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The development of cancer theranostic nanomedicines is recommended to concurrently achieve and evaluate the therapeutic benefit and progress. The current work aims to develop gallic acid-gold nanoparticles (GA-Au NPs) as a theranostic probe for 99m Tc-Doxorubicin ( 99m Tc-DOX) based on the spatiotemporal release pattern induced intra-tumoral (IT) delivery. DOX-loaded GA-Au NPs were developed and identified via UV-Vis spectroscopy. The system was characterized for drug loading efficiency%, particle size, zeta potential, topography, in vitro DOX release and anti-proliferative activity against the MCF-7 cell-line. The factors influencing radiolabeling efficiency of DOX with 99m Tc (DOX concentration, stannous chloride concentration, reaction time and pH) were optimized. The in vitro stability in mice serum and in vivo distribution studies in mice of 99m Tc-DOX-loaded GA-Au NPs were investigated following IV and IT administration. Dox-loaded GA-Au NPs had a loading efficiency of 91%, a small particle size (≈50 nm), a promising zeta potential (-20 mV) and a sustained drug release profile at pH 5.3. GA-Au NPs exhibited increased anti-proliferative activity, with approximately a four-fold lower IC 50 value (0.15 μg/ml) than free DOX. The optimized radiolabeling efficiency of 99m Tc-DOX was ≈93%. It showed good physiological stability in mice serum for at least 8 h. The IT delivery of 99m Tc-DOX-loaded GA-Au NPs in tumor-induced mice showed dramatic tumor accumulation. A maximum magnitude of 86.73%ID/g was achieved, at 15 min post-injection, with a target/non-target ratio of ≈56. 99m Tc-DOX-loaded GA-Au NPs could be used for the selective IT delivery of a chemotherapeutic agent and an imaging agent to a target organ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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 3 1 2 2 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 125 I-MPD with histone deacetylase 8 (HDAC8) receptor. Accordingly, radioiodination of MPDME1 and MPDS was done via direct electrophilic substitution reaction. Biodistribution of 125 I-MPDME1 and 125 I-MPDS in normal and tumor (ascites and solid) bearing mice showed high accumulation of 125 I-MPDME1 in tumor tissues. Overall, the results proved that MPDME represents promising parenteral delivery system capable of improving antineoplastic activity of MPD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chlorambucil (CHL) is a water-insoluble antineoplastic drug having a short elimination half-life. It suffers from remarkable differences in pharmacokinetics following oral administration. The current work aimed to assess safety and pharmacokinetics of CHL-loaded, lipoprotein-mimic, nanoparticles (NPs) following intravenous administration. The design of NPs was based on complexation between egg yolk lecithin (EYL) and bovine serum albumin (BSA). The NPs were preliminary evaluated via FT-IR, DSC and P-XRD. The NPs were characterized for particle size, zeta potential, morphology and drug entrapment efficiency (EE%). The best achieved NP dispersion (LP6) and CHL solution were challenged for in vitro hemolytic potential, in vivo vascular irritation studies in rabbits and in vivo pharmacokinetics following intravenous administration in rats. The results confirmed that NPs were stabilized by hydrophobic-attractions and hydrogen-bondings between CHL, BSA and EYL. The amorphous dispersion of CHL within NPs was revealed. LP6 dispersion displayed monodispersed nano-spherical particles (144.33 ± 2.17 nm). It possessed the highest negative zeta potential (-30.55 ± 0.24 mV) and the largest EE% (86.35 ± 2.33%). The significantly (P < 0.05) prolonged MRT(0-∞), longer elimination t50% and reduced plasma clearance highlighted the long-circulating characteristics of LP6. The preliminary safety evaluations and the seven-fold increase in bioavailability elucidated potentiality for smart intravenous delivery of CHL., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Pravastatin sodium (PVS) is a hydrophilic HMG-CoA reductase inhibitor that is mainly absorbed from duodenum. PVS has a short elimination half-life (1-3 h), suffers from instability at gastric pH, extensive hepatic first-pass metabolism and low absolute bioavailability (18%). The current work aimed to develop enteric surface-coated spanlastic dispersions as controlled-release duodenum-triggered systems able to surmount PVS drawbacks. PVS-loaded spanlastic dispersions were prepared by ethanol-injection method using span(®) 60. Tween(®) 60 and Tween(®) 80 were explored as edge activators. As a novel approach, the fine spanlastic dispersions were surface-coated with an enteric-polymer (Eudragit(®) L100-55) via freeze-drying. The systems were evaluated, before and after enteric-coating, for particle size, zeta potential, PVS entrapment efficiency (EE%), morphology and PVS release studies. PVS pharmacokinetics from the best achieved system and an aqueous solution were estimated in rats by UPLC-MS/MS. The best achieved enteric surface-coated spanlastic dispersion (E-S6) displayed spherical nanosized vesicles (647.60 nm) possessing negative zeta potential (-6.93 mV), promising EE% (63.22%) and a biphasic drug-release pattern characterized by a retarded-release phase (0.1 N HCl, 2 h) and a controlled-release phase (pH 6.8, 10 h). The higher Cmax, delayed Tmax, prolonged MRT(0-∞), longer elimination t50% and enhanced oral bioavailability unravel E-S6 potential for oral PVS delivery., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The current work aimed to develop novel composite sponges of chitosan (CH)-chondroitin sulfate (CS) as a low-density gastroretentive delivery system for lornoxicam (LOR). This triple anti-inflammatory therapy-loaded matrices are expected to expand and float upon contact with gastric fluids for prolonged times. CH and CS solutions (3%, w/w) were prepared, mixed in different ratios, lyophilized, coated with magnesium stearate and compressed. The CH:CS interpolymer complex (IPC) was evaluated via FT-IR, DSC, and XRD. The compressed-sponges were evaluated for appearance, structure, porosity, pore diameter, density, wetting-time, floating characteristics, adhesion-retention, and LOR-release. The gastroretentivity of the best achieved magnetite-loaded sponges was monitored in healthy volunteers via MRI. The interaction between CH (protonated amino groups) and CS (anionic carboxylate/sulfate groups) proved IPC formation. DSC and XRD studies confirmed loss of LOR crystallinity. The sponges possessed interconnecting porous-network structures. The porosity, mean pore diameter, and bulk density of CH:CS (10:3) IPC sponges were 11.779%, 25.4 nm, and 0.670 g/mL, respectively. They showed complete wetting within seconds, gradual size-expansion within minutes and prolonged adhesion for hours. Controlled LOR-release profiles were tailored over 12h to satisfy individual patient needs. Monitoring of sponges via MRI proved their gastroretentivity for at least 5h., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Olanzapine (OZ) is atypical antipsychotic drug that suffers from low brain permeability due to efflux by P-glycoproteins and hepatic first-pass metabolism. The current work aimed to develop OZ-loaded micellar nanocarriers and investigate their nose-to-brain targeting potential. OZ-loaded (5mg/ml) micelles (F1-F12) were prepared, using a Pluronic(®) mixture of L121 and P123, adopting thin-film hydration method. The micelles were evaluated for turbidity, particle size, morphology, drug-entrapment efficiency (EE%), drug-loading characteristics, in vitro drug release and ex vivo nasal toxicity in sheep. The in vivo biodistribution and pharmacokinetic studies in the brain/blood following intravenous (i.v.) and intranasal (i.n.) administrations of technetium-labeled OZ-loaded micelles and OZ-solution were evaluated in rats. Spherical micelles ranging in size from 18.97 to 380.70 nm were successfully developed. (1)H NMR studies confirmed OZ incorporation into micelle core. At a drug:Pluronic(®) L121:Pluronic(®) P123 ratio of 1:8:32 (F11), the micelles achieved a conciliation between kinetic and thermodynamic stability, high drug-EE%, controlled drug-release characteristics and evoked minor histopathological changes in sheep nasal mucosa. The significantly (P<0.05) higher values for F11 micelles (i.n.); brain/blood ratio (0.92), drug targeting index (5.20), drug targeting efficiency (520.26%) and direct transport percentage (80.76%) confirm the development of a promising non-invasive OZ-loaded nose-to-brain delivery system., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Terbinafine hydrochloride (T-HCl) is recommended for the management of fungal keratitis. To maintain effective aqueous humor concentrations, frequent instillation of T-HCl drops is necessary. This work aimed to develop alternative controlled-release in situ ocular drug-loaded nanoemulsion (NE) gels. Twelve pseudoternary-phase diagrams were constructed using oils (isopropyl myristate/Miglyol 812), surfactants (Tween 80/Cremophor EL), a co-surfactant (polyethylene glycol 400) and water. Eight drug-loaded (0.5%, w/v) NEs were evaluated for thermodynamic stability, morphology, droplet size and drug release in simulated tear fluid (pH 7.4). Following dispersion in gellan gum solution (0.2%, w/w), the in situ NE gels were characterized for transparency, rheological behavior, mucoadhesive force, drug release and histopathological assessment of ocular irritation. Drug pharmacokinetics of sterilized F31 [Miglyol 812, Cremophor EL: polyethylene glycol 400 (1:2) and water (5, 55 and 40%, w/w, respectively)] in situ NE gel and oily drug solution were evaluated in rabbit aqueous humor. The NEs were thermodynamically stable and have spherical droplets (<30 nm). The gels were transparent, pseudoplastic, mucoadhesive and showed more retarded zero-order drug release rates. F31 in situ NE gel showed the least ocular irritation potential and significantly (P<0.01) higher C(max), delayed T(max), prolonged mean residence time and increased bioavailability., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A Novel approach was developed for the preparation of controlled release proniosome-derived niosomes, using sucrose stearates as non-ionic biocompatible surfactants for the nebulisable delivery of cromolyn sodium. Conventional niosomes were prepared by a reverse phase evaporation method followed by the preparation of proniosomes by spraying the optimized surfactant-lipid mixture of sucrose stearate, cholesterol and stearylamine in 7:3:0.3 molar ratio onto the surface of spray dried lactose powder. Proniosome-derived niosomes were obtained by hydrating proniosomes with 0.9% saline at 50 degrees C and mixing for approximately 2 min. All vesicles were evaluated for their particle size, morphological characteristics, entrapment efficiency, in vitro drug release, nebulisation efficiency and physical stability at 2-8 degrees C. In addition, coating carrier surface with the surfactant-lipid mixture, during preparation of proniosomes, resulted in smaller, free flowing, homogenous and smooth vesicles with high drug entrapment efficiency. Compared to a standard drug solution, a successful retardation of the drug release rate was achieved with the proniosome-derived niosomes, where the t50% value of the release profile was 18.1h compared to 1.8h. Moreover, high nebulisation efficiency percentage and good physical stability were also achieved. The results are very encouraging and offer an alternative approach to minimize the problems associated with conventional niosomes like degradation, sedimentation, aggregation and fusion.