Codelivery of methotrexate and silibinin by niosome nanoparticles for enhanced chemotherapy of CT26 colon cancer cells.

Colon cancer (CC) is one of the most prevalent cancers in the world, and chemotherapy is widely applied to combat it. However, chemotherapy drugs have severe side effects and emergence of multi drug resistance (MDR) is common. This bottleneck can be overcome by niosome nanocarriers that minimize drug dose/toxicity meanwhile allow co-loading of incompatible drugs for combination therapy. In this research, silibinin (Sil) as a hydrophobic drug was loaded into the lipophilic part, and methotrexate (MTX) into the hydrophilic part of niosome by the thin film hydration (TFH) method to form Nio@MS NPs for CT26 colon cancer therapyin vitro. Our results indicated synthesis of ideal niosome nanoparticles (NPs) with spherical morphology, size of ∼100 nm, and a zeta potential of -10 mV. The IC50value for Nio@MS was determined ∼2.6 µg ml-1, which was significantly lower than MTX-Sil (∼6.86 µg ml-1), Sil (18.46 µg ml-1), and MTX (9.8 µg ml-1). Further, Nio@MS significantly reduced cell adhesion density, promoted apoptosis and increased gene expression level of caspase 3 and BAX while promoted significant downregulation of BCL2. In conclusion, the design and application of niosome to co-administer Sil and MTX can increase the drugs cytotoxicity, reduce their dose and improve anti-cancer potential by combating MDR.

Self-activating chitosan-based nanoparticles for sphingosin-1 phosphate modulator delivery and selective tumor therapy.

This study reports on the design and synthesis of hypoxia responsive nanoparticles (HRNPs) composed of methoxy polyethylene glycol-4,4 dicarboxylic azolinker-chitosan (mPEG-Azo-chitosan) as ideal drug delivery platform for Fingolimod (FTY720, F) delivery to achieve selective and highly enhanced TNBC therapy in vivo. Herein, HRNPs with an average size of 49.86 nm and a zeta potential of +3.22 mV were synthetized, which after PEG shedding can shift into a more positively-charged NPs (+30.3 mV), possessing self-activation ability under hypoxia situation in vitro, 2D and 3D culture. Treatment with lower doses of HRNPs@F significantly reduced MDA-MB-231 microtumor size to 15 %, induced apoptosis by 88 % within 72 h and reduced highly-proliferative 4 T1 tumor weight by 87.66 % vs. ∼30 % for Fingolimod compared to the untreated controls. To the best of our knowledge, this is the first record for development of hypoxia-responsive chitosan-based NPs with desirable physicochemical properties, and selective self-activation potential to generate highly-charged nanosized tumor-penetrating chitosan NPs. This formulation is capable of localized delivery of Fingolimod to the tumor core, minimizing its side effects while boosting its anti-tumor potential for eradication of TNBC solid tumors.

Dendritic cell-derived exosomes: A new horizon in personalized cancer immunotherapy?

Dendritic cells (DCs) release nanometer-sized membrane vesicles known as dexosomes, containing different molecules, particularly proteins, for presenting antigens, i.e., major histocompatibility complex (MHC)-I/II and CD86. Dexosomes can, directly and indirectly, stimulate antigen-reactive CD8+ and CD4+ T cell responses. Antigen-loaded dexosomes can lead to the development of potent anti-tumoral immune responses. Notably, developing dexosome-based cell-free vaccines could serve as a new vaccination platform in the era of immunotherapy for various cancers. Furthermore, combining dexosomes vaccination strategies with other treatment approaches can considerably increase tumor-specific T cell responses. Herein, we aimed to review how dexosomes interact with immune cells, e.g., CD4+ and CD8+ T cells and natural killer (NK) cells. Besides, we discussed the limitations of this approach and suggested potential strategies to improve its effectiveness for affected patients.

Prospects for hypoxia-based drug delivery platforms for the elimination of advanced metastatic tumors: From 3D modeling to clinical concepts.

Hypoxia is a unique characteristic of the solid tumor microenvironment. Hypoxia contributes to multi-drug resistance, metastasis and cancer relapse through numerous molecular pathways, but at the same time provides an opportunity for the development of novel drugs or modalities specifically targeting hypoxic tumor regions. Given the high significance of tumor hypoxia in therapeutic results, we here discuss a variety of hypoxia-adopted strategies, and their potential and utility in the treatment of deep-seated hypoxic tumor cells. We discuss the merits and demerits of these approaches, as well as their combination with other approaches such as photodynamic therapy. We also survey the currently available 3D hypoxia modeling systems, in particular organoid-based microfluidics. Finally, we discuss the potential and the current status of preclinical tumor hypoxia approaches in clinical trials for advanced cancer. We believe that multi-modal imaging and therapeutic hypoxia adopted drug delivery platforms could provide better efficacy and safety profiles, and more importantly personalized therapy. Determining the hypoxia status of tumors could offer a second chance for the clinical translation of hypoxia-based agents, such as hypoxia activated prodrugs (HAPs) from bench to bedside.

Tumor microenvironment penetrating chitosan nanoparticles for elimination of cancer relapse and minimal residual disease.

Chitosan and its derivatives are among biomaterials with numerous medical applications, especially in cancer. Chitosan is amenable to forming innumerable shapes such as micelles, niosomes, hydrogels, nanoparticles, and scaffolds, among others. Chitosan derivatives can also bring unprecedented potential to cross numerous biological barriers. Combined with other biomaterials, hybrid and multitasking chitosan-based systems can be realized for many applications. These include controlled drug release, targeted drug delivery, post-surgery implants (immunovaccines), theranostics, biosensing of tumor-derived circulating materials, multimodal systems, and combination therapy platforms with the potential to eliminate bulk tumors as well as lingering tumor cells to treat minimal residual disease (MRD) and recurrent cancer. We first introduce different formats, derivatives, and properties of chitosan. Next, given the barriers to therapeutic efficacy in solid tumors, we review advanced formulations of chitosan modules as efficient drug delivery systems to overcome tumor heterogeneity, multi-drug resistance, MRD, and metastasis. Finally, we discuss chitosan NPs for clinical translation and treatment of recurrent cancer and their future perspective.

Comparison of Cognitive Rehabilitation versus Donepezil Therapy on Memory Performance, Attention, Quality of Life, and Depression among Multiple Sclerosis Patients.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that affects cognitive performance and leads to depression and decreased quality of life (QOL). The current study aims to assess the effects of cognitive rehabilitation versus donepezil therapy on memory, attention, depression, and QOL in MS patients compared to placebo and control groups. METHODS: Eighty MS patients were randomly selected from parallel randomized trials and divided into four groups: A: cognitive rehabilitation (10 sessions of 120 minutes), B: control (no intervention), C: donepezil (10 mg daily), and D: placebo. Patients received the intervention for three months. They were assessed for cognitive status, depression, and QOL prior to the intervention and immediately after that using abbreviated mental test (AMT), prospective and retrospective memory questionnaire (PRMQ), everyday memory questionnaire (EMQ), digit span, MSQOL-54, and second edition Beck depression inventory (BDI). We compared scores between groups after the intervention, as well as the progression of scores in every single group. RESULT: s. The cognitive rehabilitation group showed improvement in EMQ, RPMQ, digit span, physical and mental health subscales of MSQOL54, and depression (P < 0.05). We observed the same effect for donepezil except for the digit span test (P = 0.15). Intergroup comparison of scores showed the superiority of cognitive rehabilitation over donepezil in digit span, depression, and mental health scores. CONCLUSION: Both donepezil and cognitive rehabilitation effectively improve memory performance, attention, depression, and QOL in MS patients. Cognitive rehabilitation is superior altogether. This study is registered with the Iranian registry of clinical trials http://clinicaltrials.gov/ct2/show/IRCT2016042227522N1.

Upregulation of MTOR, RPS6KB1, and EIF4EBP1 in the whole blood samples of Iranian patients with multiple sclerosis compared to healthy controls.

Various genetic and epigenetic mechanisms have been suggested to play roles as the underlying pathophysiology of Multiple Sclerosis (MS). Changes in different parts of the mTOR signaling pathway are among the potential suggested mechanisms based on the specific roles of this pathway in CNS. MTOR, RPS6KB1, and EIFEBP1 genes are among important genes in the mTOR pathway, responsible for the proper function of acting proteins in this signaling pathway. This study aimed to investigate the relative expression levels of these genes in the blood samples of relapsing-remitting MS (RRMS) patients compared to healthy controls. In this case-control study blood samples were collected from 30 newly diagnosed RRMS patients and 30 age and sex-matched healthy controls. mRNA level of MTOR, RPS6KB1, and EIFEBP1 genes were assessed using Real-Time PCR. The expression of MTOR, RPS6KB1, and EIF4EBP1 genes was up regulated in MS patients compared to healthy controls (p < 0.001 for all mentioned genes). Considering gender differences, expression of the mentioned genes was increased among female patients (all P < 0.001). However, no statistically significant changes were observed among male patients. Based on the receiver operating characteristic, MTOR gene had the highest diagnostic value followed by EIF4EBP1 and RPS6KB1 genes in differentiating RRMS patients from controls. In conclusion, we found the simultaneous upregulation of MTOR, RPS6KB1, and EIF4EBP1 genes among RRMS patients. MTOR showed to have the highest diagnostic value compared to other 2 genes in differentiating RRMS patients. Further studies evaluating the importance of these findings from pharmacological and prognostic perspectives are necessary.

Effect of Donepezil on Cognitive Impairment, Quality of Life, and Depression in Multiple Sclerosis Patients: A Randomized Clinical Trial.

BACKGROUND: Cognitive impairment is one of the debilitating consequences of multiple sclerosis (MS) with negative effects on daily life, individual and social activities, quality of life (QOL), and depression. No approved medication is introduced so far for affected individuals. We aimed to evaluate the efficacy of donepezil on cognitive performance, QOL, and depression in MS. METHODS: This is a double-blinded randomized clinical trial conducted on 100 patients with MS during 2018. Patients were assessed prior to intervention abbreviated mental test (AMT), prospective and retrospective mental questionnaire (PRMQ), everyday memory questionnaire (EMQ), digit span test, Beck depression inventory (BDI), and MSQOL questionnaire. Then patients were randomly divided into two groups of treatment (daily regimen of 10 mg donepezil) and placebo for 3 months. Subjects were reassessed using the same instruments at the end of intervention. RESULTS: Fifty patients remained in each group at the end of study. The mean age in donepezil and placebo groups was 31.9 ± 5.89 and 30.65 ± 5.43 years, respectively. EMQ, PRMQ, digit span test, MSQOL, and depression scores improved following donepezil therapy (P < 0.001) while no statistically significant difference was found in the placebo group (P > 0.05). Comparison of two groups also showed more favorable scores in donepezil group with respect to all assessment tools (P < 0.001). CONCLUSIONS: Donepezil could effectively improve cognitive impairment in MS patients. Also, its positive effect on QOL and depression could result in a smaller number of interventions in this group of patients.

Evaluation of cognitive rehabilitation on the cognitive performance in multiple sclerosis: A randomized controlled trial.

BACKGROUND: Multiple sclerosis (MS) can involve cognitive entities, including memory, attention, performance, and information processing. Furthermore, MS causes depression and negatively affects the quality of life (QOL). This study was aimed to assess the efficacy of cognitive rehabilitation on cognitive entities of MS patients. MATERIALS AND METHODS: This is a clinical trial study conducted on 56 MS patients in 2016-2017. Patients were randomly divided into two Groups of A (cognitive rehabilitation) and B (control group). Patients were evaluated in terms of memory, attention, QOL, and depression. Questionnaires included Abbreviated Mental Test, Prospective and Retrospective Memory Questionnaire, Everyday Memory Questionnaire, Digit Spam test for attention assessment, QOL-54 questionnaire, and Second version of Beck questionnaire assessing depression. They were filled through an interview before the study initiation, and then, the intervention group underwent ten sessions of cognitive rehabilitation and questionnaires refilled within 3 months after study initiation. Outcomes of the two groups were compared. RESULTS: Memory, attention, QOL, and depression improved significantly following the intervention in cases (P < 0.05), while no significant change was observed among controls (P > 0.05). Comparison of cases and controls in the second evaluation showed a significant difference between cases and controls (P < 0.05). CONCLUSION: Ten sessions of cognitive rehabilitation could significantly improve MS patients' cognitive performance. Moreover, this approach affected their QOL and sense of depression in a decisive trend. It can be concluded that cognitive rehabilitation can successfully affect numerous aspects of MS patients, while numerous medical therapies may be required for treatment of each mere aspect. Further evaluations are strongly recommended.

Anticoagulant therapy for ischemic stroke: A review of literature.

For many years, anticoagulants have been used in the emergent treatment of patients with acute ischemic stroke. Anticoagulants are prescribed in an effort to prevent first or recurrent stroke, especially among patients with cardioembolism due to arterial fibrillation and large-artery atherosclerotic disease. Despite the widespread use, efficacy and safety of anticoagulants are controversial. Experts have given a broad spectrum of opinions. Surveys of practitioners have also demonstrated a lack of consensus on the use of anticoagulants for ischemic stroke. The uncertainty is due, in large part, to the lack of definitive clinical data. A review by the panel of the Stroke Council of the American Heart Association found no strong evidence for effectiveness of anticoagulants in treating acute ischemic stroke. Several clinical trials have suggested that utility of emergent anticoagulation has no significant effect in improving clinical outcomes for patients with acute ischemic stroke. In the present review, we have attempted to provide a framework for the emergent use of anticoagulants in acute ischemic stroke patients.