Platelet rich fibrin and simvastatin-loaded pectin-based 3D printed-electrospun bilayer scaffold for skin tissue regeneration.

Designing multifunctional wound dressings is a prerequisite to prevent infection and stimulate healing. In this study, a bilayer scaffold (BS) with a top layer (TL) comprising 3D printed pectin/polyacrylic acid/platelet rich fibrin hydrogel (Pec/PAA/PRF) and a bottom nanofibrous layer (NL) containing Pec/PAA/simvastatin (SIM) was produced. The biodegradable and biocompatible polymers Pec and PAA were cross-linked to form hydrogels via Ca2+ activation through galacturonate linkage and chelation, respectively. PRF as an autologous growth factor (GF) source and SIM together augmented angiogenesis and neovascularization. Because of 3D printing, the BS possessed a uniform distribution of PRF in TL and an average fiber diameter of 96.71 ± 18.14 nm was obtained in NL. The Young's modulus of BS was recorded as 6.02 ± 0.31 MPa and its elongation at break was measured as 30.16 ± 2.70 %. The wound dressing gradually released growth factors over 7 days of investigation. Furthermore, the BS significantly outperformed other groups in increasing cell viability and in vivo wound closure rate (95.80 ± 3.47 % after 14 days). Wounds covered with BS healed faster with more collagen deposition and re-epithelialization. The results demonstrate that the BS can be a potential remedy for skin tissue regeneration.

A double-layer cellulose/pectin-soy protein isolate-pomegranate peel extract micro/nanofiber dressing for acceleration of wound healing.

Multi-layered wound dressings can closely mimic the hierarchical structure of the skin. Herein, a double-layer dressing material is fabricated through electrospinning, comprised of a nanofibrous structure as a healing-support layer or the bottom layer (BL) containing pectin (Pec), soy protein isolate (SPI), pomegranate peel extract (P), and a cellulose (Cel) microfiber layer as a protective/monitoring layer or top layer (TL). The formation of a fine bilayer structure was confirmed using scanning electron microscopy. Cel/Pec-SPI-P dressing showed a 60.05 % weight loss during 7 days of immersion in phosphate buffered solution. The ultimate tensile strength, elastic modulus, and elongation at break for different dressings were within the range of 3.14-3.57 MPa, 32.26-36.58 MPa, and 59.04-63.19 %, respectively. The release of SPI and phenolic compounds from dressings were measured and their antibacterial activity was evaluated. The fabricated dressing was non-cytotoxic following exposure to human keratinocyte cells. The Cel/Pec-SPI-P dressing exhibited excellent cell adhesion and migration as well as angiogenesis. More importantly, in vivo experiments on Cel/Pec-SPI-P dressings showed faster epidermal layer formation, blood vessel generation, collagen deposition, and a faster wound healing rate. Overall, it is anticipated that the Cel/Pec-SPI-P bilayer dressing facilitates wound treatment and can be a promising approach for clinical use.

Mupirocin loaded core-shell pluronic-pectin-keratin nanofibers improve human keratinocytes behavior, angiogenic activity and wound healing.

In the current study, a core-shell nanofibrous wound dressing based on Pluronic-F127 (F127) containing 2 wt% mupirocin (Mup) core and pectin (Pec)-keratin (Kr) shell was fabricated through coaxial electrospinning technique, and the blended nanofibers were also fabricated from the same materials. The fiber diameter and specific surface area of the blended nanofibers were about 101.56 nm and 20.16 m2/g, while for core-shell nanofibers they were about 97.32 nm and 25.26 m2/g, respectively. The resultant blended and core-shell nanofibers experienced a degradation of 27.65 % and 32.28 % during 7 days, respectively. The drug release profile of core-shell nanofibers revealed a sustained release of Mup over 7 days (87.66 %), while the blended F127-Pec-Kr-Mup nanofibers had a burst release within the first few hours (89.38 % up to 48 h) and a cumulative release of 91.36 % after 7 days. Due to the controlled release of Mup, the core-shell structure significantly improved the human keratinocytes behavior, angiogenic potential and wound healing in a rat model compared to the blended structure. In conclusion, the F127-Mup/Pec-Kr core-shell nanofibrous wound dressing appears to be a promising candidate for the prevention of infection, and can potentially accelerate the recovery and healing of chronic and ischemic wounds.

Sodium-borohydride exfoliated bismuthene loaded with Mitomycin C for chemo-photo-radiotherapy of triple negative breast cancer.

In current study, a new remotely controlled drug delivery, radio-sensitizing, and photothermal therapy agent based on thioglycolic acid modified bismuth nanosheets is thoroughly evaluated. Bismuth nanosheets were synthesized using sodium borohydride (NaBH4) and Tween 20 through low energy (400 W) sonication within 2 h. The resultant nanosheets were 40-60 nm in size and 1-3 atomic layers in thickness. The morphological and structural characteristics of the nanosheets were studied using transmission electron microscopy, high-resolution transmission electron microscopy, X-ray diffraction, Raman spectroscopy and ultraviolet spectroscopy. The surface of the nanosheets was modified using thioglycolic acid, which resulted in enhanced Mitomycin C loading capacity to 274.35% and circumvented the burst drug release due to the improved electrostatic interactions. At pH 7.4 and 5.0, the drug release was significantly boosted from 45.1 to 69.8%, respectively. Thioglycolic acid modified bismuth nanosheets under 1064 nm laser irradiation possessed photothermal conversion efficiency of η=51.4% enabling a temperature rise of 24.9 °C at 100 µg/ml in 5 min. The combination of drug delivery, photothermal therapy, and radio-sensitization greatly damaged the MDA-MB-231 cells through apoptosis and diminished their colony forming.

Preparation, optimization, and in vitro-in vivo evaluation of sorafenib-loaded polycaprolactone and cellulose acetate nanofibers for the treatment of cutaneous leishmaniasis.

The most common form of leishmaniasis is cutaneous leishmaniasis (CL). The major difficulties in the treatment of leishmaniasis include emergence of resistance, toxicity, long-term treatment, and the high cost of the current drugs. Although the therapeutic effect of sorafenib (SF) has been demonstrated in both in vitro and in vivo models of Leishmania infection, the therapeutic applications are limited due to severe drug-related toxicity; this is, in turn, due to non-specific distribution in the body. Thus, topical delivery has the advantage of the site directed delivery of SF. This research study evaluated SF-loaded hybrid nanofibers (NFs) which were composed of polycaprolactone (PCL) and cellulose acetate (CA) for the CL topical treatment. Accordingly, SF-loaded hybrid NFs were prepared using the electrospinning method. Formulation variables including total polymer concentration, drug/polymer ratio, and CA concentration were optimized using a full factorial design. The prepared SF-loaded NFs were then characterized for morphology, diameter, encapsulation efficiency (EE)%, drug loading (DL) %, and percentage of release efficiency during a 24-h period (RE24h%); the mechanical characteristics were also considered. The physical state of the drug in the optimized NF was evaluated by the X-ray diffraction analysis. Finally, its in vivo efficacy was determined in L. major-infected mice. The optimized formulation had a smooth, cylindrical, non-beaded shape fiber with a diameter of 281.44 nm, EE of 97.96%, DL of 7.48%, RE of 51.05%, ultimate tensile strength of 1.08 MPa, and Young's moduli of 74.96 MPa. The XRD analysis also demonstrated the amorphous state of SF in NF. Further, the in vivo results displayed the higher anti-leishmanial activity of the SF-loaded hybrid NF by efficiently healing lesion and successfully reducing the parasite burden. This, thus, indicated the potential of the clinical capability of the SF-loaded hybrid NF for the effective treatment of CL.

Noninvasive thrombectomy of graft by nano-magnetic ablating particles.

Artificial vascular treatment is an emerging interdisciplinary subject of medicine. Although the use of artificial vessels has led to many successful advancements, blood clotting remains a major challenge, especially in terms of mural clots created along the vessel wall that do not completely block the vessel. The main objective of this study is to present a method for declotting artificial vessels. This research introduces a novel thrombectomy technique in artificial vessels by employing nano-magnetic particles under a rotating magnetic field to remove mural clots in artificial vessels. A mathematical model describes the relationship between process parameters. In vitro tests confirm the feasibility of nano-magnetic thrombectomy in cleaning and declotting artificial vessels. The results show that the clot fragments are nano-sized, which eliminates the risk of distal emboli as a concern of using current atherectomy techniques. Meanwhile, no damage to the artificial vessels is observed. The results show that the frequency of rotating the magnetic field has the greatest effect on clot removal. The conceptual principles stated in this study also have the potential to be used in other vascular depositions, such as the accumulation of lipids, and calcification atherosclerosis.

Pomegranate seed oil nanoemulsion enriched by α-tocopherol; the effect of environmental stresses and long-term storage on its physicochemical properties and oxidation stability.

In this study, pomegranate seed oil (PSO) nanoemulsions loading different amounts of α-tocopherol (0-40%) were produced. The nanoemulsions were fabricated by ultra-sonication method and the influence of thermal treatment (20-90 °C), pH (2-8) and ionic strength (0-500 mM NaCl) were investigated on physicochemical properties of all treatments. Moreover, the oxidative stability and α-tocopherol degradation were also assessed on optimal enriched nanoemulsion formulation during 50-day storage. The droplet diameter, viscosity, antioxidant activity, encapsulation efficiency and loading capacity of optimal formulation were 37.5 nm, 514 cp, 92%, 3.45% and 92.5%, respectively. The peroxide value changed in the range of 4.5-5.3 and 6.7-10.5 meq O2/kg in loaded and unloaded nanoemulsions, respectively. Transmission electron microscopy demonstrated spherical morphology of nanoemulsion droplets with diameter average of 40 nm. This study suggested that PSO nanoemulsion loading α-tocopherol could be introduced as delivery system with favorable features under severe environmental conditions.

Folate-Targeted Polyacrylamide/Punicic Acid Nanomicelles for Flutamide Delivery in Prostate Cancer: Characterization, In Vitro Biological Evaluation, and its DFT Study.

BACKGROUND: Targeted nanocarriers can be used for reducing the unwanted side effects of drugs in non-target organs. Punicic acid, the polyunsaturated fatty acid of pomegranate seed oil, has been shown to possess anti-cancer effects on prostate cancer and the study also covers recent patents related to prostate cancer. The objective of the current study was to synthesize a co-polymeric micelle for delivery of Flutamide (FL) in prostate cancer using Polyacrylamide (PAM) and Punicic Acid (PA). METHODS: The co-polymer of PAM and PA was synthesized and conjugated to folic acid. The successful conjugation was studied computationally by the density functional theory method and was confirmed by the FT- IR and 1HNMR. The folate-PAMPA micelles produced by the film casting method were characterized physically. FL was loaded in the nanomicelles and its release test was done at different pH. The Critical Micelle Concentration (CMC) was measured by pyrene as a fluorescent probe. Their cellular uptake and cytotoxicity were evaluated on PC3 prostate cancer cells. The molecular geometry and vibrational frequencies of two different possibilities for conjugation were calculated using the B3LYP/6-31G basis set. RESULTS: The CMC of the micelles and their particle size were 79.05 µg/ml and 88 nm, respectively. The resulting nanocarriers of FL showed significantly more cytotoxic effects than the free drug at a concentration of 25 µM. The calculated results showed that the optimized geometries could well reproduce the structural parameters, and the theoretical vibrational frequencies were in good agreement with the experimental values. CONCLUSION: Folate-PAMPA nanomicelles may be promising for the enhancement of FL cytotoxicity and seem to potentiate the effect of chemotherapeutic agents used in prostate cancer treatment.

Synthesis of pectin-deoxycholic acid conjugate for targeted delivery of anticancer drugs in hepatocellular carcinoma.

Sorafenib (SF) a chemotherapeutic drug is used in hepatocellular carcinoma (HCC) with vast side effects. The aim of the project ahead was synthesis of SF loaded co-polymeric micelles of pectin-deoxycholic acid (P-DOCA) to target the overexpressed asialoglycoprotein receptors of hepatocytes by pectin. DOCA was modified with ethylenediamine and conjugated to pectin. FT-IR and 1HNMR confirmed the bio-conjugation. Pyrene was used to measure critical micelle concentration (CMC) by fluorimetry technique. P-DOCA micelles were loaded with SF and their particle size, zeta potential, drug loading and release efficiency were measured. MTT assay was used for determining cytotoxicity. The cell cycle arrest was studied by flow cytometry analysis and the cellular uptake was studied using cumarin-6 as the fluorophore agent. The micelles capability in preventing the cells migration was tested by Transwell plates. The CMC of P-DOCA micelles was 10.747 µg/mL. The best formulation obtained from SF to polymer ratio of 1:2. SF loaded micelles showed 30% increased cytotoxicity. The micelles cellular uptake was more than the free drug. Relative migration of HepG2 cells treated with SF loaded micelles was reduced to 6.67% compared to free SF which was 26.67%. The designed micelles are promising for antitumor drug targeting to HCC.

Preparation and in vitro evaluation of novel cross-linked chondroitin sulphate nanoparticles by aluminium ions for encapsulation of green tea flavonoids.

Chondroitin sulphate is a sulphated glycosaminoglycan biopolymer composed over 100 individual sugars. Chondroitin sulphate nanoparticles (NPs) loaded with catechin were prepared by an ionic gelation method using AlCl3 and optimised for polymer and cross-linking agent concentration, curing time and stirring speed. Zeta potential, particle size, loading efficiency, and release efficiency over 24 h (RE24%) were evaluated. The surface morphology of NPs was investigated by scanning electron microscopy and their thermal behaviour by differential scanning calorimetric. Antioxidant effect of NPs was determined by chelating activity of iron ions. The cell viability of mesenchymal stem cells was determined by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide assay and the calcification of osteoblasts was studied by Alizarin red staining. The optimised NPs showed particle size of 176 nm, zeta potential of -20.8 mV, loading efficiency of 93.3% and RE24% of 80.6%. The chatechin loaded chondroitin sulphate NPs showed 70-fold more antioxidant activity, 3-fold proliferation effect and higher calcium precipitation in osteoblasts than free catechin.

Propolis wax nanostructured lipid carrier for delivery of ß sitosterol: Effect of formulation variables on physicochemical properties.

Preparation and characterization of novel functional nanostructured lipid carriers containing ß sitosterol has been studied. The nanostructured lipid carrires (NLCs) were formulated with propolis wax (PW) alone or in mixture (1:1 w/w) with glyceryl behenate (GB), and pomegranate seed oil (PSO) and produced by a hot melt emulsification method. Response surface methodology was used to optimize formulations with respect to ß sitosterol concentration, liquid lipid content and solid lipid composition. The NLCs formulated with less oil and higher drug content showed higher size and lower encapsulation efficiency. Solid state analysis exhibited lower crystallinity of optimal formulations compared to raw lipids and a drug amorphization into the NLC matrix. The compatibility between drug and encapsulating materials was confirmed by Fourier transform infrared spectroscopy. Transmission electron microscopy showed spherical particles ranged around 100 nm confirming the applicability of such formulations for the production of functional foods.

Poly(methyl vinyl ether-co-maleic acid) for enhancement of solubility, oral bioavailability and anti-osteoporotic effects of raloxifene hydrochloride.

Raloxifene HCl (RH) has poor water solubility and due to its extensive first pass metabolism; its bioavailability is only 2%. The purpose of the present study was to enhance the aqueous solubility, oral bioavailability and anti-osteoporotic effects of RH by electro-sprayed nanoparticles (NPs) in ovariectomized rats. NPs containing RH and different ratio of poly(methyl vinyl ether-co-maleic acid) (PMVEMA) were electrosprayed. The voltage, distance of needle to the collector, flow rate of the solution and polymeric percentage were optimized according to the size of NPs and drug solubility. The optimized formulation was characterized by SEM, XRD, DSC, and FTIR. The pharmacokinetic parameters were studies by oral administration of a single dose of 15mg/kg in Wistar rats. The anti-osteoporotic effects were studied in female ovariectomized rats. Animals were treated with 6mg/kg/day for 2months then serum calcium, phosphorous and alkaline phosphatase levels were measured. RH loaded electrosprayed NPs showed 10-fold enhanced solubility compared to the free drug. Moreover, the XRD and SEM tests displayed an amorphous state of drug in the NPs. FTIR and DSC tests revealed no interaction between the polymer and the drug. Serum calcium, phosphorous and alkaline phosphatase levels were significantly decreased in ovariectomized rats receiving oral RH NPs (P<0.05). No significant difference was detected between RH NPs and estradiol groups (P>0.05). Oral bioavailability of NPs showed 7.5-fold increase compared to the pure drug. The electrosprayed PMVEMA nanoparticles can enhance solubility, bioavailability and antiosteoporotic effects of RH.

Formulation and characterization of novel nanostructured lipid carriers made from beeswax, propolis wax and pomegranate seed oil.

The objective of this study was to develop functional nanostructured lipid carriers (NLCs) using beeswax (BW), propolis wax (PW) and pomegranate seed oil (PSO). NLCs were prepared by a melt emulsification-ultra sonication technique. The influences of solid lipid composition, surfactant blend concentration (2, 4, and 6% of formulation) and PSO content (10, 30 and 50% of total lipid phase) were investigated. Statistical evaluations revealed that the formulation variables had significant effects on physical properties of NLC. The developed nanocarriers presented particle sizes ranging from 71 to 366 nm, leading to excellent physical stability. The optimum formulations with minimum particle size and high zeta potential value were PW and BW + glycerol behenate samples, containing 10% oil and 6% surfactant. DSC and XRD studies indicated that the addition of oil to the lipid phase could disturb the crystalline order and form lattice defects. TEM observations exhibited spherical morphology of the NLCs.

Dextran conjugates in drug delivery.

INTRODUCTION: Dextran is a family of natural polysaccharides that is widely under investigation for use as polymeric carriers in novel drug delivery systems. The optimal drug delivery (and consequently maximum therapeutic effect) will be accomplished when carrier systems are used mainly for drugs with antitumoral activity, as they increase their blood permanence time, taking advantage of the increased mass that reduces kidney ultrafiltration. AREAS COVERED: This review summarizes the attempts that have been made in the development of dextran conjugates and their application. The manuscript describes dextran hydrogels, the use of conjugates of dextran in bioadhesive oral delivery systems, colon drug delivery, reduction of ulcerogenicity of drugs, production of micelles, solubilization, long-circulating pharmaceutical carriers as anticancer drug carriers, non-viral vectors, stabilization of enzymes, functionalization of nanomaterials, diagnosis of solid tumors and hyperthermic treatment and liver targeting. EXPERT OPINION: Dextran conjugation has aided the design of new tailor-made polymers with different molecular weights, shapes, structures and with the functional groups needed for coupling at the desired positions in the chain. Dextran prodrugs are very useful systems for achieving controlled drug release and drug targeting. In particular, various dextran-antitumor drug conjugates enhance the effectiveness and improve the cytotoxic effects of chemotherapeutic agents. Future studies should concentrate on barriers for their clinical use and safety as a drug carrier.

Effectiveness of budesonide-succinate-dextran conjugate as a novel prodrug of budesonide against acetic acid-induced colitis in rats.

BACKGROUND: Anti-inflammatory drugs with high potency and low systemic adverse effects, such as budesonide, are drugs of choice for the treatment of ulcerative colitis (UC). Budesonide controlled-release formulations are now being used to induce and maintain clinical remission of Crohn's disease. Budesonide-dextran conjugates were synthesized as novel prodrugs of budesonide for oral controlled delivery of the major part of the drug to the colon without needing to coat the pellets of the drug. The aim of this study was to evaluate the in vivo efficacy of this conjugate against acetic acid-induced colitis in rats. MATERIALS AND METHODS: Experimental UC was induced by rectal instillation of 4% solution of acetic acid to rats. After induction of colitis, rats were treated with vehicle (dextran solution), mesalasine (120 mg/kg), budesonide suspension (300 microg/kg) and BSD-70 (equivalent to 300 microg/kg of budesonide), prednisolon (4 mg/kg), hydrocortisone acetate enema (20 mg/kg), and 5-ASA enema (Asacol) (400 mg/kg) for 5 days and then colon macroscopic and microscopic sections were examined for inflammatory response. RESULTS: Vehicle-treated rats presented bloody diarrhoea and gross lesions. The effective formulations for attenuating the damage were BSD-70, oral prednisolon and hydrocortisone acetate enema. Rats treated with BSD-70 showed huge improvement in macroscopic and histological scores of colitis compared to the negative control group and mesalasine and budesonide suspension. CONCLUSION: Data indicated that budesonide-dextran conjugate is effective in improving signs of inflammation in experimental model of colitis through selective delivery of the drug to the inflamed area.

Systemic toxicity following ingestion of the chlorhexidine gluconate solution: a case report.

The purpose of this article is to discuss possible adverse effects and emergency treatments following the ingestion of chlorhexidine (CHX). In this case a dental student (age 25, male) accidentally swallowed one shot of 20% CHX solution, which is equal to 100 shots of the standard 0.2% CHX mouthwash. Clinical emergency treatment included: washing the oral cavity with 30 g of toothpaste, drinking 100 ml of 5% (w/v) alginate syrup and ingestion of 5 g of cork. The following adverse effects were experienced: headache, euphoria, giddiness, blurred vision (duration = 12 h), stomachache, gastric lavage with demulcents (duration = 24 h) and complete loss of taste sensation (duration = 8 h), which recurred during the next 48 h. No change in plasma aminotransferase level was seen. We used basic chemical information about the incompatibilities of CHX for clinical management of unintentional ingestion. It is known that CHX is a cation, and, therefore, first aid in case of intoxication with CHX involves using anionic materials.