Fexofenadine-loaded chitosan coated solid lipid nanoparticles (SLNs): A potential oral therapy for ulcerative colitis.

The targeting and mucoadhesive features of chitosan (CS)-linked solid lipid nanoparticles (SLNs) were exploited to efficiently deliver fexofenadine (FEX) into the colon, forming a novel and potential oral therapeutic option for ulcerative colitis (UC) treatment. Different FEX-CS-SLNs with varied molecular weights of CS were prepared and optimized. Optimized FEX-CS-SLNs exhibited 229 ± 6.08 nm nanometric size, 36.3 ± 3.18 mV zeta potential, 64.9 % EE, and a controlled release profile. FTIR, DSC, and TEM confirmed good drug entrapment and spherical particles. Mucoadhesive properties of FEX-CS-SLNs were investigated through mucin incubation and exhibited considerable mucoadhesion. The protective effect of FEX-pure, FEX-market, and FEX-CS-SLNs against acetic acid-induced ulcerative colitis in rats was examined. Oral administration of FEX-CS-SLNs for 14 days before ulcerative colitis induction reversed UC symptoms and almost restored the intestinal mucosa to normal integrity and inhibited Phosphatidylinositol-3 kinase (73.6 %), protein kinase B (73.28 %), and elevated nuclear factor erythroid 2-related factor 2 (185.9 %) in colonic tissue. Additionally, FEX-CS-SLNs inhibited tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) to (70.79 % & 72.99 %) in colonic tissue. The ameliorative potential of FEX-CS-SLNs outperformed that of FEX-pure and FEX-market. The exceptional protective effect of FEX-CS-SLNs makes it a potentially effective oral system for managing ulcerative colitis.

Effect of chitosan and curcumin nanoparticles against skeletal muscle fibrosis at early regenerative stage of glycerol-injured rat muscles.

INTRODUCTION: Chitosan and curcumin are natural products that have a wide range of beneficial effects including wound healing. However, their high molecular weight and poor water solubility limit their applications. AIMS: Therefore, the current study aims to evaluate the effects of chitosan (Cs) and curcumin (Cn) nanoparticles (NPs) on fibrosis and regeneration of glycerol-injured muscle. METHODS: Muscle injury was induced by intramuscular injection of glycerol into the tibialis anterior muscle of rats. Cs-NPs and Cn-NPs were administered at different doses intraperitoneally after injury. Injured muscles were collected at day 7 after injury, and muscle fibrosis and regeneration were assessed. RESULTS: The present results revealed that Cs-NPs and Cn-NPs treatment significantly decreased fibrosis index and increased the average myotube diameter with shifting of the distribution of myotube diameters towards larger diameters in a dose-dependent manner. Immunohistochemical analysis revealed that Cs-NPs and Cn-NPs treatment significantly decreased the number of CD-68+ cells and Col-1+ area. Results showed that Cn-NPs had a higher protective effect, in the form of attenuating muscle fibrosis and inflammation, and enhancing muscle regeneration, than that of Cs-NPs. CONCLUSIONS: To our knowledge, this is the first study to document the effects of Cs-NPs in injured muscles. The results of study might be a novel approach to attenuate muscle fibrosis in humans using curcumin and chitosan nanoparticles.

Pirarubicin-loaded CalliSpheres® drug-eluting beads for the treatment of patients with stage III-IV lung cancer.

BACKGROUND: CalliSpheres® beads (CB) have been used recently for patients with hepatocellular carcinoma. However, the safety and effect of drug-eluting bead transarterial chemoembolization (DEB-TACE) in patients with stage III-IV lung cancer are still unknown. PURPOSE: To evaluate the safety and efficacy of DEB-TACE with pirarubicin-loaded CB for the treatment of stage III-IV lung cancer. MATERIAL AND METHODS: From July 2016 to April 2020, 29 patients with stage III-IV primary lung cancer underwent DEB-TACE with pirarubicin-loaded CB. The objective response rate (ORR) was the primary endpoint; the secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-nine patients received DEB-TACE with pirarubicin-loaded (median 60 mg) CB, with no severe adverse events or treatment-related deaths. After DEB-TACE, hemoptysis disappeared within 1-3 days in all patients, and the symptoms of cough or expectoration were significantly improved in 12 patients. ORR and disease control rate at one, three, and six months after DEB-TACE were 39.3% and 96.4%, 26.1% and 69.6%, and 29.4% and 58.8%, respectively. The median PFS was 6.3 months (range 1.1-30.1 months), and the three-, six-, and 12-month PFS rates were 70.2%, 50.1%, and 27.1%, respectively. The median OS was 10.2 months (range 1.1-44.6 months), and the three-, six, and 12-month OS rates were 87.9%, 68.6%, and 39.8%, respectively. CONCLUSION: DEB-TACE with pirarubicin-loaded CB is safe, feasible, and well-tolerated for patients with stage III-IV lung cancer, and symptom control was a potential benefit of treatment.

Were magnetic materials useful in cancer therapy?

Cancer is one of the major challenges fronting the biomedical basic researches in our time. The study and development of effective therapeutic strategies for cancer therapy are vital. Among the many probable core constituents of nanoparticles, magnetite-based nanoparticles have been widely studied for cancer therapy owing to their inherent magnetic features, multifunctional design, biodegradable and biocompatible properties. Magnetic nanoparticles have been also designed for utilizing as contrast enhancer agents for magnetic resonance imaging, drug delivery systems, and most recently as a therapeutic element in inducing cellular death in tumor ablation therapies. This review aimed to provide an overview of the various applications of magnetic nanoparticles and recent achievements in developing these advanced materials for cancer therapy.

Key Points in Remote-Controlled Drug Delivery: From the Carrier Design to Clinical Trials.

The increased research activity aiming at improved delivery of pharmaceutical molecules indicates the expansion of the field. An efficient therapeutic delivery approach is based on the optimal choice of drug-carrying vehicle, successful targeting, and payload release enabling the site-specific accumulation of the therapeutic molecules. However, designing the formulation endowed with the targeting properties in vitro does not guarantee its selective delivery in vivo. The various biological barriers that the carrier encounters upon intravascular administration should be adequately addressed in its overall design to reduce the off-target effects and unwanted toxicity in vivo and thereby enhance the therapeutic efficacy of the payload. Here, we discuss the main parameters of remote-controlled drug delivery systems: (i) key principles of the carrier selection; (ii) the most significant physiological barriers and limitations associated with the drug delivery; (iii) major concepts for its targeting and cargo release stimulation by external stimuli in vivo. The clinical translation for drug delivery systems is also described along with the main challenges, key parameters, and examples of successfully translated drug delivery platforms. The essential steps on the way from drug delivery system design to clinical trials are summarized, arranged, and discussed.

Carbol fuchsin stain enhances detection of poly-(d, l-lactide-co-glycolide) microspheres in exenatide extended-release cutaneous injection-site foreign body reaction.

Injection of high-viscosity fluids into subcutaneous tissues may lead to a granulomatous reaction called sclerosing lipogranuloma (SL). Poly-(d,l-lactide-co-glycolide) (PLG or PLGA) microspheres are used as vehicles for extended-release drugs. Here we describe the histopathologic features of a case of SL induced by exenatide extended-release injections, and the staining pattern of PLG microspheres and microsphere remnants with carbol fuchsin.

Magnetic-core-based silibinin nanopolymeric carriers for the treatment of renal cell cancer.

AIMS: Silibinin offers potential anticancer effect with less aqueous solubility and high permeability. The present study aimed to develop biocompatible magnetic-core-based nanopolymeric carriers of poly (D, l-lactide-co-glycolic) acid (PLGA) encapsulated silibinin for the sustained release action on renal cancerous cell. MAIN METHODS: The synthesized iron oxide nanoparticles were prepared by precipitation method via encapsulation of silibinin in PLGA network using double emulsion method. The nanoparticle formulations were characterized for morphological, physicochemical properties (HRTEM, FTIR, Raman Spectroscopy and VSM), in vitro drug release and cytotoxicity study on kidney cancer cells (A-498). The safety of magnetic-core-based silibinin nanopolymeric carriers was conducted by i.v. administration at a dose of 50 mg/kg in mice. KEY FINDINGS: The mean particle size, zeta potential and % encapsulation efficiency of magnetic-core-based silibinin nanopolymeric carriers were found to be 285.9 ± 0.28 nm, -14.71 ± 0.15 mV and 84.76 ± 1.29%, respectively. The saturation magnetization of magnetic core and optimized nanoparticles were reported as 36.35 emu/g and 12.78 emu/g, respectively. HRTEM analyses revealed the spherical shapes of the particles with uniform size distribution. The in vitro release profile of silibinin from the nanoparticles exhibited a sustained delivery for 15 days and displayed better cytotoxicity against human kidney cancer cells (A-498) than silibinin. In vivo study showed the safety of magnetic-core-based silibinin nanopolymeric carriers in mice. SIGNIFICANCE: The magnetic-core-based silibinin nanopolymeric carriers will act as a potential carrier for targeted transportation of actives in cancer therapy.

Preparation and characterization of nanocurcumin based hybrid virosomes as a drug delivery vehicle with enhanced anticancerous activity and reduced toxicity.

The present study represents a formulation of nanocurcumin based hybrid virosomes (NC-virosome) to deliver drugs at targeted sites. Curcumin is a bioactive component derived from Curcuma longa and well-known for its medicinal property, but it exhibits poor solubility and rapid metabolism, which led to low bioavailability and hence limits its applications. Nanocurcumin was prepared to increase the aqueous solubility and to overcome all the limitations associated with curcumin. Influenza virosomes were prepared by solubilization of the viral membrane with 1,2-distearoyl-sn-glycerol-3-phosphocholine (DSPC). During membrane reconstitution, the hydrophilic nanocurcumin was added to the solvent system, followed by overnight dialysis to obtain NC-virosomes. The same was characterized using a transmission electron microscope (TEM) and scanning electron microscope (SEM), MTT assay was used to evaluate it's in vitro-cytotoxicity using MDA-MB231 and Mesenchyme stem cells (MSCs). The results showed NC-virosomes has spherical morphology with size ranging between 60 and 90 nm. It showed 82.6% drug encapsulation efficiency. The viability of MDA-MB231 cells was significantly inhibited by NC-virosome in a concentration-dependent manner at a specific time. The IC50 for nanocurcumin and NC-virosome was 79.49 and 54.23 µg/ml, respectively. The site-specific drug-targeting, high efficacy and non- toxicity of NC-virosomes proves its future potential as drug delivery vehicles.

Safe and effective aerosolization of in vitro transcribed mRNA to the respiratory tract epithelium of horses without a transfection agent.

Vaccines and therapeutics using in vitro transcribed mRNA hold enormous potential for human and veterinary medicine. Transfection agents are widely considered to be necessary to protect mRNA and enhance transfection, but they add expense and raise concerns regarding quality control and safety. We found that such complex mRNA delivery systems can be avoided when transfecting epithelial cells by aerosolizing the mRNA into micron-sized droplets. In an equine in vivo model, we demonstrated that the translation of mRNA into a functional protein did not depend on the addition of a polyethylenimine (PEI)-derived transfection agent. We were able to safely and effectively transfect the bronchial epithelium of foals using naked mRNA (i.e., mRNA formulated in a sodium citrate buffer without a delivery vehicle). Endoscopic examination of the bronchial tree and histology of mucosal biopsies indicated no gross or microscopic adverse effects of the transfection. Our data suggest that mRNA administered by an atomization device eliminates the need for chemical transfection agents, which can reduce the cost and the safety risks of delivering mRNA to the respiratory tract of animals and humans.

Assessing the safety of transarterial locoregional delivery of low-density lipoprotein docosahexaenoic acid nanoparticles to the rat liver.

Hepatic-arterial infusion (HAI) of low-density lipoprotein (LDL) nanoparticles reconstituted with docosahexaenoic acid (DHA) (LDL-DHA) has been shown in a rat hepatoma model to be a promising treatment for hepatocellular carcinoma. To date, little is known regarding the safety of HAI of LDL-DHA to the liver. Therefore, we aimed to investigate the deposition, metabolism and safety of HAI of LDL-DHA (2, 4 or 8 mg/kg) in the rat. Following HAI, fluorescent labeled LDL nanoparticles displayed a biexponential plasma concentration time curve as the particles were rapidly extracted by the liver. Overall, increasing doses of HAI of LDL-DHA was well tolerated in the rat. Body weight, plasma biochemistry and histology were all unremarkable and molecular markers of inflammation did not increase with treatment. Lipidomics analyses showed that LDL-DHA was preferentially oxidized to the anti-inflammatory mediator, protectin DX. We conclude that HAI of LDL-DHA nanoparticles is not only safe, but provides potential hepatoprotective benefits.

The Challenge of Nanovesicles for Selective Topical Delivery for Acne Treatment: Enhancing Absorption Whilst Avoiding Toxicity.

Acne is a common skin disease that affect over 80% of adolescents. It is characterized by inflammation of the hair bulb and the attached sebaceous gland. To date, many strategies have been used to treat acne as a function of the disease severity. However, common treatments for acne seem to show several side effects, from local irritation to more serious collateral effects. The use of topical vesicular carriers able to deliver active compounds is currently considered as an excellent approach in the treatment of different skin diseases. Many results in the literature have proven that drug delivery systems are useful in overcoming the toxicity induced by common drug therapies, while maintaining their therapeutic efficacy. Starting from these assumptions, the authors reviewed drug delivery systems already realized for the topical treatment of acne, with a focus on their limitations and advantages over conventional treatment strategies. Although their exact mechanism of permeation is not often completely clear, deformable vesicles seem to be the best solution for obtaining a specific delivery of drugs into the deeper skin layers, with consequent increased local action and minimized collateral effects.

Zinc oxide nanoparticles: A comprehensive review on its synthesis, anticancer and drug delivery applications as well as health risks.

In recent years, zinc oxide nanoparticles (ZnONPs) emerged as an excellent candidate in the field of optical, electrical, food packaging and particularly in biomedical research. ZnONPs show cancer cell specific toxicity via the pH-dependent (low pH) dissolution into Zn2+ ions, which generate reactive oxygen species and induce cytotoxicity in cancer cells. Further, ZnONPs have also been used as an effective carrier for the targeted delivery of several anticancer drugs into tumor cells. The increasing focus on ZnONPs resulted in the development of various synthesis approaches including chemical, pHysical, and green or biological for the manufacturing of ZnONPs. In this article, at first we have discussed the various synthesis methods of ZnONPs and secondly its biomedical applications. We have extensively reviewed the anticancer mechanism of ZnONPs on different types of cancers considering its size, shape and surface charge dependent cytotoxicity. Photoirradiation with UV light or NIR laser further increase its anticancer activity via synergistic chemo-photodynamic effect. The drug delivery applications of ZnONPs with special emphasis on drug loading mechanism, stimuli-responsive controlled release and therapeutic effects have also been discussed in this review. Finally, its side effects to vital body organs with mechanism via different exposure routes, the future direction of the ZnONPs research and application are also discussed.

Replacing Synthetic Ingredients by Sustainable Natural Alternatives: A Case Study Using Topical O/W Emulsions.

With the increasing debate on sustainability, there is a strong market trend to formulate more sustainable products for topical application. Several studies emphasize the potential applications of natural, organic, or green chemistry-derived ingredients, but comparative studies between conventional ingredients and sustainable alternatives are lacking. This type of study is considered an excellent baseline and time-saving strategy for future studies. In addition, one of the main challenges of replacing ingredients by sustainable alternatives in topical vehicles is to maintain high-quality products. Thus, the main goal of this research study was to create a well-defined strategy supported by specific experimental data for the development of sustainable topical vehicles with high-quality standards. The study was designed to evaluate the effects of replacing conventional ingredients (e.g., hydrocarbons, silicones, and preservatives) by sustainable ones on the physical, chemical, and microbiological features of topical emulsions. Additionally, in vivo assessment studies were performed to evaluate the safety, biological efficacy, and sensorial aspects of the developed formulations. The results obtained showed that the replacement of ingredients by sustainable alternatives has an effective impact on the physicochemical and structural properties of the emulsions, mainly on their rheological behavior. However, using appropriate strategies for ingredient selection and rheological adjustment, it is possible to overcome some barriers created by the use of natural raw materials, thus developing appealing and high-quality sustainable topical vehicles.

Biomedical application of mesoporous silica nanoparticles as delivery systems: a biological safety perspective.

The application of mesoporous silica nanoparticles (MSNs) as drug delivery systems to deliver drugs, proteins, and genes has expanded considerably in recent years, using in vitro and animal studies. For future translation to clinical applications, the biological safety aspects of MSNs must be considered carefully. This paper reviews the biosafety of MSNs, examining key issues such as biocompatibility, effects on immune cells and erythrocytes, biodistribution, biodegradation and clearance, and how these vary depending on the effects of the physical and chemical properties of MSNs such as particle size, porosity, morphology, surface charge, and chemical modifications. The future use of MSNs as a delivery system must extend beyond what has been learnt thus far using rodent animal models to encompass larger animals.

Evaluation of Cytotoxic Effect of Cholesterol End-Capped Poly(N-Isopropylacrylamide)s on Selected Normal and Neoplastic Cells.

PURPOSE: Efficient intracellular delivery of a therapeutic compound is an important feature of smart drug delivery systems (SDDS). Modification of a carrier structure with a cell-penetrating ligand, ie, cholesterol moiety, is a strategy to improve cellular uptake. Cholesterol end-capped poly(N-isopropylacrylamide)s offer a promising foundation for the design of efficient thermoresponsive drug delivery systems. METHODS: A series of cholesterol end-capped poly(N-isopropylacrylamide)s (PNIPAAm) with number-average molar masses ranging from 3200 to 11000 g·mol-1 were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization from original xanthate-functionalized cholesterol and self-assembled into micelles. The physicochemical characteristics and cytotoxicity of cholesterol end-capped poly(N-isopropylacrylamide)s have been thoroughly investigated. RESULTS: Phase transition temperature dependence on the molecular weight and hydrophilic/hydrophobic ratio in the polymers were observed in water. Biological test results showed that the obtained materials, both in disordered and micellar form, are non-hemolytic, highly compatible with fibroblasts, and toxic to glioblastoma cells. It was found that the polymer termini dictates the mode of action of the system. CONCLUSION: The cholesteryl moiety acts as a cell-penetrating agent, which enables disruption of the plasma membrane and in effect leads to the restriction of the tumor growth. Cholesterol end-capped PNIPAAm showing in vitro anticancer efficacy can be developed not only as drug carriers but also as components of combined/synergistic therapy.

Acute Immune Response of Micro- and Nanosized Erythrocyte-Derived Optical Particles in Healthy Mice.

Erythrocyte-derived particles activated by near-infrared (NIR) light present a platform for various phototheranostic applications. We have engineered such a platform with indocyanine green as the NIR-activated agent. A particular feature of these particles is that their diameters can be tuned from micro- to nanoscale, providing a potential capability for broad clinical utility ranging from vascular to cancer-related applications. An important issue related to clinical translation of these particles is their immunogenic effects. Herein, we have evaluated the early-induced innate immune response of these particles in healthy Swiss Webster mice following tail vein injection by measurements of specific cytokines in blood serum, the liver, and the spleen following euthanasia. In particular, we have investigated the effects of particle size and relative dose, time-dependent cytokine response for up to 6 h postinjection, functionalization of the nanosized particles with folate or Herceptin, and dual injections of the particles 1 week apart. Mean concentrations of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein (MCP)-1 in response to injection of microsized particles at the investigated relative doses were significantly lower than the corresponding mean concentrations induced by lipopolysaccharide (positive control) at 2 h. All investigated doses of the nanosized particles induced significantly higher concentrations of MCP-1 in the liver and the spleen as compared to phosphate buffer saline (PBS) (negative control) at 2 h. In response to micro- and nanosized particles at the highest investigated dose, there were significantly higher levels of TNF-α in blood serum at 2 and 6 h postinjection as compared to the levels associated with PBS treatment at these times. Whereas the mean concentration of TNF-α in the liver significantly increased between 2 and 6 h postinjection in response to the injection of the microsized particles, it was significantly reduced during this time interval in response to the injection of the nanosized particles. In general, functionalization of the nanosized particles was associated with a reduction of IL-6 and MCP-1 in blood serum, the liver, and the spleen, and TNF-α in blood serum. With the exception of IL-10 in the spleen in response to nanosized particles, the second injection of micro- or nanosized particles did not lead to significantly higher concentrations of other cytokines at the investigated dose as compared to a single injection.

Nano-bio interactions: the implication of size-dependent biological effects of nanomaterials.

Due to their many advantageous properties, nanomaterials (NMs) have been utilized in diverse consumer goods, industrial products, and for therapeutic purposes. This situation leads to a constant risk of exposure and uptake by the human body, which are highly dependent on nanomaterial size. Consequently, an improved understanding of the interactions between different sizes of nanomaterials and biological systems is needed to design safer and more clinically relevant nano systems. We discuss the sizedependent effects of nanomaterials in living organisms. Upon entry into biological systems, nanomaterials can translocate biological barriers, distribute to various tissues and elicit different toxic effects on organs, based on their size and location. The association of nanomaterial size with physiological structures within organs determines the site of accumulation of nanoparticles. In general, nanomaterials smaller than 20 nm tend to accumulate in the kidney while nanomaterials between 20 and 100 nm preferentially deposit in the liver. After accumulating in organs, nanomaterials can induce inflammation, damage structural integrity and ultimately result in organ dysfunction, which helps better understand the size-dependent dynamic processes and toxicity of nanomaterials in organisms. The enhanced permeability and retention effect of nanomaterials and the utility of this phenomenon in tumor therapy are also highlighted.

Acute Damage to the Sperm Quality and Spermatogenesis in Male Mice Exposed to Curcumin-Loaded Nanoparticles.

BACKGROUND: Curcumin has shown many pharmacological activities in both preclinical and clinical studies. Many technologies have been developed and applied to improve the solubility and bioavailability of curcumin, especially the nanotechnology-based delivery systems. However, there has been evidence that certain nanoparticles have potential reproductive toxicity in practice. METHODS: Curcumin-poly (lactic-co-glycolic acid) (PLGA)-PEG nanoparticles (Cur-PLGA-NPs for short) were prepared. The Cur-PLGA-NPs were evaluated with its effect on the proliferation of mouse testicular cell lines in vitro and spermatogenesis in vivo, while PLGA-NPs were used as control. For animal experiments, male BALB/c mice were treated with 20 mg/kg of Cur-PLGA-NPs for continuous 10 days via tail vein injection. RESULTS: We found the curcumin nanoparticles suppressed the proliferation of testicular cell lines in vitro. Furthermore, a short-term intravenous delivery of curcumin-loaded nanoparticles could be harmful to the differentiation of spermatogonia, the elongation of spermatids, as well as the motility of mature sperms. CONCLUSION: In the present study, we disclosed the acute damage on mouse spermatogenesis and sperm parameters by curcumin-loaded nanoparticles. Our results suggested that the reproductive toxicity of nanoformulated curcumin needs to be prudently evaluated before its application.

Degradable nanohydrogel with high doxorubicin loadings exhibiting controlled drug release and decreased toxicity against healthy cells.

A new nanogel/drug carrier of 100-150 nm size, based on poly(N-isopropylacrylamide-co-sodium acrylate) and degradable crosslinker (cystine derivative), was synthesized. Using the electrostatic interactions between the carboxylic groups in the polymer network and the protonated amine groups of doxorubicin it was possible to load the drug into the carrier to a very high level of 28-30% relative to the dry mass of the polymer. The presence of the -S-S- groups made the polymer network susceptible to degradation by glutathione. The size of the nanoparticles was small enough to enable them to easily penetrate the cells. The MTT assay indicated that compared to free doxorubicin the nanogel particles loaded with doxorubicin were more cytotoxic against the MCF-7 and A2780 cancer cells, while they were 150 times less toxic against the MCF-10A healthy cells. The new carrier nanoparticles appeared also to be useful for prolonged drug delivery.