Therapeutic targeting of siRNA/anti-cancer drug delivery system for non-melanoma skin cancer. Part I: Development and gene silencing of JAK1siRNA/5-FU loaded liposome nanocomplexes.

Non-melanoma skin cancer (NMSC) is one of the most prevalent cancers, leading to significant mortality rates due to limited treatment options and a lack of effective therapeutics. Janus kinase (JAK1), a non-receptor tyrosine kinase family member, is involved in various cellular processes, including differentiation, cell proliferation and survival, playing a crucial role in cancer progression. This study aims to provide a more effective treatment for NMSC by concurrently silencing the JAK1 gene and administering 5-Fluorouracil (5-FU) using liposome nanocomplexes as delivery vehicles. Utilizing RNA interference (RNAi) technology, liposome nanocomplexes modified with polyethylene imine (PEI) were conjugated with siRNA molecule targeting JAK1 and loaded with 5-FU. The prepared formulations (NL-PEI) were characterized in terms of their physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, and stability. Cell cytotoxicity, cell uptake and knockdown efficiency were evaluated in human-derived non-melanoma epidermoid carcinoma cells (A-431). High contrast transmission electron microscopy (CTEM) images and dynamic light scattering (DLS) measurements revealed that the nanocomplexes formed spherical morphology with uniform sizes ranging from 80-120 nm. The cationic NL-PEI nanocomplexes successfully internalized within the cytoplasm of A-431, delivering siRNA for specific sequence binding and JAK1 gene silencing. The encapsulation of 5-FU in the nanocomplexes was achieved at 0.2 drug/lipid ratio. Post-treatment with NL-PEI for 24, 48 and 72 h showed cell viability above 80 % at concentrations up to 8.5 × 101 µg/mL. Notably, 5-FU delivery via nanoliposome formulations significantly reduced cell viability at 5-FU concentration of 5 µM and above (p < 0.05) after 24 h of incubation. The NL-PEI nanocomplexes effectively silenced the JAK1 gene in vitro, reducing its expression by 50 %. Correspondingly, JAK1 protein level decreased after transfection with JAK1 siRNA-conjugated liposome nanocomplexes, leading to a 37 % reduction in pERK (phosphor extracellular signal-regulated kinase) protein expression. These findings suggest that the combined delivery of JAK1 siRNA and 5-FU via liposomal formulations offers a promising and novel treatment strategy for targeting genes and other identified targets in NMSC therapy.

Production of 5-fluorouracil-loaded PLGA nanoparticles with toroidal microfluidic system and optimization of process variables by design of experiments.

In recent decades, microfluidics has presented new opportunities for the production of nanoparticles (NPs). However, to achieve rapid clinical translation, the production of PLGA NPs in a single microfluidic channel for both the pharmaceutical research and industry without the need for scaling is still limited. The aim of this study was to accomplish the production of reproducible and stable 5-FU loaded Poly(lactic-co-glycolic acid) (PLGA) NPs, using an innovative toroidal microfluidic system, for cancer therapy. The toroidal microfluidic system enabled the production of spherical NPs ranging from 100 to 150 nm by adjusting both the TFR within the range of 5-15 mL/min and FRR between 1:3 and 1:7. A systematic assessment of critical process variables (total flow rate; TFR, flow rate ratio; FRR) for the production of PLGA NPs was conducted using Design of Experiment (DoE). The NPs, which exhibit a uniform size distribution, remained stable even after centrifugation and storage for 3 months at 4 °C. The encapsulation efficiency of drug and the concentration of NPs were not affected by changing process parameters. The effective 5-FU encapsulation into NPs resulted in a controlled in vitro drug release. Due to the controlled release profile of the 5-FU loaded PLGA NPs, the formulation was a promising candidate for mitigating the toxic side effects of free 5-FU and improving cancer treatment. In conclusion, toroidal microfluidic system enables high-volume production of stable PLGA NPs, both with and without 5-FU.

Gold nanoparticles-mediated photothermal and photodynamic therapies for cancer.

Cancer remains one of the major causes of death globally, with one out of every six deaths attributed to the disease. The impact of cancer is felt on psychological, physical, and financial levels, affecting individuals, communities, and healthcare institutions. Conventional cancer treatments have many challenges and inadequacies. Nanomedicine, however, presents a promising solution by not only overcoming these problems but also offering the advantage of combined therapy for treatment-resistant cancers. Nanoparticles specifically engineered for use in nanomedicine can be efficiently targeted to cancer cells through a combination of active and passive techniques, leading to superior tumor-specific accumulation, enhanced drug availability, and reduced systemic toxicity. Among various nanoparticle formulations designed for cancer treatment, gold nanoparticles have gained prominence in the field of nanomedicine due to their photothermal, photodynamic, and immunologic effects without the need for photosensitizers or immunotherapeutic agents. To date, there is no comprehensive literature review that focuses on the photothermal, photodynamic, and immunologic effects of gold nanoparticles. In this review, significant attention has been devoted to examining the parameters pertaining to the structure of gold nanoparticles and laser characteristics, which play a crucial role in influencing the efficacy of photothermal therapy (PTT) and photodynamic therapy (PDT). Moreover, this article provides insights into the success of PTT and PDT mediated by gold nanoparticles in primary cancer treatment, as well as the immunological effects of PTT and PDT on metastasis and recurrence, providing a promising strategy for cancer therapy. In summary, gold nanoparticles, with their unique properties, have the potential for clinical application in various cancer therapies, including the treatment of primary cancer, recurrence and metastasis.

Omic Studies on In Vitro Cystinosis Model: siRNA-Mediated CTNS Gene Silencing in HK-2 Cells.

Cystinosis is an autosomal recessive disease caused by mutations in the CTNS gene encoding a protein called cystinosine, which is a lysosomal cystine transporter. Disease-causing mutations lead to accumulation of cystine crystals in the lysosomes, thereby causing dysfunction of vital organs. Determination of the increased leukocyte cystine level is one of the most used methods for diagnosis. However, this method is expensive, difficult to perform, and may yield different results in different laboratories. In this study, a disease model was created with CTNS gene-silenced HK2 cells, which can mimic cystinosis in cell culture, and multiomics methods (ie, proteomics, metabolomics, and fluxomics) were implemented at this cell culture to investigate new biomarkers for the diagnosis. CTNS-silenced cell line exhibited distinct metabolic profiles compared with the control cell line. Pathway analysis highlighted significant alterations in various metabolic pathways, including alanine, aspartate, and glutamate metabolism; glutathione metabolism; aminoacyl-tRNA biosynthesis; arginine and proline metabolism; beta-alanine metabolism; ascorbate and aldarate metabolism; and histidine metabolism upon CTNS silencing. Fluxomics analysis revealed increased cycle rates of Krebs cycle intermediates such as fumarate, malate, and citrate, accompanied by enhanced activation of inorganic phosphate and ATP production. Furthermore, proteomic analysis unveiled differential expression levels of key proteins involved in crucial cellular processes. Notably, peptidyl-prolyl cis-trans isomerase A, translation elongation factor 1-beta (EF-1beta), and 60S acidic ribosomal protein decreased in CTNS-silenced cells. Additionally, levels of P0 and tubulin α-1A chain were reduced, whereas levels of 40S ribosomal protein S8 and Midasin increased. Overall, our study, through the utilization of an in vitro cystinosis model and comprehensive multiomics approach, led to the way toward the identification of potential new biomarkers while offering valuable insights into the pathogenesis of cystinosis.

A scoping review of tissue interposition flaps used in vesicovaginal fistulae repair.

Background: Research on the use of tissue interposition flaps (TIFs) in vesicovaginal fistulae (VVF) repair is a broad area where a very wide range of natural and synthetic materials have been used. The occurrence of VVF is also diverse in the social and clinical settings, resulting in a parallel heterogeneity in the published literature on its treatment. The use of synthetic and autologous TIFs in VVF repair is not yet standardized with a lack of the most efficacious type and technique of the TIF. Objectives: The aim of this study was to systematically review all synthetic and autologous TIFs used in the surgical repair of VVFs. Data sources and methods: In this scoping review, the surgical outcomes of autologous and synthetic interposition flaps used in VVF treatment meeting the inclusion criteria were determined. We searched the literature using Ovid MEDLINE and PubMed databases between 1974 and 2022. Study characteristics were recorded, and data on the change in fistulae size and location, surgical approach, success rate, preoperative patient evaluation and outcome evaluation were extracted from each study independently by two authors. Results: A total of 25 articles that met the inclusion criteria were included in the final analysis. A total of 943 and 127 patients who had received autologous and synthetic flaps, respectively, were included in this scoping review. The fistulae characteristics were highly variable with regard to their size, complexity, aetiology, location and radiation. Outcome assessments of fistulae repair in included studies were mostly based on symptom evaluation. Physical examination, cystogram and methylene blue test were the methods in order of preference. Postoperative complications, such as infection, bleeding, donor site, pain, voiding dysfunction and other complications, were reported in patients after fistulae repair in all included studies. Conclusion: The use of TIFs in VVF repair was common especially in complex and large fistulae. Autologous TIFs appear to be the standard of care at the moment, and synthetic TIFs were investigated in prospective clinical trials in a limited number of selected cases. Evidence levels of clinical studies evaluating the effectiveness of interposition flaps were overall low.

Metabolomic Analyses to Identify Candidate Biomarkers of Cystinosis.

Cystinosis is a rare, devastating hereditary disease secondary to recessive CTNS gene mutations. The most commonly used diagnostic method is confirmation of an elevated leukocyte cystine level; however, this method is expensive and difficult to perform. This study aimed to identify candidate biomarkers for the diagnosis and follow-up of cystinosis based on multiomics studies. The study included three groups: newly-diagnosed cystinosis patients (patient group, n = 14); cystinosis patients under treatment (treatment group, n = 19); and healthy controls (control group, n = 30). Plasma metabolomics analysis identified 10 metabolites as candidate biomarkers that differed between the patient and control groups [L-serine, taurine, lyxose, 4-trimethylammoniobutanoic acid, orotic acid, glutathione, PE(O-18:1(9Z)/0:0), 2-hydroxyphenyl acetic acid, acetyl-N-formil-5-metoxikinuramine, 3-indoxyl sulphate]. As compared to the healthy control group, in the treatment group, hypotaurine, phosphatidylethanolamine, N-acetyl-d-mannosamine, 3-indolacetic acid, p-cresol, phenylethylamine, 5-aminovaleric acid, glycine, creatinine, and saccharic acid levels were significantly higher, and the metabolites quinic acid, capric acid, lenticin, xanthotoxin, glucose-6-phosphate, taurine, uric acid, glyceric acid, alpha-D-glucosamine phosphate, and serine levels were significantly lower. Urinary metabolomic analysis clearly differentiated the patient group from the control group by means of higher allo-inositol, talose, glucose, 2-hydroxybutiric acid, cystine, pyruvic acid, valine, and phenylalanine levels, and lower metabolite (N-acetyl-L-glutamic acid, 3-aminopropionitrile, ribitol, hydroquinone, glucuronic acid, 3-phosphoglycerate, xanthine, creatinine, and 5-aminovaleric acid) levels in the patient group. Urine metabolites were also found to be significantly different in the treatment group than in the control group. Thus, this study identified candidate biomarkers that could be used for the diagnosis and follow-up of cystinosis.

Facile One-Pot Method for All Aqueous Green Formation of Biocompatible Silk Fibroin-Poly(Ethylene Oxide) Fibers for Use in Tissue Engineering.

Silk fibroin (SF) fibers are highly regarded in tissue engineering because of their outstanding biocompatibility and tunable properties. A challenge remains in overcoming the trade-off between functioning and biocompatible fibers and the use of cytotoxic, environmentally harmful organic solvents in their processing and formation. The aim of this research was to produce biocompatible SF fibers without the use of cytotoxic solvents, via pressurized gyration (PG). Aqueous SF was blended with poly(ethylene oxide) (PEO) in ratios of 80:20 (labeled SF-PEO 80:20) and 90:10 (labeled SF-PEO 90:10) and spun into fibers using PG, assisted by a range of applied pressures and heat. Pure PEO (labeled PEO-Aq) and SF solubilized in hexafluoro-isopropanol (HFIP) (labeled SF-HFIP) and aqueous SF (labeled SF-Aq) were also prepared for comparison. The resulting fibers were characterized using SEM, TGA, and FTIR. Their in vitro cell behavior was analyzed using a Live/Dead assay and cell proliferation studies with the SaOS-2 human bone osteosarcoma cell line (ATCC, HTB-85) and human fetal osteoblast cells (hFob) (ATCC, CRL-11372) in 2D culture conditions. Fibers in the micrometer range were successfully produced using SF-PEO blends, SF-HFIP, and PEO-Aq. The fiber thickness ranged from 0.71 ± 0.17 µm for fibers produced using SF-PEO 90:10 with no applied pressure to 2.10 ± 0.78 µm for fibers produced using SF-PEO 80:10 with 0.3 MPa applied pressure. FTIR confirmed the presence of SF via amide I and amide II bands in the blend fibers because of a change in structural conformation. No difference was observed in thermogravimetric properties among varying pressures and no significant difference in fiber diameters for pressures. SaOS-2 cells and hFOb cell studies demonstrated higher cell densities and greater live cells on SF-PEO blends when compared to SF-HFIP. This research demonstrates a scalable and green method of producing SF-based constructs for use in bone-tissue engineering applications.

Co-Axial Gyro-Spinning of PCL/PVA/HA Core-Sheath Fibrous Scaffolds for Bone Tissue Engineering.

The present study aspires towards fabricating core-sheath fibrous scaffolds by state-of-the-art pressurized gyration for bone tissue engineering applications. The core-sheath fibers comprising dual-phase poly-ε-caprolactone (PCL) core and polyvinyl alcohol (PVA) sheath are fabricated using a novel "co-axial" pressurized gyration method. Hydroxyapatite (HA) nanocrystals are embedded in the sheath of the fabricated scaffolds to improve the performance for application as a bone tissue regeneration material. The diameter of the fabricated fiber is 3.97 ± 1.31 µm for PCL-PVA/3%HA while pure PCL-PVA with no HA loading gives 3.03 ± 0.45 µm. Bead-free fiber morphology is ascertained for all sample groups. The chemistry, water contact angle and swelling behavior measurements of the fabricated core-sheath fibrous scaffolds indicate the suitability of the structures in cellular activities. Saos-2 bone osteosarcoma cells are employed to determine the biocompatibility of the scaffolds, wherein none of the scaffolds possess any cytotoxicity effect, while cell proliferation of 94% is obtained for PCL-PVA/5%HA fibers. The alkaline phosphatase activity results suggest the osteogenic activities on the scaffolds begin earlier than day 7. Overall, adaptations of co-axial pressurized gyration provides the flexibility to embed or encapsulate bioactive substances in core-sheath fiber assemblies and is a promising strategy for bone healing.

Assessment of electromechanically stimulated bone marrow stem cells seeded acellular cardiac patch in a rat myocardial infarct model.

In this study, we evaluated cardiomyogenic differentiation of electromechanically stimulated rat bone marrow-derived stem cells (rt-BMSCs) on an acellular bovine pericardium (aBP) and we looked at the functioning of this engineered patch in a rat myocardial infarct (MI) model. aBP was prepared using a detergent-based decellularization procedure followed by rt-BMSCs seeding, and electrical, mechanical, or electromechanical stimulations (3 millisecond pulses of 5 V cm-1at 1 Hz, 5% stretching) to enhance cardiomyogenic differentiation. Furthermore, the electromechanically stimulated patch was applied to the MI region over 3 weeks. After this period, the retrieved patch and infarct region were evaluated for the presence of calcification, inflammatory reaction (CD68), patch to host tissue cell migration, and structural sarcomere protein expressions. In conjunction with any sign of calcification, a higher number of BrdU-labelled cells, and a low level of CD68 positive cells were observed in the infarct region under electromechanically stimulated conditions compared with static conditions. More importantly, MHC, SAC, Troponin T, and N-cad positive cells were observed in both infarct region, and retrieved engineered patch after 3 weeks. In a clear alignment with other results, our developed acellular patch promoted the expression of cardiomyogenic differentiation factors under electromechanical stimulation. Our engineered patch showed a successful integration with the host tissue followed by the cell migration to the infarct region.

Effectiveness of Oil-Layered Albumin Microbubbles Produced Using Microfluidic T-Junctions in Series for In Vitro Inhibition of Tumor Cells.

This work focuses on the synthesis of oil-layered microbubbles using two microfluidic T-junctions in series and evaluation of the effectiveness of these microbubbles loaded with doxorubicin and curcumin for cell invasion arrest from 3D spheroid models of triple negative breast cancer (TNBC), MDA-MB-231 cell line. Albumin microbubbles coated in the drug-laden oil layer were synthesized using a new method of connecting two microfluidic T-mixers in series. Double-layered microbubbles thus produced consist of an innermost core of nitrogen gas encapsulated in an aqueous layer of bovine serum albumin (BSA) which in turn, is coated with an outer layer of silicone oil. In order to identify the process conditions leading to the formation of double-layered microbubbles, a regime map was constructed based on capillary numbers for aqueous and oil phases. The microbubble formation regime transitions from double-layered to single layer microbubbles and then to formation of single oil droplets upon gradual change in flow rates of aqueous and oil phases. In vitro dissolution studies of double-layered microbubbles in an air-saturated environment indicated that a complete dissolution of such bubbles produces an oil droplet devoid of a gas bubble. Incorporation of doxorubicin and curcumin was found to produce a synergistic effect, which resulted in higher cell deaths in 2D monolayers of TNBC cells and inhibition of cell proliferation from 3D spheroid models of TNBC cells compared to the control.

Surface modified nanoliposome formulations provide sustained release for 5-FU and increase cytotoxicity on A431 cell line.

Malignant melanoma is a type of skin cancer with high risk of metastasis. 5-Fluorouracil is commonly used for treatment of skin cancer, however its penetration through the skin is found to be insufficient in some cases. Therefore, we optimized its pharmacokinetics by fabricating 5- Fluorouracil-loaded nanoliposome formulations modified with Poly-L-lysine coating. 5-Fluorouracil-loaded nanoliposome formulations were prepared using dipalmitoylphosphatidylcholine, dicethylphosphate and cholesterol having encapsulation efficiency of 45 ± 9.61%. The particle size, zeta potential, polydispersity index and encapsulation rate of the prepared formulation was found to be 237.9 ± 0.986 nm, 41.4 ± 1.060 mV, 0.233 ± 0.019 and 88.2 ± 7.85%, respectively. Surface characterization, molecular structure and thermal property illumination of the formulations were performed alongside stability studies. The In-vitro release of 5-FU from Lipo-FU6 and PLL-1 formulations was investigated by dialysis membrane method. Within the first 12 hours, the percentage release of 5-FU from Lipo-FU6 and PLL-1 formulations was observed to be 47.17% and 20.84%, respectively. Moreover, the cytotoxicity study on A431 epidermal carcinoma cell lines has revealed that 5-FU-loaded formulations were toxic to cells unlike the 5-FU free formulations. In conclusion, PLL coated nanoliposome formulations showed a potential to be an effective option for further combined drug/gene therapy applications.

The Effects of Polymer Coating of Gold Nanoparticles on Oxidative Stress and DNA Damage.

Gold nanoparticles (AuNPs) have been widely used in many biological and biomedical applications. In this regard, their surface modification is of paramount importance in order to increase their cellular uptake, delivery capability, and optimize their distribution inside the body. The aim of this study was to examine the effects of AuNPs on cytotoxicity, oxidant/antioxidant parameters, and DNA damage in HepG2 cells and investigate the potential toxic effects of different surface modifications such as polyethylene glycol (PEG) and polyethyleneimine (PEI; molecular weights of 2,000 (low molecular weight [LMW]) and 25,000 (high molecular weight [HMW]). The study groups were determined as AuNPs, PEG-coated AuNPs (AuNPs/PEG), low-molecular weight polyethyleneimine-coated gold nanoparticles (AuNPs/PEI LMW), and high-molecular weight polyethyleneimine-coated gold nanoparticles (AuNPs/PEI HMW). After incubating HepG2 cells with different concentrations of nanoparticles for 24 hours, half maximal inhibitory concentrations (the concentration that kills 50% of the cells) were determined as 166.77, 257.73, and 198.44 µg/mL for AuNPs, AuNPs/PEG, and AuNPs/PEI LMW groups, respectively. Later, inhibitory concentration 30 (IC30, the concentration that kills 30% of the cells) doses were calculated, and further experiments were performed on cells that were exposed to IC30 doses. Although intracellular reactive oxygen species levels significantly increased in all nanoparticles, AuNPs as well as AuNPs/PEG did not cause any changes in oxidant/antioxidant parameters. However, AuNPs/PEI HMW particularly induced oxidative stress as evidence of alterations in lipid peroxidation and protein oxidation. These results suggest that at IC30 doses, AuNPs do not affect oxidative stress and DNA damage significantly. Polyethylene glycol coating does not have an impact on toxicity, however PEI coating (particularly HMW) can induce oxidative stress.

Composite nanofibers incorporating alpha lipoic acid and atorvastatin provide neuroprotection after peripheral nerve injury in rats.

Despite the new treatment strategies within the last 30 years, peripheral nerve injury (PNI) is still a worldwide clinical problem. The incidence rate of PNIs is 1 in 1000 individuals per year. In this study, we designed a composite nanoplatform for dual therapy in peripheral nerve injury and investigated the in-vivo efficacy in rat sciatic nerve crush injury model. Alpha-lipoic acid (ALA) was loaded into poly lactic-co-glycolic acid (PLGA) electrospun nanofibers which would release the drug in a faster manner and atorvastatin (ATR) loaded chitosan (CH) nanoparticles were embedded into PLGA nanofibers to provide sustained release. Sciatic nerve crush was generated via Yasargil aneurism clip with a holding force of 50 g/cm2. Nanofiber formulations were administered to the injured nerve immediately after trauma. Functional recovery of operated rat hind limb was evaluated using the sciatic functional index (SFI), extensor postural thrust (EPT), withdrawal reflex latency (WRL) and Basso, Beattie, and Bresnahan (BBB) test up to one month in the post-operative period at different time intervals. In addition to functional recovery assessments, ultrastructural and biochemical analyses were carried out on regenerated nerve fibers. L-929 mouse fibroblast cell line and B35 neuroblastoma cell line were used to investigate the cytotoxicity of nanofibers before in-vivo experiments. The neuroprotection potential of these novel nanocomposite fiber formulations has been demonstrated after local implantation of composite nanofiber sheets incorporating ALA and ATR, which contributed to the recovery of the motor and sensory function and nerve regeneration in a rat sciatic nerve crush injury model.

Targeted Therapies for Pancreatic Cancer and Hurdles Ahead.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with a median survival of 6 months after diagnosis. Intrinsic resistance to chemotherapeutics and lack of effective targeted therapies are the major factors contributing to dismal prognosis. Several important genetic alterations (i.e., mutations, deletions) have been identified to be involved in the initiation and progression of pancreatic cancer, including KRAS and inactivation of tumor suppressors, such as TP53, SMAD4 and CDKN2A. Unique tumor microenvironment with excessive stroma due to desmoplastic reaction is one of the major characteristics of PDAC, promoting tumor growth and leading to treatment failures. In addition, tumor stroma represents an important biological barrier for drug delivery and successful treatment of PDAC. Small interfering RNA (siRNA) has recently emerged as a potential and targeted therapeutic approach which is now evaluated in clinical trials. However, siRNA-based therapeutics face important challenges, including rapid serum degradation, poor tumor cell uptake and cellular uptake, leading to off-target effects. Therefore, there is a great need for the development of safe and effective nanoparticles for better tumor-specific delivery of anti-cancer therapeutics. In this article, the main challenges in the treatment of pancreatic cancer and recent advancements on nano delivery systems of chemotherapeutics and gene-targeted agents, used both in preclinical and clinical trials are reviewed.

Gold nano-decorated aligned polyurethane nanofibers for enhancement of neurite outgrowth and elongation.

Neurite outgrowth and elongation of neural cells is the most important subject that is considered in nerve tissue engineering. In this regard, aligned nanofibers have taken much attention in terms of providing guidance for newly outgrown neurites. The main objective of this study was to fabricate aligned polyurethane nanofibers by electrospinning process and decorate them with gold nanoparticles to further investigate the synergistic effects of nanotopography, biological nerve growth factor (NGF) and electrical stimulations on neurite outgrowth and elongation of pheochromocytoma (PC-12) model cells. In this regard, smooth and uniform aligned polyurethane nanofibers with the average diameter of 519 ± 56 nm were fabricated and decorated with the gold nanoparticles with the average diameter of ∼50 nm. PC-12 cells were cultured on the various nanofiber surfaces inside the bio-mimetic bioreactor system and exposed either to NGF alone or combination of NGF and electrical stimulation. It was found that 50 ng/mL NGF concentration is an optimal value for the stimulation of neurite outgrowth. After 4 days of culture under 100 mV, 10 ms electrical stimulation in 1 h/day period it was found that the gold nanoparticle decorated aligned polyurethane nanofibers increased the neurite outgrowth and elongation more with the combinational NGF and electrical stimulation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1604-1613, 2018.

Modified gold-based siRNA nanotherapeutics for targeted therapy of triple-negative breast cancer.

AIM: In this study, we aimed to therapeutically target eukaryotic elongation factor 2 kinase (eEF-2K) in an in vivo triple-negative breast cancer (TNBC) tumor model. MATERIALS & METHODS: We synthesized a highly monodisperse nanoformulation using polyethylenimine-modified gold nanoparticles (AuNP-PEI) as siRNA delivery vehicle and evaluated gene downregulation. RESULTS: We found that AuNP-PEI/eEF-2K nanoformulation was highly effective for in vitro and in vivo gene downregulation and showed remarkable antitumor efficacy that was associated with eEF-2K knockdown, inhibition of Src and MAPK-ERK signaling pathways in a TNBC orthotopic tumor model. CONCLUSION: Our study suggests that eEF-2K plays an important role in TNBC tumorigenesis and its inhibition by AuNP-PEI/eEF-2K siRNA-based nanotherapeutics may be a potential therapeutic strategy for TNBC.

Oligonucleotide-based theranostic nanoparticles in cancer therapy.

Theranostic approaches, combining the functionality of both therapy and imaging, have shown potential in cancer nanomedicine. Oligonucleotides such as small interfering RNA and microRNA, which are powerful therapeutic agents, have been effectively employed in theranostic systems against various cancers. Nanoparticles are used to deliver oligonucleotides into tumors by passive or active targeting while protecting the oligonucleotides from nucleases in the extracellular environment. The use of quantum dots, iron oxide nanoparticles and gold nanoparticles and tagging with contrast agents, like fluorescent dyes, optical or magnetic agents and various radioisotopes, has facilitated early detection of tumors and evaluation of therapeutic efficacy. In this article, we review the advantages of theranostic applications in cancer therapy and imaging, with special attention to oligonucleotide-based therapeutics.

Silk fibroin based antibacterial bionanotextiles as wound dressing materials.

New applications for medical biotextiles have been identified with the development of nanotechnological manufacturing technologies. Combination of nanotechnology and biotextile technology has resulted into a new field called bionanotextiles. Bionanotextiles are used in many areas which include wound dressings, bandages and tissue scaffolds. Silk fibroin (SF) from the cocoon of Bombyx mori, is one of the most favorable wound dressing materials due to its unique properties including biocompatibility, permeability, biodegradability, morphologic flexibility, and proper mechanical properties. The modification of antimicrobial properties of SFs can provide a barrier for bacterial penetration as wound dressing materials. In the present study, antibacterial polyethylenimine (PEI) (10, 20 and 30% (w/w)) was blended with SF and bionanotextiles were successfully fabricated by electrospinning. In addition, silk fibroin nanofibers were also functionalized with sulphate group in order to test whether they exhibit an antibacterial activity or not. Fibroin based bionanotextiles were characterized by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The cytotoxicity evaluations were carried out by L929 fibroblasts with MTT assay. The indirect cytotoxicity results demonstrate that all fibroin and PEI/fibroin extracts have no cytotoxicity on L929 cancer cell line. PEI/fibroin bionanotextiles showed strong antibacterial activities against gram positive Staphylococcus aureus and gram negative Pseudomonas aeruginosa.