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The present study aimed on the site specific delivery and enhanced in-vivo efficacy of antimonial drugs against the visceral leishmaniasis via macrophage targeted mannose anchored thiomer based nanoparticles. Mannose anchored thiolated nanoformulation [M-(CS-g-PEI)-TGA] was developed and evaluated in terms particle size, zeta-potential and entrapment efficacy. The TEM and EDX analysis was carried out to evaluate the morphology and successful entrapment of antimonial drug. Mucodhesion, permeation enhancement, oral pharmacokinetics, and in-vivo anti-leishmanial activity were carried out. The M-(CS-g-PEI)-TGA were found to be spherical having particle size of 287 ± 20 nm. Ex-vivo permeation indicated a 7.39-fold enhanced permeation of Meglumine Antimoniate with M-(CS-g-PEI)-TGA across Caco-2 cells compared to the Glucantime. Evaluation of in-vitro reduction in the parasitic burden via flow cytometric analysis indicated a 5.7-fold lower IC 50 for M-(CS-g-PEI)-TGA compared to Glucantime. A 6.1-fold improvement in the oral bioavailability and 5.2-fold reduced parasitic burden in the L. donovani infected BALB/c mice model was observed with M-(CS-g-PEI)-TGA compared to Glucantime. The results encouraged the concept of M-(CS-g-PEI)-TGA nanoformulations as a promising strategy for oral therapy against visceral leishmaniasis., 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.)

We describe daylight responsive silver (Ag) doped semiconductor nanoparticles of zinc oxide (DSNs) for photodynamic therapy (PDT) against Leishmania. The developed materials were characterized by X-ray diffraction analysis (XRD), Rutherford backscattering (RBS), diffused reflectance spectroscopy (DRS), and band-gap analysis. The Ag doped semiconductor nanoparticles of zinc oxide were PEGylated to enhance their biocompatibility. The DSNs demonstrated effective daylight response in the PDT of Leishmania protozoans, through the generation of reactive oxygen species (ROS) with a quantum yield of 0.13 by nondoped zinc oxide nanoparticles (NDSN) whereas 0.28 by DSNs. None of the nanoparticles have shown any antileishmanial activity in dark, confirming that only ROS produced in the daylight were involved in the killing of leishmanial cells. Furthermore, the synthesized nanoparticles were found biocompatible. Using reactive oxygen species scavengers, cell death was attributable mainly to 77-83% singlet oxygen and 18-27% hydroxyl radical. The nanoparticles caused permeability of the cell membrane, leading to the death of parasites. Further, the uptake of nanoparticles by Leishmania cells was confirmed by inductively coupled plasma atomic emission spectroscopy (ICP-AES). We believe that these DSNs are widely applicable for the PDT of leishmaniasis, cancers, and other infections due to daylight response., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The aim of this study was to design thiolated surface stabilized superparamagnetic iron oxide nanoparticles (TSS-SPIONs) for efficient internalization with high MRI sensitivity. TSS-SPIONs were developed by chelation between thiolated chitosan-thioglycolic acid (chitosan-TGA) hydrogel and iron ions (Fe(2+)/Fe(3+)). Likely, unmodified chitosan hydrogel SPIONs (UC-SPIONs) and uncoated SPIONs were used as control. Moreover, TSS-SPIONs were investigated regarding to their iron core size, hydrodynamic diameter, zeta potential, iron contents, molar relaxivities (r1 and r2), and cellular internalization. TSS-SPIONs demonstrated an iron oxide core diameter (crystallite size by XRD) of 3.1 ± 0.02 nm, a hydrodynamic diameter of 94 ± 20 nm, a zeta potential of +21 ± 5 mV, and an iron content of 3.6 ± 0.9 mg/mL. In addition, internalization of TSS-SPIONs into human endothelial progenitor cells (EPC) from umbilical cord blood was more than threefold and 17-fold higher in contrast to UC-SPIONs and SPIONs, respectively. With twofold lower incubation iron concentration of TSS-SPIONs, more than threefold higher internalization was achieved as compared to Resovist®. Also, cell viability of more than 90% was observed in the presence of TSS-SPIONs after 24h. The molar MR relaxivities (r2) value at 1.5 T was threefold higher than that of Resovist® and demonstrated that TSS-SPIONs have the potential as very effective T2 contrast-enhancement agent. According to these findings, TSS-SPIONs with efficient internalization, lower cytotoxicity, and high MRI sensitivity seem to be promising for cell tracking., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Within this study, HEC-cysteamine nanoparticles with free thiol groups in the range of 117-1548 μmol/g were designed and characterized. Nanoparticles were generated via ionic gelation of the cationic polymer with tripolyphosphate (TPP) followed by covalent crosslinking via disulfide bond formation using H2O2 as oxidant. The mean diameter of the particles was in the range of 270-360 nm, and zeta potential was determined to be +4 to +10 mV. Nanoparticles were evaluated in terms of mucoadhesive, permeation enhancing, and biocompatible properties as well as biodegradability. The particles remained attached to porcine intestinal mucosa up to 70% after 3h of incubation. The more nanoparticles were oxidized; however, the less were their mucoadhesive properties. Nanoparticles applied in a concentration of 0.5% (m/v) with the highest content of free thiol groups improved the transport of fluorescein isothiocyanate dextran 4 (FD4) across Caco-2 cell monolayer 3.94-fold in comparison with control (buffer). In addition, the transport of FD4 was even 1.84-fold enhanced in the presence of 0.5% (m/v) nanoparticles with the lowest free thiol group content. The higher the disulfide bond content within nanoparticles was, to a lower degree nanoparticles were hydrolyzed by cellulase. None of these nanoparticles showed pronounced cytotoxicity. Accordingly, HEC-cysteamine could be a promising excipient for nanoparticulate delivery systems for poorly absorbed drugs., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Nanoparticles generated by complex coacervation of plasmid DNA (pDNA) and modified chitosans namely chitosan-thioglycolic acid (TGA) conjugate and chitosan-HIV-1 Tat peptide conjugate were evaluated as gene delivery systems. In order to optimize transfection efficiency, chitosan-HIV-1 Tat peptide conjugate was combined with chitosan-TGA before its complexation with pDNA. Particle size and zeta potential measurements were performed to characterize the generated nanoparticles. The nanoparticles transfection efficiencies were assessed by exploitation of the green fluorescent protein (GFP) reporter gene. HEK293 cells were incubated for 24 h with the nanoparticles and the GFP positive cells were observed by fluorescence microscopy. The nanoparticles in the size range of 200-300 nm could transfect HEK293 cells as a model cell line with different transfection efficiencies. Unlike chitosan-TGA, chitosan-HIV-1 Tat peptide led to increased zeta potential of nanoparticles as compared to unmodified chitosan. The transfection efficiency of the nanoparticles generated by combination of chitosan-HIV-1 Tat peptide with chitosan-TGA was comparatively higher than that of the nanoparticles generated by either chitosan-TGA or the combination of chitosan-HIV-1 Tat peptide with unmodified chitosan. After 72 h of incubation, the combination of chitosan-HIV-1 Tat peptide with chitosan-TGA was found to be 7.12- and 67.37 times more efficient than unmodified chitosan and pDNA alone, respectively and showed a synergistic effect in transfection of pDNA into the cells. Moreover, none of the nanoparticles showed any severe cytotoxicity. Accordingly, this strategy might result in a potent carrier for gene delivery., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

This study was aimed to synthesize polymeric excipients with improved mucoadhesive, cohesive and in situ-gelling properties to assure a prolonged retention time of dosage forms at a given target site, thereby achieving an increased uptake and improved oral bioavailability of certain challenging therapeutic agents such as peptides and proteins. Accordingly, poly(acrylic acid)-cysteine-2-mercaptonicotinic acid (PAA-cys-2MNA) conjugates were synthesized by the oxidative S-S coupling of PAA-cys (100-, 250- and 450 kDa) with 2-mercaptonicotinic acid (2MNA). Unmodified PAAs, PAAs-cys (thiomers) and PAA-cys-2MNA (100-, 250- and 450 kDa) conjugates were compressed into tablets to perform disintegration tests, mucoadhesion studies and rheological measurements. Moreover, cytotoxicty of the polymers was determined using Caco-2 cells. The resulting PAA-cys-2MNA (100-, 250- and 450 kDa) conjugates displayed 113.5 ± 12.7, 122.7 ± 12.2 and 117.3 ± 4.6 μmol/g of 2-mercaptonicotinic acid, respectively. Due to the immobilization of 2MNA, the PAA-cys-2MNA (pre-activated thiomers) conjugates exhibit comparatively higher swelling properties and disintegration time to the corresponding unmodified and thiolated polymers. On the rotating cylinder, tablets based on PAA-cys-2MNA (100-, 250- and 450 kDa) conjugates displayed 5.0-, 5.4- and 960-fold improved mucoadhesion time in comparison to the corresponding unmodified PAAs. Results achieved from tensile studies were found in good agreement with the results obtained by rotating cylinder method. The apparent viscosity of PAA-cys-2MNA (100-, 250- and 450 kDa) conjugates was improved 1.6-, 2.5- and 206.2-fold, respectively, in comparison to the corresponding unmodified PAAs. Moreover, pre-activated thiomers/mucin mixtures showed a time dependent increase in viscosity up to 24 h, leading to 7.0-, 18.9- and 2678-fold increased viscosity in comparison to unmodified PAAs (100-, 250- and 450 kDa), respectively. All polymers were found non-toxic over Caco-2 cells. Thus, on the basis of achieved results the pre-activated thiomers seem to represent a promising generation of mucoadhesive polymers which are safe to use for prolonged residence time of drug delivery systems to target various mucosa., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The aim of the present study was to develop an oral delivery system for the peptide drug leuprolide. Gel formulations based on unmodified chitosan/reduced glutathione (GSH) and chitosan-thioglycolic acid (chitosan-TGA)/GSH were prepared, and their effect on the absorption of leuprolide was evaluated in vitro and in vivo in male Sprague Dawley rats. Transport studies were performed with freshly excised rat intestinal mucosa mounted in Ussing-type chambers. Due to the addition of gel formulations comprising 0.5% (m/v) unmodified chitosan/0.5% (m/v) GSH and 0.5% (m/v) chitosan-TGA/0.5% (m/v) GSH, the transport of leuprolide across excised mucosa was improved up to 2.06-fold and 3.79-fold, respectively, in comparison with leuprolide applied in buffer (P(app)=2.87 ± 0.77 × 10⁻⁶ cm/s). In vivo, the addition of oral gel formulation comprising 8 mg of unmodified chitosan, 1mg of GSH and 1mg of leuprolide increased the area under the plasma concentration-time curve (AUC₀₋₈) of leuprolide 1.39-fold in comparison with leuprolide having been administered just in saline. Moreover, the administration of oral gel formulation comprising 8 mg of chitosan-TGA, 1mg of GSH and 1mg of leuprolide resulted in a further enhanced leuprolide plasma concentration, and the area under the plasma concentration-time curve (AUC₀₋₈) of leuprolide was increased 3.72-fold in comparison with the control. With the oral gel formulation comprising 8 mg of chitosan-TGA, a relative bioavailability (versus s.c. injection) of 4.5% was achieved in contrast to the control displaying a relative bioavailability of 1.2%. Thus, according to the achieved results, it is suggested that chitosan-TGA in combination with GSH is a valuable tool for improving the oral bioavailability of the peptide drug leuprolide., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The aim of this study was to examine the potential of self-nanoemulsifying drug delivery systems (SNEDDS) on the uptake of the lipophilic and poorly water soluble phenothiazines thioridazine and chlorpromazine with the isolated plasma derived chylomicron (CM) ex vivo model. The multi-component delivery systems were optimized by evaluating their ability to self-emulsify when introduced to an aqueous medium under gentle agitation. The uptake of phenothiazines by isolated plasma derived chylomicrons was investigated with short chain triglyceride (SCT) SNEDDS, medium chain triglyceride (MCT) SNEDDS, and long chain triglyceride (LCT) SNEDDS. SNEDDS were also evaluated for their stabilities, dispersibilities, percentage transmittances and by particle size analyses. For thioridazine a 5.6-fold and for chlorpromazine a 3.7-fold higher CM uptake could be observed using a LCT-SNEDDS formulation compared to the drugs without formulation. In contrast, ex vivo uptake by isolated CM was not significantly increased by SNEDDS formulations based on MCT and SCT. Compared with isolated CM, the CM sizes were increased 2.5-fold in LCT-SNEDDS, whereas in MCT-SNEDDS or SCT-SNEDDS only a small, non-significant (P<0.05) increase in CM size was observed. These results show that distinct SNEDDS formulations containing phenothiazines are efficiently uptaken by plasma derived chylomicrons ex vivo., (Copyright © 2011 Elsevier B.V. All rights reserved.)