Synthesis and Characterization of Novel pH-Responsive Aminated Alginate Derivatives Hydrogels for Tissue Engineering and Drug Delivery.

AIMS: The aims of this study are to synthesize new derivatives of sodium alginate that improve the inherent properties, such as hydrogel strengthening, and create environmental sensitivity, such as pH sensitivity, for use in drug delivery. BACKGROUND: Today, hydrogels, due to outstanding properties such as biodegradability, biocompatibility, mechanical properties, and response to stimuli properties, are widely used as harmless biomaterials in various fields in drug delivery, wound dressing, and tissue engineering. Stimulus-sensitive polymers significantly respond to slight changes in their environment. Different types of stimuli are used to influence the properties of polymers, the most important of which are temperature and pH because these are two vital factors in the human body; hence, temperature-sensitive and pHsensitive hydrogels have been extensively studied. The ability to absorb water and swell the hydrogel is due to hydrophilic chains in the hydrogel network, and water absorption by hydrogel can be controlled by response to the stimuli. Since hydrogels mimic human tissue, the ability to retain water in them is essential. As a result, it is considered in many biomedical drug delivery systems. Stimulusresponsive swelling can control diffusion out of and into the hydrogel network, which allows temporal and spatial control of drug release. When a drug is loaded onto a biodegradable and stimulisensitive hydrogel, the drug delivery system has the added advantage of sustained release of the drug, which reduces side effects. METHODS: In this study, two different hydrocarbons, [1,3-diaminopropane (DAP)] as a short-chain hydrocarbon, and [1,7-diaminoheptane (DAH)] as a long-chain hydrocarbon were grafted onto three types ofsodium alginate (SA), through amide bond linkages. The hydrogel copolymer matrices were compared with sodium alginate (SA) beads. The graft copolymers were characterized using FTIR, 1HNMR, XRD spectroscopy, elemental analysis (CHNS) and thermal analysis (TGA, DTA and DSC). An environmental scanning electron microscope (ESEM) was used to investigate the surface morphology of hydrogels. RESULTS: Effects of variables such as the length of hydrocarbon chains cross-linked to alginate, temperature, pH, and cross-linkers on the properties of hydrogels investigated in the temperature range of 2-70 ˚C and two different pH values (4.4 and 7.4). The results showed that when the hydrocarbon chain length of diamines decreases, the extent of cross-linking and strength of the hydrogels are increased. Other results suggest that the hydrogels obtained from high-viscosity alginate derivatives had positive pH sensitivity. Hydrogels prepared in this study demonstrated good mechanical and swelling ratios that are necessary for wound dressing. CONCLUSION: DAP-g-SA and DAH-g-SA pH-sensitive hydrogels were successfully synthesized through amide bond linkages. The new synthesis derivatives showed lower swelling levels at low pH (4.4). In contrast, their swelling levels at higher pH (7.4) were significantly enhanced. Higher swelling degree could be obtained at high pH. pH-responsive hydrogels are especially useful for various biological applications due to their unique feature of controlled swelling, biodegradability, biocompatibility, and fluid retention in their network structures. pH-responsive hydrogels, as intelligent systems, can be used in controlled-release drug delivery systems such as insulin delivery.

Cationic liposomes as promising vehicles for timolol/brimonidine combination ocular delivery in glaucoma: formulation development and in vitro/in vivo evaluation.

Glaucoma is a chronic eye disease in which the pressure inside the eye increases and leads to damage to the optic nerve, and eventually causes blindness. In this disease, it is often necessary to use a multi-drug treatment system. There is a fixed combination of timolol maleate and brimonidine tartrate among the combination drugs in glaucoma treatment. Liposomes are one of the most important targeted drug delivery systems to eye tissue, which leads to improved drug permeability and durability in ocular tissue. In this study, thin layer hydration was used to make liposomal formulations containing timolol maleate (TM) and brimonidine tartrate (BT). After the necessary evaluations, one of the eight initial formulations was selected as an optimization formulation. Then, characteristics such as drug loading percentage, particle size, pH, zeta potential, and drug release were performed on the optimized formulation. The study of reducing intraocular pressure was performed on the optimized formulation. This study in total was performed on 18 rabbits in three groups. Hydroxypropyl methylcellulose (HPMC) polymer was injected into the anterior chamber to experimental induce glaucoma. The selected formulation was within the acceptable range of ocular products in terms of physical properties. HPMC polymer injection successfully induced glaucoma in the animal model, resulting in a 79% increase in intraocular pressure. The results showed that the liposomal formulation significantly reduced the intraocular pressure compared to the simple formulation of the aqueous solution, and both formulations were able to significantly reduce the intraocular pressure compared to the control group (P < 0.001). The results also showed that liposomal formulation has a therapeutic effect in reducing intraocular pressure. It seems that the selected liposomal formulation made by thin layer hydration can act as a suitable drug carrier to increase the effectiveness of the fixed combination of timolol maleate and brimonidine tartrate and be proposed as a new drug formulation for targeted and controlled drug delivery in the treatment of glaucoma.

Topical ocular delivery of vancomycin loaded cationic lipid nanocarriers as a promising and non-invasive alternative approach to intravitreal injection for enhanced bacterial endophthalmitis management.

Vancomycin (VCM) is a drug of choice for treating infections caused by Staphylococcus species, reported being the most causative agent of bacterial endophthalmitis. However, the ocular bioavailability of topically applied VCM is low due to its high molecular weight and hydrophilicity. The current study sought to explore whether the nanostructured lipid carriers (NLCs) fabricated via cold homogenization technique could improve ocular penetration and prolong the ophthalmic residence of VCM. A 23 full factorial design was adopted to evaluate the influence of different process and formulation variables on VCM-loaded NLC formulae. The optimized formula with the particle size of 96.4 ±â€¯0.71 nm and narrow size distribution showed spherical morphology obtained by AFM and represented sustained drug release up to 67% in 48 h fitted to the Korsmeyer-Peppas model with probably non-Fickian diffusion kinetic. FTIR studies visualized the drug-carrier interactions in great detail. High encapsulation of VCM (74.8 ±â€¯4.3% w/w) in NLC has been established in DSC and PXRD analysis. The optimal positively charged (+ 29.7 ±â€¯0.47 mV) colloidal dispersion was also stable for 12 weeks at both 4 °C and 25 °C. According to in vivo studies, incorporation of VCM in NLC resulted in a nearly 3-fold increase in the intravitreal concentration of VCM after eye-drop instillation over control groups. Besides, microbiological evaluation admitted its therapeutic effect within five days is comparable to intravitreal injection of VCM. Further, the optimized formula was found to be nonirritant and safe for ophthalmic administration in RBC hemolytic assay. Also, fluorescent tracking of NLCs on rabbit's cornea showed an increase in corneal penetration of nanoparticles. Thus, it is possible to infer that the evolved NLCs are promising drug delivery systems with superior attainments for enhanced Vancomycin ophthalmic delivery to the eye's posterior segment and improved bacterial endophthalmitis management.

Preparation and characterization of topical solid lipid nanoparticles containing Deferoxamine / Preparación y caracterización de nanopartículas lipídicas sólidas tópicas que contienen deferoxamina

Introducción: El mesilato de deferoxamina aumenta la transactivación alfa inducible por hipoxia del factor 1 al prevenir el estrés por oxígeno reactivo catalizado por hierro, por lo que puede usarse para mejorar la cicatrización de la úlcera diabética. Este estudio se llevó a cabo para desarrollar y estudiar las propiedades fisicoquímicas de nanopartículas lipídicas sólidas cargadas con deferoxamina tópica. Método: Se prepararon nanopartículas de lípidos sólidos utilizando la técnica de homogeneización en frío y un diseño factorial completo para evaluar el efecto del tipo de tensioactivo y la cantidad de lípidos. Se llevó a cabo la caracterización in vitro de las formulaciones, incluido el tamaño y la distribución de las partículas, el comportamiento térmico mediante calorimetría de barrido diferencial, la eficiencia de atrapamiento y el perfil de liberación. Resultados: Los resultados mostraron un rango aceptable de tamaño de partícula (2,88-174 nm), una distribución de tamaño estrecha y un promedio del 60% para la eficacia de atrapamiento del fármaco, lo que es significativo para un fármaco hidrófilo. Los resultados del estudio de liberación mostraron una liberación de ráfaga inicial seguida de una manera lenta y prolongada. Los resultados de la calorimetría diferencial de barrido también confirmaron los resultados obtenidos de las evaluaciones de carga y liberación. La mejor formulación que tenía un alto nivel de carga de fármaco y la menor tasa de liberación de fármaco contenía compritol y ácido oleico en una cantidad del 8% de la fórmula total, así como tween 80 y lecitina como una mezcla de tensioactivos. Conclusiones: El estudio demostró que el mesilato de deferoxamina podría cargarse en nanopartículas de lípidos sólidos para administrar por vía tópica. (AU)

Introduction: Deferoxamine mesylate increases hypoxia inducible factor-1 alpha transactivation by preventing iron-catalyzed reactive oxygen stress, so it can be used to improve diabetic ulcer healing. This study was undertaken to develop and study physicochemical properties of topical deferoxamine-loaded solid lipid nanoparticles. Method: Solid lipid nanoparticles were prepared using cold homogenization technique and full factorial design to evaluate the effect of surfactant type and amount of lipid. In-vitro characterization of formulations including particle size and distribution, thermal behavior using Differential Scanning Calorimetry, entrapment efficiency, and release profile were carried out. Results: The results showed an acceptable range of particle size (2.88–174 nm), a narrow size distribution, and an average of 60% for drug entrapment efficiency which is significant for a hydrophilic drug. The results from release study showed an initial burst release followed by a slow and prolonged manner. Differential Scanning Calorimetry results also confirmed the results obtained from loading and release evaluations. The best formulation which had a high level of drug loading and the lowest drug release rate contained compritol and oleic acid in the amount of 8% of the total formula, as well as tween 80 and lecithin as a mixture of surfactants. Conclusions: The study demonstrated deferoxamine could be loaded in solid lipid nanoparticles to deliver topi-cally. (AU)

Functionalized Caprolactone-Polyethylene Glycol Based Thermo-Responsive Hydrogels of Silibinin for the Treatment of Malignant Melanoma.

PURPOSE: Silibinin, is a natural compound, which has shown anticancer activity in various malignancies. In this study, we evaluated the anticancer effects of silibinin in B16-F10 melanoma cells and developed a novel thermoresponsive hydrogel for local delivery of this compound. METHOD: A thermoresponsive hydrogel loaded with silibinin was prepared using triblock copolymers of poly[(α-benzyl carboxylate-e-caprolactone)-co-(α-carboxyl-e-caprolactone)]ran-b-PEG-b-[(α-benzyl carboxylate-e-caprolactone) -co-(α-carboxyl-e-caprolactone)]ran (PCBCL-b-PEG-b-PCBCL), namely PolyGelTM, and compared with a Pluronic F-127 formulation of silibinin. Sol-gel transition temperature of hydrogels was measured by inverse flow method and modulated differential scanning calorimetry (MDSC). Silibinin loading efficiency was measured by HPLC. The MTT and clonogenic assays were used to assess the cytotoxicity and anti-proliferative effects of silibinin on B16-F10 melanoma cells. Flow cytotmetry was used to quantify the induced level of apoptosis and measure the intracellular level of activated STAT3 (pSTAT3) following silibinin treatment in B16.F10 cells. The effects of silibinin on the activation of oncogenic proteins were also evaluated by western blot. RESULTS: Silibinin inhibited cell proliferation (IC50 = 67 µM), provoked cell cycle arrest, induced apoptosis, suppressed key oncogenic pathways (i.e STAT3 and MEK/ERK), and enhanced the cytotoxic effects of doxorubicin in B16-F10 cells. Both PolyGelTM and Pluronic F-127 hydrogels were effective in loading silibinin. A lower drug release pattern within 24h, fitting first- order release kinetics, was observed for the release of silibinin from both gels compared to free drug.  PolyGelTM demonstrated enhanced percutaneous absorption of silibinin through increasing mouse skin intracellular lipid fluidity as documented by DSC of skin following PolyGelTM use. Silibinin loaded in PolyGel TM inhibited the growth of B16-F10 cells (IC50 = 30 µM) and effectively suppressed pSTAT3 activity in B16-F10 cells at 10 µM. CONCLUSION: Our results imply a great potential for PolyGel TM formulations of silibinin for local treatment of malignant melanoma. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's content page.

Nanomedicine for immunosuppressive therapy: achievements in pre-clinical and clinical research.

INTRODUCTION: Immunosuppression is the mainstay therapy in organ transplantation and autoimmune diseases. The effective clinical application of immunosuppressive agents has suffered from the emergence of systemic immunosuppression and/or individual drug side effects. Nanotechnology approaches may be used to modify the mentioned shortcomings by enhancing the delivery of immunosuppressants to target cells of the immune system, thus reducing the required dose for function, and/or reducing drug distribution to non-target tissues. AREAS COVERED: We provide an overview on the development of nanotechnology products for the most commonly used immunosuppressive agents. At first, the rationale for the use of nanoparticles as means for immunosuppressive therapy is discussed. This is followed by a review of major accomplishments in this area, particularly in preclinical in vivo studies. EXPERT OPINION: The results of research conducted in this area to date, points to a great promise for nano-medicine in increasing the bioavailability, reducing the toxicity, and/or potentiating the activity of immunosuppressive agents. It is, therefore, safe to speculate the more rapid translation of nanotechnologyin clinical immunosuppressive therapy in the near future providing to the overcoming of hurdles associated with nano-drug delivery such as high cost, inadequate reproducibility and potential safety concerns of the delivery systems themselves.

Efficacy of Dragon's blood cream on wound healing: A randomized, double-blind, placebo-controlled clinical trial.

The blood-red sap of Dragon's blood has been used in folk medicine for fractures, wounds, inflammation, gastrointestinal disorders, rheumatism, blood circulation dysfunctions, and cancer. Existing in vitro and in vivo bioactivity of this herb on different mechanisms of healing shows strong potential of this sap in wound healing. This clinical trial study was designated to evaluate the wound healing effect of Dragon's blood on human wounds. Sixty patients, between the ages of 14-65 years, who were referred to remove their skin tag, were assigned to this double-blind, placebo-controlled, randomized clinical trial and received either Dragon's blood or a placebo cream. They were visited on the 3rd, 5th, 7th, 10th, 14th, and 20th day of the trial to check the process of healing and to measure the wound's surface. At the end of trial, there was a significant difference in the mean duration of wound healing between the two groups (p = 0.0001). The phenolic compounds and the alkaloid taspine, which exist in Dragon's-blood resin, are probably the main reasons for the wound healing property of this plant. Being natural accessible, safe, and affordable makes Dragon's blood cream, a good choice for addition to the wound healing armamentarium. Further studies on wounds with different causes and among larger populations are suggested to ensure the effectiveness and safety of Dragon's blood.