Novel mucoadhesive celecoxib-loaded cubosomal sponges: Anticancer potential and regulation of myeloid-derived suppressor cells in oral squamous cell carcinoma.

Oral squamous-cell carcinoma (OSCC) is a widespread health problem. Myeloid-derived suppressor cells (MDSCs) are major tumor microenvironment (TME) population that govern many carcinogenesis aspects by establishing immunosuppressive milieu favoring tumor aggressiveness and treatment resistance. Cyclooxygenase-2 (COX-2) regulates MDSCs activity, hence, COX-2-selective inhibition by celecoxib (CXB) showed good anticancer effect at relatively high doses with possible subsequent cardiovascular complications. Therefore, targeted CXB delivery to MDSCs may represent a promising OSCC treatment strategy. Novel mucoadhesive-cubosomal buccal sponges were prepared for MDSCs targeting and were evaluated for their in-vitro quality attributes, ex-vivo mucoadhesion using buccal chicken-mucosa. Optimally-selected formulation showed considerable uptake by CD33+/11b+MDSCs in human OSCC cell-line (SCC-4) when quantitatively analyzed by flow-cytometry and examined using confocal-laser microscope. Optimum formulations loaded with low CXB doses (12 mg) were promoted to in-vivo studies via local application, using 4-nitroquinoline-1-oxide-induced OSCC in rats, and compared to their corresponding CXB gels. SP16 revealed the highest ability to decrease MDSC activation, recruitment and TME-immunosuppression in the isolated tumors. Consequently, SP16 exerted the greatest capacity to reduce histologic tumor grade, the OSCC-specific serum tumor markers levels, cancer hallmarks and stemness markers. CXB-loaded cubosomal sponges preferentially target MDSCs with noticeable anticancer potential and may exemplify novel mucoadhesive nanocarriers for OSCC treatment.

Development and Characterization of PLGA Nanoparticle-Laden Hydrogels for Sustained Ocular Delivery of Norfloxacin in the Treatment of Pseudomonas Keratitis: An Experimental Study.

AIM: Norfloxacin (NFX) has low ocular bioavailability. The current work aimed to develop NFX-loaded nanoparticle (NP)-laden hydrogels to improve the ocular potential of NFX, minimize the need for frequent instillations and lower undesirable side effects. METHODS: NFX-loaded NPs were developed via the double-emulsion/solvent evaporation technique, according to 21.41 full factorial design, using two types of polylactic-co-glycolic acid (PLGA) polymer and four (drug: polymer) ratios. NPs were evaluated for particle size (PS), polydispersity index (PDI), zeta potential (ZP), drug entrapment efficiency percentage (EE%), drug percentage released after 30 min (Q30min) and 12 hours (Q12h), drug percentage permeated through goat corneas after 30 min (P30min) and 12 hours (P12h) and morphology. Two formulae were statistically selected and incorporated into hydroxypropyl methylcellulose (HPMC)-based hydrogels; G1 - G4. The latter systems were evaluated for appearance, clarity, pH, spreadability, rheology, drug percentages released, drug percentages permeated, antimicrobial activity against Pseudomonas aeruginosa, and histopathological changes. RESULTS: The selected NPs (NP2 and NP6) were spherical in shape and possessed suitable PS (392.02 nm and 190.51 nm) and PDI (0.17 and 0.18), high magnitude of ZP (-30.43 mV and -33.62 mV), high EE% (79.24% and 91.72%), low Q30min (10.96% and 16.65%) and P30min (17.39% and 21.05%) and promising Q12h (58.23% and 71.20%) and P12h (53.31% and 65.01%), respectively. Clear, spreadable, tolerable, pseudoplastic, and thixotropic HPMC-based hydrogels were developed. They showed more prolonged drug release and drug permeation profiles. NP2- and NP6-laden hydrogels (G3 and G4 systems, respectively) had promising antibacterial activity, and reasonable histopathological safety. CONCLUSION: G3 and G4 are potential ocular delivery systems for NFX.

Eudragit®-S100 Coated PLGA Nanoparticles for Colon Targeting of Etoricoxib: Optimization and Pharmacokinetic Assessments in Healthy Human Volunteers.

AIM: Etoricoxib is a selective inhibitor of COX-2 enzyme. It is proposed as a potent anti-inflammatory drug intended for the control of irritable bowel syndrome. The current work aimed at developing etoricoxib-loaded nanoparticles for colon- targeting. MATERIALS AND METHODS: PLGA nanoparticles were developed via nano-spray drying technique. The D-optimal design was adopted for the investigation of the influence of i) DL-lactide-coglycolide (PLGA) concentration, ii) polyvinylpyrrolidone K30 (PVP K30) concentration and iii) lactide:glycolide ratio in the copolymer chain on the yield%, the encapsulation efficiency (EE%), particle size (PS) and percentage of drug release after 2h (P2h), 4h (P4h) and 12h (P12h). To promote colon targeting of the systems, the best achieved system (M14) was either directly coated with poly(methacrylic acid-co-methyl methacrylate) [Eudragit®-S100] or loaded into hard gelatin capsules and the capsules were coated with poly(methacrylic acid-co-methyl methacrylate) (E-M14C). The pharmacokinetic parameters of etoricoxib following oral administration of E-M14C in healthy volunteers were assessed relative to commercial etoricoxib tablets. RESULTS: M14 system was prepared using PLGA (0.5% w/v) at a lactide:glycolide ratio of 100:0, in the presence of PVP K30 (2% w/v). M14 system was nano-spherical particles of 488 nm size possessing promising yield% (63.5%) and EE% (91.2%). The percentage drug released after 2, 4 and 12 hours were 43.41%, 47.34 and 64.96%, respectively. Following M14-loading into hard gelatin capsules and coating with poly(methacrylic acid-co-methyl methacrylate) [Eudragit-S100], the respective P2h, P4h and P12h were 10.1%, 28.60% and 65.45%. Significant (p < 0.05) differences between the pharmacokinetic parameter of E-M14C in comparison with the commercial product were revealed with a delay in Tmax (from 2.5h to 6h), a prolongation in MRT0-∞ (from 24.4h to 34.7h) and an increase in the relative oral bioavailability (4.23 folds). CONCLUSION: E-M14C is a potential system for possible colon targeting of etoricoxib.

Therapeutic Strategies for Erectile Dysfunction With Emphasis on Recent Approaches in Nanomedicine.

This review addressed erectile dysfunction, regarding pathophysiology and therapeutic strategies. The line of treatment includes phosphodiesterase type-5 inhibitors and other types of therapy like topical and stem-cell transplant. Scientific literature was assessed to investigate the impact of nanotechnology on erectile dysfunction therapy. Various nanotechnology approaches were applied, like vesicular systems, lipid-based carriers, nanocrystals, dendrimers, liquid crystalline systems and nanoemulsions. Smart nano-systems can alter the landscape of the modern pharmaceutical industry by re- investigation of pharmaceutically suboptimal but biologically active entities for treatment of erectile dysfunction which were previously considered undeveloped.

Improved Targeting and Tumor Retention of a Newly Synthesized Antineoplaston A10 Derivative by Intratumoral Administration: Molecular Docking, Technetium 99m Radiolabeling, and In Vivo Biodistribution Studies.

BACKGROUND: Recently, the direct intratumoral (i.t.) injection of anticancer agents has been investigated. A newly synthesized Antineoplaston A10 analog 3-(4-methoxybenzoylamino)-2,6-piperidinedione (MPD) showed an antitumor activity in human breast cancer cell line. Unfortunately, MPD suffered from poor water solubility. MATERIALS AND METHODS: Pseudoternary phase diagram of oil (isopropyl myristate), surfactant (Tween 80), cosurfactant (ethanol), and water was plotted. MPD microemulsion (MPDME) was developed and characterized for particle size (PS), polydispersity index (PDI), zeta potential (ZP), and morphology (transmission electron microscopy). MPDME and MPD solution (MPDS) were radiolabeled with technetium 99m (99mTc) using stannous chloride dihydrate (SnCl2.2H2O). Molecular docking of MPD and 99mTc-MPD was performed to study the interaction with DNA. RESULTS: The impacts of intravenous (i.v.) and i.t. injections of 99mTc-MPDME and 99mTc-MPDS on biodistribution were studied. The developed MPDME showed spherical droplets with mean PS (74.00 ± 5.69 nm), PDI (0.25 ± 0.03), and ZP (33.90 ± 0.90 mV). Labeling yield of 99mTc-MPDME and 99mTc-MPDS was 97.00% ± 0.60% and 92.02% ± 0.45%, respectively. MPD and 99mTc-MPD showed almost same binding affinity with DNA binding site. Biodistribution results showed that i.t. injection of 99mTc-MPDME significantly enhanced tumor retention compared to i.v. route. CONCLUSIONS: Herein, the authors concluded that microemulsion could be used as i.t. injectable delivery vehicle to improve targeting and tumor retention of MPD.

Design and development of microemulsion systems of a new antineoplaston A10 analog for enhanced intravenous antitumor activity: In vitro characterization, molecular docking, 125I-radiolabeling and in vivo biodistribution studies.

A10, (3-phenylacetylamino-2,6-piperidinedione), is a natural peptide with broad antineoplastic activity. Recently, in vitro antitumor effect of a new A10 analog [3-(4-methoxybenzoylamino)-2,6-piperidinedione] (MPD) has been verified. However, poor aqueous solubility represents an obstacle towards intravenous formulation of MPD and impedes successful in vivo antitumor activity. To surmount such limitation, MPD microemulsion (MPDME) was developed. A 3122 full factorial design using Design-Expert® software was adopted to study the influence of different parameters and select the optimum formulation (MPDME1). Transmission electron microscopy (TEM) displayed spherical droplets of MPDME1. The cytotoxicity of MPDME1 in Michigan Cancer Foundation 7 (MCF-7) breast cancer cell line exceeded that of MPD solution (MPDS) and tamoxifen. Compatibility with injectable diluents, in vitro hemolytic studies and in vivo histopathological examination confirmed the safety of parenteral application of MPDME1. Molecular docking results showed almost same binding affinity of A10, MPD and 125I-MPD with histone deacetylase 8 (HDAC8) receptor. Accordingly, radioiodination of MPDME1 and MPDS was done via direct electrophilic substitution reaction. Biodistribution of 125I-MPDME1 and 125I-MPDS in normal and tumor (ascites and solid) bearing mice showed high accumulation of 125I-MPDME1 in tumor tissues. Overall, the results proved that MPDME represents promising parenteral delivery system capable of improving antineoplastic activity of MPD.

The influence of sodium hyaluronate, L-leucine and sodium taurocholate on the nebulization of aqueous betamethasone-17-valerate suspensions.

The purpose of this research was to evaluate the variables that are suggested to influence the adsorption of the hydrophilic hyaluronic acid (HA) onto the surface of the hydrophobic betamethasone-17-valerate (BV) particles in order to formulate a nebulizable suspension. The adsorption of HA from aqueous solutions (0.04% to 0.16%, w/v) to a fixed BV concentration (0.04%, w/v) under different experimental conditions, was investigated. The method of preparation of HA-BV suspensions involved suspending BV particles either in the hydrated HA solution (method 1) or in water followed by addition of solid HA (method 2). Other variables like the time required for the adsorption to complete and temperature at which adsorption is carried out were studied. The nebulization of the suspensions was tested via an air jet nebulizer connected to a twin stage impinger. In order to improve the nebulization behavior of the optimized suspension, L-leucine or sodium taurocholate was incorporated in increasing concentrations (0.01-0.04%, w/v). The optimized suspension, having a nebulization efficiency of 33.75%, was achieved following the adsorption of HA (0.1%, w/v) onto BV particles adopting method 2 of preparation and extending for three days at 4 degrees C. Incorporation of either l-leucine or sodium taurocholate significantly decreased the aggregate size of the optimized suspension and consequently caused significant increases in the nebulization efficiency to reach 46.87% and 56.25%, respectively.

Promising ternary dry powder inhaler formulations of cromolyn sodium: formulation and in vitro-in vivo evaluation.

Glucose monohydrate and sorbitol were evaluated as alternative carriers to á-lactose monohydrate in dry powder inhalations. Cromolyn sodium (CS) - carrier binary formulae were prepared and tested in vitro by aerosolization via a twin stage impinger using three types of inhaler devices; Spinhaler, Aerolizer and Handihaler. Glucose monohydrate and sorbitol-containing formulae that were inhaled via a Handihaler showed significantly higher drug fine particle fractions (P<0.001) than that of the same formulae aerosolized via other devices. Upon storage of the prepared formulae under uncontrolled humidity, that may be encountered during storage and use, marked reductions in these fractions were observed. Incorporation of an optimum Aerosil 200 concentration, as a ternary component, minimized this effect. A urinary excretion pharmacokinetic method was used to evaluate the bioavailability of the selected ternary formulae, inhaled via a Handihaler, relative to the marketed Intal Spincaps, inhaled via a Spinhaler. It was found that the relative bioavailability percentages of the developed formulae were more than twice that of the marketed one suggesting possible future utilization of these more effective ternrry formulae using the more efficient Handihaler inhaler device.

Implantable biodegradable sponges: effect of interpolymer complex formation of chitosan with gelatin on the release behavior of tramadol hydrochloride.

The effect of interpolymer complex formation between positively charged chitosan and negatively charged gelatin (Type B) on the release behavior of tramadol hydrochloride from biodegradable chitosan-gelatin sponges was studied. Mixed sponges were prepared by freeze-drying the cross-linked homogenous stable foams produced from chitosan and gelatin solutions where gelatin acts as a foam builder. Generation of stable foams was optimized where concentration, pH of gelatin solution, temperature, speed and duration of whipping process, and, chitosan-gelatin ratio drastically affect the properties and the stability of the produced foams. The prepared sponges were evaluated for their morphology, drug content, and microstructure using scanning electron microscopy, mechanical properties, uptake capacity, drug release profile, and their pharmacodynamic activity in terms of the analgesic effect after implantation in Wistar rats. It was revealed that whipping 7% (w/w) gelatin solution, of pH 5.5, for 15 min at 25 degrees C with a stirring speed of 1000 rpm was the optimum conditions for stable gelatin foam generation. Moreover, homogenous, uniform chitosan-gelatin foam with small air bubbles were produced by mixing 2.5% w/w chitosan solution with 7% w/w gelatin solution in 1:5 ratio. Indeed, polyionic complexation between chitosan and gelatin overcame the drawbacks of chitosan sponge mechanical properties where, pliable, soft, and compressible sponge with high fluid uptake capacity was produced at 25 degrees C and 65% relative humidity without any added plasticizer. Drug release studies showed a successful retardation of the incorporated drug where the t50% values of the dissolution profiles were 0.55, 3.03, and 4.73 hr for cross-linked gelatin, un-cross-linked chitosan-gelatin, and cross-linked chitosan-gelatin sponges, respectively. All the release experiments followed Higuchi's diffusion mechanism over 12 hr. The achieved drug prolongation was a result of a combined effect of both cross-linking and polyelectrolyte complexation between chitosan and gelatin. The analgesic activity of the implanted tramadol hydrochloride mixed chitosan-gelatin sponge showed reasonable analgesic effect that was maintained for more than 8 hr. Therefore, the use of chitosan and gelatin together appears to allow the formulator to manipulate both the drug release profiles and the mechanical properties of the sponge that could be effectively implanted.

Enhanced transdermal delivery of salbutamol sulfate via ethosomes.

The main objective of the present work was to compare the transdermal delivery of salbutamol sulfate (SS), a hydrophilic drug used as a bronchodilator, from ethosomes and classic liposomes containing different cholesterol and dicetylphosphate concentrations. All the systems were characterized for shape, particle size, and entrapment efficiency percentage, by image analysis optical microscopy or transmission electron microscopy, laser diffraction, and ultracentrifugation, respectively. In vitro drug permeation via a synthetic semipermeable membrane or skin from newborn mice was studied in Franz diffusion cells. The selected systems were incorporated into Pluronic F 127 gels and evaluated for both drug permeation and mice skin deposition. In all systems, the presence of spherical-shaped vesicles was predominant. The vesicle size was significantly decreased (P < .05) by decreasing cholesterol concentration and increasing dicetylphosphate and ethanol concentrations. The entrapment efficiency percentage was significantly increased (P < .05) by increasing cholesterol, dicetylphosphate, and ethanol concentrations. In vitro permeation studies of the prepared gels containing the selected vesicles showed that ethosomal systems were much more efficient at delivering SS into mice skin (in terms of quantity and depth) than were liposomes or aqueous or hydroalcoholic solutions.

Optimization of biodegradable sponges as controlled release drug matrices. I. Effect of moisture level on chitosan sponge mechanical properties.

Cross-linked chitosan sponges as controlled release drug carrier systems were developed. Tramadol hydrochloride, a centrally acting analgesic, was used as a model drug. The sponges were prepared by freeze-drying 1.25% and 2.5% (w/w) high and low M.wt. chitosan solutions, respectively, using glutaraldehyde as a cross-linking agent. The hardness of the prepared sponges was a function of glutaraldehyde concentration and volume where the optimum concentration that offered accepted sponge consistency was 5%. Below or above 5%, very soft or very hard and brittle sponges were obtained, respectively. The determined drug content in the prepared sponges was uniform and did not deviate markedly from the calculated amount. Scanning electron microscopy (SEM) was used to characterize the internal structures of the sponges. The SEM photos revealed that cross-linked high M.wt. chitosan sponges have larger size surface pores that form connections (channels) with the interior of the sponge than cross-linked low M.wt. ones. Moreover, crystals of the incorporated Tramadol hydrochloride were detected on the lamellae and within pores in both chitosan sponges. Differences in pore size and dissolution medium uptake capacity were crucial factors for the more delayed drug release from cross-linked low M.wt. chitosan sponges over high M.wt. ones at pH 7.4. Kinetic analysis of the release data using linear regression followed the Higuchi diffusion model over 12 hours. Setting storage conditions at room temperature under 80-92% relative humidity resulted in soft, elastic, and compressible sponges.