Astaxanthin-loaded alginate-chitosan gel beads activate Nrf2 and pro-apoptotic signalling pathways against oxidative stress.

Oxidative stress (OS) plays a crucial role in disease development. Astaxanthin (ATX), a valuable natural compound, may reduce OS and serve as a treatment for diseases like neurodegenerative disorders and cancer. Nuclear factor-erythroid 2-related factor 2 (Nrf2) regulates antioxidant enzymes and OS management. We evaluated ATX's antioxidant activity via Alg-CS/ATX gel beads in vitro. ATX-encapsulated alginate-chitosan (Alg-CS/ATX) gel beads were synthesized and structurally/morphologically characterized by SEM, FT-IR, and XRD. Their biological effects were examined in human umbilical vein endothelial cells (HUVECs) treated with H2O2 through MTT assay, Annexin V/PI, cell cycle studies, and western blotting. Alg-CS effectively carried ATX, with high capacity and reduced pore size. Alg-CS/ATX displayed an 84% encapsulation efficiency, maintaining stability for 30 days. In vitro studies showed a 1.4-fold faster release at pH 5.4 than at neutral pH, improving ATX's therapeutic potential. HUVECs treated with Alg-CS/ATX showed enhanced viability via increased Nrf2 expression. Alg-CS gel beads exhibit significant potential as a biocompatible vehicle for delivering ATX to combat OS with considerable opportunity for clinical applications.

Targeting long non-coding RNAs as new modulators in anti-EGFR resistance mechanisms.

Epidermal growth factor receptor (EGFR) is a cell surface protein that plays a vital role in regulating cell growth and division. However, certain tumors, such as colorectal cancer (CRC), can exhibit an overexpression of EGFR, resulting in uncontrolled cell growth and tumor progression. To address this issue, therapies targeting and inhibiting EGFR activity have been developed to suppress cancer growth. Nevertheless, resistance to these therapies poses a significant obstacle in cancer treatment. Recent research has focused on comprehending the underlying mechanisms contributing to anti-EGFR resistance and identifying new targets to overcome this striking challenge. Long non-coding RNAs (lncRNAs) are a class of RNA molecules that do not encode proteins but play pivotal roles in gene regulation and cellular processes. Emerging evidence suggests that lncRNAs may participate in modulating resistance to anti-EGFR therapies in CRC. Consequently, combining lncRNA targeting with the existing treatment modalities could potentially yield improved clinical outcomes. Illuminating the involvement of lncRNAs in anti-EGFR resistance mechanisms of cancer cells can provide valuable insights into the development of novel anti-EGFR therapies in several solid tumors.

Fabrication of mesoporous silica nanoparticles for targeted delivery of sunitinib to ovarian cancer cells.

Introduction: Mesoporous silica nanoparticles (MSNPs) are considered innovative multifunctional structures for targeted drug delivery owing to their outstanding physicochemical characteristics. Methods: MSNPs were fabricated using the sol-gel method, and polyethylene glycol-600 (PEG600) was used for MSNPs modification. Subsequently, sunitinib (SUN) was loaded into the MSNPs, MSNP-PEG and MSNP-PEG/SUN were grafted with mucin 16 (MUC16) aptamers. The nanosystems (NSs) were characterized using FT-IR, TEM, SEM, DLS, XRD, BJH, and BET. Furthermore, the biological impacts of MSNPs were evaluated on the ovarian cancer cells by MTT assay and flow cytometry analysis. Results: The results revealed that the MSNPs have a spherical shape with an average dimension, pore size, and surface area of 56.10 nm, 2.488 nm, and 148.08 m2g-1, respectively. The cell viability results showed higher toxicity of targeted MSNPs in MUC16 overexpressing OVCAR-3 cells as compared to the SK-OV-3 cells; that was further confirmed by the cellular uptake results. The cell cycle analysis exhibited that the induction of sub-G1 phase arrest mostly occurred in MSNP-PEG/SUN-MUC16 treated OVCAR-3 cells and MSNP-PEG/SUN treated SK-OV-3 cells. DAPI staining showed apoptosis induction upon exposure to targeted MSNP in MUC16 positive OVCAR-3 cells. Conclusion: According to our results, the engineered NSs could be considered an effective multifunctional targeted drug delivery platform for the mucin 16 overexpressing cells.

Deciphering anti-biofilm property of Arthrospira platensis-origin peptides against Staphylococcusaureus.

Arthrospira platensis is a valuable natural health supplement consisting of various types of vitamins, dietary minerals, and antioxidants. Although different studies have been conducted to explore the hidden benefits of this bacterium, its antimicrobial property has been poorly understood. To decipher this important feature, here, we extended our recently introduced optimization algorithm (Trader) for aligning amino acid sequences associated with the antimicrobial peptides (AMPs) of Staphylococcus aureus and A.platensis. As a result, similar amino acid sequences were identified, and several candidate peptides were generated accordingly. The obtained peptides were then filtered based on their potential biochemical and biophysical properties, and their 3D structures were simulated based on homology modeling techniques. Next, to investigate how the generated peptides can interact with S. aureus proteins (i.e., heptameric state of the hly and homodimeric form of the arsB), molecular docking approaches were used. The results indicated that four peptides included better molecular interactions relative to the other generated ones in terms of the number/average length of hydrogen bonds and hydrophobic interactions. Based on the outcomes, it can be concluded that the antimicrobial property of A.platensis might be associated with its capability in disturbing the membrane of pathogens and their functions.

Advanced nanoscale drug delivery systems for bone cancer therapy.

Bone tumors are relatively rare, which are complex cancers and primarily involve the long bones and pelvis. Bone cancer is mainly categorized into osteosarcoma (OS), chondrosarcoma, and Ewing sarcoma. Of these, OS is the most intimidating cancer of the bone tissue, which is mostly found in the log bones in young children and older adults. Conspicuously, the current chemotherapy modalities used for the treatment of OS often fail mainly due to (i) the non-specific detrimental effects on normal healthy cells/tissues, (ii) the possible emergence of drug resistance mechanisms by cancer cells, and (iii) difficulty in the efficient delivery of anticancer drugs to the target cells. To impose the maximal therapeutic impacts on cancerous cells, it is of paramount necessity to specifically deliver chemotherapeutic agents to the tumor site and target the diseased cells using advanced nanoscale multifunctional drug delivery systems (DDSs) developed using organic and inorganic nanoparticles (NPs). In this review, we provide deep insights into the development of various DDSs applied in targeting and eradicating OS. We elaborate on different DDSs developed using biomaterials, including chitosan, collagen, poly(lactic acid), poly(lactic-co-glycolic acid), polycaprolactone, poly(ethylene glycol), polyvinyl alcohol, polyethyleneimine, quantum dots, polypeptide, lipid NPs, and exosomes. We also discuss DDSs established using inorganic nanoscale materials such as magnetic NPs, gold, zinc, titanium NPs, ceramic materials, silica, silver NPs, and platinum NPs. We further highlight anticancer drugs' role in bone cancer therapy and the biocompatibility of nanocarriers for OS treatment.

SYNDEEP: a deep learning approach for the prediction of cancer drugs synergy.

Drug combinations can be the prime strategy for increasing the initial treatment options in cancer therapy. However, identifying the combinations through experimental approaches is very laborious and costly. Notably, in vitro and/or in vivo examination of all the possible combinations might not be plausible. This study presented a novel computational approach to predicting synergistic drug combinations. Specifically, the deep neural network-based binary classification was utilized to develop the model. Various physicochemical, genomic, protein-protein interaction and protein-metabolite interaction information were used to predict the synergy effects of the combinations of different drugs. The performance of the constructed model was compared with shallow neural network (SNN), k-nearest neighbors (KNN), random forest (RF), support vector machines (SVMs), and gradient boosting classifiers (GBC). Based on our findings, the proposed deep neural network model was found to be capable of predicting synergistic drug combinations with high accuracy. The prediction accuracy and AUC metrics for this model were 92.21% and 97.32% in tenfold cross-validation. According to the results, the integration of different types of physicochemical and genomics features leads to more accurate prediction of synergy in cancer drugs.

Electrochemical microfluidic paper-based analytical devices for cancer biomarker detection: From 2D to 3D sensing systems.

Microfluidic paper-based analytical devices (µPADs) offer a unique possibility for a cost-effective portable and rapid detection of a wide range of small molecules and macromolecules and even microorganisms. In this line, electrochemical detection methods are key techniques for the qualitative analysis of different types of ligands. The electrochemical sensing µPADs have been devised for the rapid, accurate, and quantitative detection of oncomarkers through two-/three-dimensional (2D/3D) approaches. The 2D µPADs were first developed and then transformed into 3D systems via folding and/or twisting of paper. The microfluidic channels and connections were created within the layers of paper. Based on the fabrication methods, 3D µPADs can be classified into origami and stacking devices. Various fabrication methods and materials have been used to create hydrophilic channels in µPADs, among which the wax printing technique is the most common method in fabricating µPADs. In this review, we discuss the fabrication and design strategies of µPADs, elaborate on their detection modes, and highlight their applications in affinity-based electrochemical µPADs methods for the detection of oncomarkers.

Targeted Delivery of Sunitinib by MUC-1 Aptamer-Capped Magnetic Mesoporous Silica Nanoparticles.

Magnetic mesoporous silica nanoparticles (MMSNPs) are being widely investigated as multifunctional novel drug delivery systems (DDSs) and play an important role in targeted therapy. Here, magnetic cores were synthesized using the thermal decomposition method. Further, to improve the biocompatibility and pharmacokinetic behavior, mesoporous silica was synthesized using the sol-gel process to coat the magnetic cores. Subsequently, sunitinib (SUN) was loaded into the MMSNPs, and the particles were armed with amine-modified mucin 1 (MUC-1) aptamers. The MMSNPs were characterized using FT-IR, TEM, SEM, electrophoresis gel, DLS, and EDX. MTT assay, flow cytometry analysis, ROS assessment, and mitochondrial membrane potential analysis evaluated the nanoparticles' biological impacts. The physicochemical analysis revealed that the engineered MMSNPs have a smooth surface and spherical shape with an average size of 97.6 nm. The biological in vitro analysis confirmed the highest impacts of the targeted MMSNPs in MUC-1 overexpressing cells (OVCAR-3) compared to the MUC-1 negative MDA-MB-231 cells. In conclusion, the synthesized MMSNP-SUN-MUC-1 nanosystem serves as a unique multifunctional targeted delivery system to combat the MUC-1 overexpressing ovarian cancer cells.

Electrochemiluminescent immunosensor for detection of carcinoembryonic antigen using luminol-coated silver nanoparticles.

Recently, electrochemiluminescent (ECL) immunosensors have received much attention in the field of biomarker detection. Here, a highly enhanced ECL immunosensing platform was designed for ultrasensitive detection of carcinoembryonic antigen (CEA). The surface of the glassy carbon electrode was enhanced by applying functional nanostructures such as thiolated graphene oxide (S-GO) and streptavidin-coated gold nanoparticles (SA-AuNPs). The selectivity and sensitivity of the designed immunosensor were improved by entrapping CEA biomolecules using a sandwich approach. Luminol/silver nanoparticles (Lu-SNPs) were applied as the main core of the signaling probe, which were then coated with streptavidin to provide overloading of the secondary antibody. The highly ECL signal enhancement was obtained due to the presence of horseradish peroxidase (HRP) in the signaling probe, in which the presence of H2O2 further amplified the intensity of the signals. The engineered immunosensor presented excellent sensitivity for CEA detection, with limit of detection (LOD) and linear detection range (LDR) values of 58 fg mL-1 and 0.1 pg mL-1 to 5 pg mL-1 (R2 = 0.9944), respectively. Besides its sensitivity, the fabricated ECL immunosensor presented outstanding selectivity for the detection of CEA in the presence of various similar agents. Additionally, the developed immunosensor showed an appropriate repeatability (RSD 3.8%) and proper stability (2 weeks). Having indicated a robust performance in the real human serum with stated LOD and LDR, the engineered immunosensor can be considered for the detection and monitoring of CEA in the clinic.

Nesting and fate of transplanted stem cells in hypoxic/ischemic injured tissues: The role of HIF1α/sirtuins and downstream molecular interactions.

The nesting mechanisms and programming for the fate of implanted stem cells in the damaged tissue have been critical issues in designing and achieving cell therapies. The fracture site can induce senescence or apoptosis based on the surrounding harsh conditions, hypoxia, and oxidative stress (OS). Respiration deficiency, disruption in energy metabolism, and consequently OS induction change the biophysical, biochemical, and cellular components of the native tissue. Additionally, the homeostatic molecular players and cell signaling might be changed. Despite all aforementioned issues, in the native stem cell niche, physiological hypoxia is not toxic; rather, it is vitally required for homing, self-renewal, and differentiation. Hence, the key macromolecular players involved in the support of stem cell survival and re-adaptation to a new dysfunctional niche must be understood for managing the cell therapy outcome. Hypoxia-inducible factor 1-alpha is the master transcriptional regulator, involved in the cell response to hypoxia and the adaptation of stem cells to a new niche. This protein is regulated by interaction with sirtuins. Sirtuins are highly conserved NAD+-dependent enzymes that monitor the cellular energy status and modulate gene transcription, genome stability, and energy metabolism in response to environmental signals to modulate the homing and fate of stem cells. Herein, new insights into the nesting of stem cells in hypoxic-ischemic injured tissues were provided and their programming in a new dysfunctional niche along with the involved complex macromolecular players were critically discussed.

Multi-dimensional modeling of nanoparticles transportation from capillary bed into the tumor microenvironment.

In this study, we examined the extravasation of pharmaceutical inorganic nanoparticles (NPs) with a new approach from the leaky endothelium of tumor microvasculature (TMV) into the tumor microenvironment (TME) multi-dimensionally. We proposed a combination of prevailing macroscopic and microscopic methods and addressed the effect of interstitial fluid (IF) retention in solid tumor as an imperative parameter in drug delivery modeling. The Navier-Stokes equations and Darcy's law were utilized for blood flow and porous media, and the Starling's law was brought in for coupling effect. The blood flow was simulated as a non-Newtonian fluid alongside the Newtonian IF. We applied the Galerkin finite element method for the simulations. Our parametric study includes examining the effect of IF retention and TMV pressure on the distribution of tumor interstitial fluid pressure (TIFP), NPs concentration, and diameter on the penetration process, together with the time effect, on two-dimensional (2D) delivery of NPs. Our findings indicate that the IF retention in tumor cells increases TIFP depending on the amount of TMV pressure and IF retained. In addition to doubling pressure in the tumor necrotic region rather than the rest of TME, it enhances the TIFP which is an important parameter in drug delivery to solid tumors. By decreasing pressure drop within the TMV, pressure distribution within the TME becomes more uniform, creating a better condition for homogeneous penetration of NPs. Increasing both inlet pressure and NPs concentration leads to a nonlinear increase in the average concentration of tumor. Decreasing the diameter of NPs increases the penetration of NPs with a higher ratio in the TME.

EpCAM aptamer activated 5-FU-loaded PLGA nanoparticles in CRC treatment; in vitro and in vivo study.

In this study, epithelial cell adhesion molecule (EpCAM) aptamer-activated nanoparticles (Ap-NPs) were synthesised to enhance treatment efficiency in colorectal cancer (CRC). PLGA [poly(d, l-lactide-co-glycolide)] copolymer was fabricated by conjugation of COOH-PEG-NH2 to PLGA-COOH through an EDC/NHS-mediated chemistry. Afterwards, 5-fluorouracil-loaded (FU) nanoparticles were prepared using the water/oil/water double emulsion solvent evaporation method. The in vitro cytotoxicity of formulations was evaluated using the MTT assay in HCT-116, CT-26 and HEK-293 cell lines. For in vivo study, tumour-bearing BALB/c mice were established by subcutaneous injection of CT-26 cell line. The results indicated that fabricated AP-FU-NPs had 101 nm size with a spherical surface, relatively homogeneously and, satisfactory encapsulation efficiency (83.93%). In vitro experiments revealed that Ap-FU-NPs had a superior in vitro cytotoxicity than both FU-NPs and free 5-FU in CT-26 and HCT-116 cells but, were significantly low toxic against HEK-293 cells relative to free 5-FU. Furthermore, in vivo results showed no significant haemolytic effect, hepatic and renal injury, or weight loss. After treatment of various animal groups with formulations, notable tumour growth delay was observed following the order: Ap-FU-NPs < FU-NPs < 5-FU < PBS. The results suggest that AP-FU-NPs could be an effective and promising carrier for 5-FU delivery to the EpCAM overexpressing CRC cells.

Functional properties of thermally tampered poly(ethylene oxide).

Introduction: Poly(ethylene oxide) (PEO) is the most common polymer used in commercial abuse-deterrent tablets. Due to its vulnerability to high-temperature manipulation, we investigated abuse-deterrent capability and the toxicity of this polymer upon thermal treatments at 80°C and 180°C for 1 hour. Methods: Tablets (200 mg PEO and 300 mg Avicel®) were directly compressed under 2000 lb. The thermally manipulated PEOs were evaluated for their viscosity, crushability, structural changes, and cell toxicity. Results: Our findings showed that 180°C-treated tablets underwent some degrees of oxidative degradation with profound toxicity in both mesenchymal stem cells and MG63 cells. The 180°C-treated tablets exhibited almost no resistance against crushing and were prone to abuse. While thermal processing of PEO at around its melting temperature is a common approach to enhance crush resistance of its dosage forms, thermal manipulation at close to the PEO's oxidation temperature can lead to structural changes, dramatic loss of crush and extraction resistance, and significant cell toxicity. Conclusion: Similar to the low molecular weight PEO, when thermally manipulated at its thermo-oxidative temperature, the high molecular weight PEO loses its deterrence performance and causes severe cell toxicity.

Smart chitosan-folate hybrid magnetic nanoparticles for targeted delivery of doxorubicin to osteosarcoma cells.

Chitosan (CS)-based pH-sensitive nanocomposites were fabricated for the targeted delivery of doxorubicin (DOX) to osteosarcoma cells. To prepare the nanocomposite, CS was functionalized with succinic anhydride (SA) (CS-SA). CS-folic acid (FA) conjugates were produced by the conjugation of CS with FA via an amide bond. Next, Fe3O4 magnetic nanoparticles (MNPs) ferrofluid was fabricated, and nanocomposite was produced using MNPs and synthesized CS-SA/CS-FA and CS-SA via an inclusion formation between -COOH groups of CS-SA and hydroxyl groups of Fe3O4. Finally, DOX molecules were loaded onto the nanocomposites. The nanocomposites were characterized through FT-IR, DLS, XRD, VSM, TEM, and UV-Vis spectroscopy analyses. DOX release profile at various pHs indicated an enhanced release of DOX in acidic conditions. The cytotoxicity assay demonstrated that the nanocarriers alone were cytocompatible on cells examined. The MG-63 cells, which partly express the folate receptors (FRs), particularly FR-α, showed meaningfully higher cellular uptake of the DOX-loaded CS-FA/CS-SA@MNPs than the FR-negative lung cancer A549 cells. The DOX-loaded CS-FA/CS-SA-MNPs could induce significant cytotoxicity in the MG-63 cells but not in A549 cells. Based on these findings, the DOX-loaded CS-FA/ CS-SA-MNPs might be considered a smart pH-sensitive nanosystem for the targeted delivery of anticancer agents to osteosarcoma cancer cells.

Recent advances in the production, reprogramming, and application of CAR-T cells for treating hematological malignancies.

As genetically engineered cells, chimeric antigen receptor (CAR)-T cells express specific receptors on their surface to target and eliminate malignant cells. CAR proteins are equipped with elements that enhance the activity and survival of T cells. Once injected, CAR-T cells act as a "living drug" against tumor cells in the body. Up to now, CAR-T cell therapy has been demonstrated as a robust adoptive cell transfer (ACT) immunotherapeutic modality for eliminating tumor cells in refractory hematological malignancies. CAR-T cell therapy modality involves several steps, including the collecting of the blood from patients, the isolation of peripheral blood mononuclear cells (PBMCs), the enrichment of CD4+/CD8+ T cell, the genetic reprogramming, the expansion of modified T cells, and the injection of genetically engineered T cells. The production of CAR-T cells is a multi-step procedure, which needs precise and safety management systems, including good manufacturing practice (GMP), and in-line quality control and assurance. The current study describes the structure of CARs and concentrates on the next generations of CARs that are engaged in enhancing the anti-tumor responses and safety of the engineered T cells. This paper also highlights the important concerns in quality control and nonclinical research of CAR-T cells, as well as general insights into the manufacture, reprogramming, and application of CAR-T cells based on new and enhanced techniques for treating hematological malignancies. Besides, the application of the CRISPR-Cas9 genome editing technology and nanocarrier-based delivery systems containing CAR coding sequences to overcome the limitations of CAR-T cell therapy has also been explained.

Optogenetics: A new tool for cancer investigation and treatment.

Despite the progress made in the diagnosis and treatment of cancer, it has remained the second cause of death in industrial countries. Cancer is a complex multifaceted disease with unique genomic and proteomic hallmarks. Optogenetics is a biological approach, in which the light-sensitive protein modules in combination with effector proteins that trigger reversibly fundamental cell functions without producing a long-term effect. The technology was first used to address some key issues in neurology. Later on, it was also used for other diseases such as cancer. In the case of cancer, there exist several signaling pathways with key proteins that are involved in the initiation and/or progression of cancer. Such aberrantly expressed proteins and the related signaling pathways need to be carefully investigated in terms of cancer diagnosis and treatment, which can be managed with optogenetic tools. Notably, optogenetics systems offer some advantages compared to the traditional methods, including spatial-temporal control of protein or gene expression, cost-effective and fewer off-target side effects, and reversibility potential. Such noticeable features make this technology a unique drug-free approach for diagnosis and treatment of cancer. It can be used to control tumor cells, which is a favorable technique to investigate the heterogeneous and complex features of cancerous cells. Remarkably, optogenetics approaches can provide us with outstanding tool to extend our understanding of how cells perceive, respond, and behave in meeting with complex signals, particularly in terms of cancer evasion from the anticancer immune system functions.

Recombinant production and characterization of L-glutaminase (glsA) as a promiscuity therapeutic enzyme.

Because of the therapeutical impacts of hydrolytic enzymes in different diseases, in particular malignancies, we aimed to produce a recombinant putative L-glutaminase (GLS ASL-1) from a recently characterized halo-thermotolerant Bacillus sp. SL-1. For this purpose, the glsA gene was identified and efficiently overexpressed in the Origami™ B (DE3) strain. The yield of the purified GLS ASL-1 was ~ 20 mg/L, indicating a significant expression of recombinant enzyme in the Origami. The enzyme activity assay revealed a significant hydrolytic effect of the recombinant GLS ASL-1 on L-asparagine (Asn) (i.e., Km 39.8 µM, kcat 19.9 S-1) with a minimal affinity for L-glutamine (Gln). The GLS ASL-1 significantly suppressed the growth of leukemic Jurkat cells through apoptosis induction (47.5%) in the IC50 dosage of the enzyme. The GLS ASL-1 could also change the Bax/Bcl2 expression ratio, indicating its apoptotic effect on cancer cells. The in silico analysis was conducted to predict structural features related to the histidine-tag exposure in the N- or C-terminal of the recombinant GLS ASL-1. In addition, molecular docking simulation for substrate specificity revealed a greater binding affinity of Asn to the enzyme binding-site residues than Gln, which was confirmed in experimental procedures as well. In conclusion, the current study introduced a recombinant GLS ASL-1 with unique functional and structural features, highlighting its potential pharmaceutical and medical importance. GLS ASL-1 represents the first annotated enzyme from Bacillus with prominent asparaginase activity, which can be considered for developing alternative enzymes in therapeutic applications. KEY POINTS: • Hydrolytic enzymes have critical applications in different types of human malignancies. • A recombinant L-glutaminase (GLS ASL-1) was produced from halo-thermotolerant Bacillus sp. SL-1. • GLS ASL-1 displayed a marked hydrolytic activity on L-asparagine compared to the L-glutamine. • GLS ASL-1 with significant substrate promiscuity may be an alternative for developing novel pharmaceuticals.

Toxicity of the polymeric excipients in geriatric polypharmacy.

Geriatric polypharmacy is already a complicated issue in pharmacotherapy as multiple biological and pharmaceutical factors are involved. Given the fact that the geriatric population, in general, takes more than five medications for multiple diseases and most likely takes several supplements, there is a hidden issue with the types and amounts of the pharmaceutical inactive ingredients (polymers in particular) as they, as well as their impurities, may build up in an ill-performing body beyond their safety levels. In this commentary, we impart on biological factors, the importance of polymers, and the types and amounts of the impurities within each polymeric excipient that can potentially lead to severe pharmacological and biological impacts. Given the complex safety and toxicity issues in polypharmacy, we may need to revisit the safety standards and regulations on the inactive materials that are widely used in geriatric medications.

Multifunctional magnetic nanoparticles for MRI-guided co-delivery of erlotinib and L-asparaginase to ovarian cancer.

The use of magnetic nanoparticles (MNPs) in biomedical applications has been wildly opted due to their unique properties. Here, we designed MNPs loaded with erlotinib (ERL/SPION-Val-PEG) and conjugated them with anti-mucin16 (MUC16) aptamer to introduce new image-guided nanoparticles (NPs) for targeted drug delivery as well as non-invasive magnetic resonance imaging (MRI) contrast agents. Also, the combination of our nanosystem (NS) along with L-Asparaginase (L-ASPN) led to synergistic effects in terms of reducing cell viability in ovarian cancer cells, which could suggest a novel combination therapy. The mean size of our NS was about 63.4 ± 3.4 nm evaluated by DLS analysis and its morphology was confirmed using TEM. Moreover, the functional groups, as well as magnetic properties of our NS, were examined by FT-IR and VSM tests, respectively. The loading efficacy of erlotinib on MNPs was about 80% and its release reached 70.85% over 7 days in the pH value of 5.4. The MR images and flow cytometry results revealed that the cellular uptake of ERL/SPION-Val-PEG-MUC16 NPs in cells with MUC16 overexpression was considerably higher than unarmed NPs. In addition, T2-weight MR images of ovarian cancer-bearing mice indicated significant signal intensity changes at the tumour site 4 h after intravenous injection compared to the non-target MNPs. Our data suggest ERL/SPION-Val-PEG NPs as an image-guided co-drug delivery system for ovarian cancer.

The protective effect of N-acetylcysteine on antimycin A-induced respiratory chain deficiency in mesenchymal stem cells.

Transplantation of mesenchymal stem cells (MSCs) is an effective treatment in tissue injuries though it is limited due to the early death of stem cells within the first few days. The main reason could be a deficiency in the respiratory chain of injured tissues which is linked to the oxidative stress (OS) and disruption of energy metabolism. The disruption in energy metabolism and OS both inhibit the homing of stem cells in the hypoxic micro-environment, however on other hand, the key functions of stem cells are mainly regulated by their cellular redox status and energy metabolism. Because of that, strategies are being developed to improve the bio-functional properties of MSCs, including preconditioning of the stem cells in hypoxic conditions and pretreatment of antioxidants. To achieve this purpose, in this study N-acetylcysteine (NAC) was used for the protection of cells from oxidative stress and the disruption in energy metabolism was induced by Antimycin A (AMA) via blocking the cytochrome C complex. Then several parameters were analyzed, including cell viability/apoptosis, mitochondrial membrane potential, and redox molecular homeostasis. Based on our findings, upon the exposure of the MSCs to the conditions of deficient respiratory chain, the cells failed to scavenge the free radicals, and energy metabolism was disrupted. The use of NAC was found to alleviate the DNA damage, cell apoptosis, and oxidative stress via Nrf2/Sirt3 pathway though without any effect on the mitochondrial membrane potential. It means that antioxidants protect the cells from OS but the problem of ATP metabolism yet remains unresolved in the hypoxic conditions.