-7 and MDA-MB-231 cancer cells with the maximum cell mortalities of 66.2 ± 1.97 and 71.8 ± 3%, respectively, after 48 h exposure with 100 µg mL-1 of the functionalized MSNs-CDs. The maximum mortality of 40.66 ± 1.3% of normal HUVEC cells was obtained under the same conditions. Based on the results of flowcytometry analysis, the apoptotic mediated cell death was recognized as the main anticancer mechanism of the MSNs-CDs. The fluorescence imaging of MCF-7 cancer cells was also studied after exposure with MSNs-CDs. The overall results indicated the high potential of the developed nanoplatform for targeted cancer theranostics.

A Systematic Review and Meta-Analysis on the Effect of Flavonoids on Insulin-like Growth Factor and Insulin-like Growth Factor Binding Protein and Incidence of Breast Cancer.

BACKGROUND: Insulin-like growth factor (IGF-1) is associated with breast cancer in menopausal women. Naturally occurring biomolecules found in common dietary protocols, such as flavonoids, play a key role in the inhibition and treatment of cancer. In-vitro/in-vivo studies showed that treatment involving flavonoids led to a reduced risk of breast cancer due to the decrease of IGF-1 level in addition to an increased insulin-like growth factor binding protein (IGFBP)-3. However, clinical studies did not show conclusive results in this regard because they are contradictory. OBJECTIVE: The aim of the present study was to find the effect of flavonoids on IGF-1 and IGFBP-3 and the incidence of breast cancer. METHODS: This systematic review was performed using PubMed, Scopus, ISI Web of Science, and EMBASE databases to collect results about the clinical use of flavonoids and their effects on breast cancer. After eliminating duplicate articles, the title and abstract of the remaining articles were examined in thematic communication, and related clinical articles were selected and studied based on inclusion criteria. The data were extracted from each article, and then statistical analysis was subsequently carried out by Comprehensive Meta-Analysis. RESULTS: The results showed that the effect of flavonoids on changes in IGF1 and IGFBP-3 was not statistically significant. No significant heterogeneity was detected across the studies. Pooled effect size also indicated that the mean change was not statistically significant. No significant heterogeneity was detected across the studies. There was no evidence of publication bias for IGF1 and IGFBP-3. CONCLUSION: This meta-analysis study suggests that flavonoid supplementations have no significant effect on IGF-1 and IGFBP-3, and a high soy diet has beneficial effects on IGF system components, which might be useful in breast cancer.

Red Blood Cell Distribution Width (RDW) as a Predictor of In-Hospital Mortality in COVID-19 Patients; a Cross Sectional Study.

INTRODUCTION: Red blood cell distribution width (RDW) has been introduced as a predictive factor for mortality in several critical illnesses and infectious diseases. This study aimed to assess the possible relationship between RDW on admission and COVID-19 in-hospital mortality. METHOD: This cross-sectional study was performed using the Isfahan COVID-19 registry. Adult confirmed cases of COVID-19 admitted to four hospitals affiliated with Isfahan University of Medical Sciences in Iran were included. Age, sex, O2 saturation, RDW on admission, Intensive Care Unit admission, laboratory data, history of comorbidities, and hospital outcome were extracted from the registry. Cox proportional hazard regression was used to study the independent association of RDW with mortality. RESULTS: 4152 patients with the mean age of 61.1 ± 16.97 years were included (56.2% male). 597 (14.4%) cases were admitted to intensive care unit (ICU) and 477 (11.5%) cases died. The mortality rate of patients with normal and elevated RDW was 7.8% and 21.2%, respectively (OR= 3.1, 95%CI: 2.6-3.8), which remained statistically significant after adjusting for age, O2 saturation, comorbidities, and ICU admission (2.03, 95% CI: 1.68-2.44). Moreover, elevated RDW mortality Hazard Ratio in patients who were not admitted to ICU was higher than ICU-admitted patients (3.10, 95% CI: 2.35-4.09 vs. 1.47, 95% CI: 1.15-1.88, respectively). CONCLUSION: The results support the presence of an association between elevated RDW and mortality in patients with COVID-19, especially those who were not admitted to ICU. It seems that elevated RDW can be used as a predictor of mortality in COVID-19 cases.

Co-delivery of rituximab targeted curcumin and imatinib nanostructured lipid carriers in non-Hodgkin lymphoma cells.

The aim of the present study was production of nanostructured lipid carriers (NLCs) of curcumin and imatinib for co-administration in non-Hodgkin lymphoma cells. NLCs were prepared and conjugated to rituximab to target CD20 receptors of lymphoma cell lines. Oleic acid or Labrafac and glyceryl monostearate or lecithin were used for production of NLCs. The antibody coupling efficiency to NLCs and their physical characteristics were studied. The cytotoxicity of NLCs on Jurkat T cells (CD20 receptor negative) and Ramos B cells (CD20 receptor positive) was studied by MTT assay. The cellular uptake was determined by fluorescent microscopy. The results indicated both curcumin and imatinib targeted NLCs had a significant cytotoxic effect much higher than the free drugs and non-targeted NLCs on Ramos cells. In both cell lines, the cytotoxicity of the co-administrated drugs was significantly higher than each drug alone. In Ramos cells the co-administration of curcumin (15 µg/ml)/imatinib (5 µg/ml) decreased the free curcumin IC50 from 8.3 ± 0.9 to 1.9 ± 0.2 µg/ml, and curcumin targeted NLCs from 6.7 ± 0.1 to 1.3 ± 0.2 µg/ml. In this case the IC50 of imatinib was reduced from 11.1 ± 0.7 to 2.3 ± 0.1 µg/ml and imatinib targeted NLCs from 4.3 ± 0.1 to 1.4 ± 0.0 µg/ml. The co-administration of ritoximab conjugated NLCs of curcumin and imatinib may enhance cytotoxicity of imatinib in treatment of non-Hodgkin lymphoma.

Encapsulation of Imatinib in Targeted KIT-5 Nanoparticles for Reducing its Cardiotoxicity and Hepatotoxicity.

BACKGROUND: Using imatinib, a tyrosine kinase inhibitor drug used in lymphoblastic leukemia, has always had limitations due to its cardiotoxicity and hepatotoxicity side effects. The objective of this study is to develop a target-oriented drug carrier to minimize these adverse effects by the controlled release of the drug. METHODS: KIT-5 nanoparticles were functionalized with 3-aminopropyltriethoxysilane and conjugated to rituximab as the targeting agent for the CD20 positive receptors of the B-cells. Then they were loaded with imatinib and their physical properties were characterized. The cell cytotoxicity of the nanoparticles was studied by MTT assay in Ramos (CD20 positive) and Jurkat cell lines (CD20 negative) and their cellular uptake was shown by fluorescence microscope. Wistar rats received an intraperitoneal injection of 50 mg/kg of the free drug or targeted nanoparticles for 21 days. Then the level of aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH) were measured in serum of animals. The cardiotoxicity and hepatotoxicity of the drug were also studied by hematoxylin and eosin staining of the tissues. RESULTS: The targeted nanoparticles of imatinib showed to be more cytotoxic to Ramos cells rather than Jurkat cells. The results of the biochemical analysis displayed a significant reduction in AST, ALT, ALP, and LDH levels in animals treated with targeted nanoparticles, compared to the free drug group. By comparison with the free imatinib, histopathological results represented less cardiotoxicity and hepatotoxicity in the animals, which received the drug through the current designed delivery system. CONCLUSION: The obtained results confirmed that the rituximab targeted KIT-5 nanoparticles are promising in the controlled release of imatinib and could decrease its cardiotoxicity and hepatotoxicity side effects.