Tailoring of Bilosomal Nanogel for Augmenting the Off-Label Use of Sildenafil Citrate in Pediatric Pulmonary Hypertension.

Pediatric pulmonary hypertension is a serious syndrome with significant morbidity and mortality. Sildenafil is widely used off-label in pediatric patients with pulmonary arterial hypertension. In this study, bile salt-stabilized nanovesicles (bilosomes) were screened for their efficacy to enhance the transdermal delivery of the phosphodiesterase type 5 inhibitor, sildenafil citrate, in an attempt to augment its therapeutic efficacy in pediatric pulmonary hypertension. A response surface methodology was implemented for fabricating and optimizing a bilosomal formulation of sildenafil (SDF-BS). The optimized SDF-BS formulation was characterized in terms of its entrapment efficiency (EE), zeta potential, vesicle size, and in vitro release profile. The optimized formula was then loaded onto hydroxypropyl methyl cellulose (HPMC) hydrogel and assessed for skin permeation, in vivo pharmacokinetics, and pharmacodynamic studies. The optimized SDF-BS showed the following characteristic features; EE of 88.7 ± 1.1%, vesicle size of 185.0 + 9.2 nm, zeta potential of -20.4 ± 1.1 mV, and efficiently sustained SDF release for 12 h. Skin permeation study revealed a remarkable improvement in SDF penetration from bilosomal gel compared to plain SDF gel. In addition, pharmacokinetic results revealed that encapsulating SDF within bilosomal vesicles significantly enhanced its systemic bioavailability (∼3 folds), compared to SDF oral suspension. In addition, pharmacodynamic investigation revealed that, compared to plain SDF gel or oral drug suspension, SDF-BS gel applied topically triggered a significant elevation (p < 0.05) in cGMP serum levels, underscoring the superior therapeutic efficacy of SDF-BS gel. Conclusively, bilosomes can be viewed as a promising nanocarrier for transdermal delivery of SDF that would grant higher therapeutic efficiency while alleviating the limitations encountered with SDF oral administration.

An Update on Emergent Nano-Therapeutic Strategies against Pediatric Brain Tumors.

Pediatric brain tumors are the major cause of pediatric cancer mortality. They comprise a diverse group of tumors with different developmental origins, genetic profiles, therapeutic options, and outcomes. Despite many technological advancements, the treatment of pediatric brain cancers has remained a challenge. Treatment options for pediatric brain cancers have been ineffective due to non-specificity, inability to cross the blood-brain barrier, and causing off-target side effects. In recent years, nanotechnological advancements in the medical field have proven to be effective in curing challenging cancers like brain tumors. Moreover, nanoparticles have emerged successfully, particularly in carrying larger payloads, as well as their stability, safety, and efficacy monitoring. In the present review, we will emphasize pediatric brain cancers, barriers to treating these cancers, and novel treatment options.

Development of Carvedilol Nanoformulation-Loaded Poloxamer-Based In Situ Gel for the Management of Glaucoma.

The objective of the current study was to fabricate a thermosensitive in situ gelling system for the ocular delivery of carvedilol-loaded spanlastics (CRV-SPLs). In situ gel formulations were prepared using poloxamer analogs by a cold method and was further laden with carvedilol-loaded spanlastics to boost the precorneal retention of the drug. The gelation capacity, rheological characteristics, muco-adhesion force and in vitro release of various in situ gel formulations (CS-ISGs) were studied. The optimized formula (F2) obtained at 22% w/v poloxamer 407 and 5% w/v poloxamer 188 was found to have good gelation capacity at body temperature with acceptable muco-adhesion properties, appropriate viscosity at 25 °C that would ease its ocular application, and relatively higher viscosity at 37 °C that promoted prolonged ocular residence of the formulation post eye instillation and displayed a sustained in vitro drug release pattern. Ex vivo transcorneal penetration studies through excised rabbit cornea revealed that F2 elicited a remarkable (p ˂ 0.05) improvement in CRV apparent permeation coefficient (Papp = 6.39 × 10-6 cm/s) compared to plain carvedilol-loaded in situ gel (CRV-ISG; Papp = 2.67 × 10-6 cm/s). Most importantly, in normal rabbits, the optimized formula (F2) resulted in a sustained intraocular pressure reduction and a significant enhancement in the ocular bioavailability of carvedilol, as manifested by a 2-fold increase in the AUC0-6h of CRV in the aqueous humor, compared to plain CRV-ISG formulation. To sum up, the developed thermosensitive in situ gelling system might represent a plausible carrier for ophthalmic drug delivery for better management of glaucoma.

Dual targeting multiwalled carbon nanotubes for improved neratinib delivery in breast cancer.

The aim of this study was to develop biotinylated chitosan (Bio-Chi) decorated multi-walled carbon nanotubes (MWCNTs) for breast cancer therapy with the tyrosine kinase inhibitor, neratinib (NT). For achieving such a purpose, carboxylic acid functionalized multiwalled carbon nanotubes (c-MWCNTs) were initially decorated non-covalently with biotin-chitosan (Bio-Chi) coating for achieving a dual targeting mode; pH-dependent release with chitosan and biotin-receptor mediated active targeting with biotin. Afterwards, Bio-Chi decorated c-MWCNTs were loaded with the tyrosine kinase inhibitor, neratinib (NT). The formulation was then characterized by dynamic light scattering, FTIR and EDX. The drug loading efficiency was estimated to be 95.6 ± 1.2%. In vitro drug release studies revealed a pH-dependent release of NT from Bio-Chi decorated c-MWCNTs, with a higher drug release under acidic pH conditions. Sulforhodamine B (SRB) cytotoxicity assay of different NT formulations disclosed dose-dependent cytotoxicities against SkBr3 cell line, with a superior cytotoxicity observed with NT-loaded Bio-Chi-coated c-MWCNTs, compared to either free NT or NT-loaded naked c-MWCNTs. The IC50 values for free NT, NT-loaded c-MWCNTs and NT-loaded Bio-Chi-coated c-MWCNTs were 548.43 ± 23.1 µg mL-1, 319.55 ± 17.9 µg mL-1, and 257.75 ± 24.5 µg mL-1, respectively. Interestingly, competitive cellular uptake studies revealed that surface decoration of drug-loaded c-MWCNTs with Bio-Chi permitted an enhanced uptake of c-MWCNTs by breast cancer cells, presumably, via biotin receptors-mediated endocytosis. To sum up, Bio-Chi-decorated c-MWCNTs might be a promising delivery vehicle for mediating cell-specific drug delivery to breast cancer cells.

Anticancer potentials of metformin loaded coconut oil nanoemulsion on MCF-7, HepG2 and HCT-116 cell lines.

In order to load metformin in a nano formula and evaluate the produced nano form towards cancer cells, metformin was loaded on natural carrier coconut oil. The formed metformin-loaded coconut oil nanoemulsion was characterized by Zeta potential, particle size, drug content, drug release, and drug stability. The formed nanoemulsion was evaluated towards MCF-7, HepG2, and HCT-116 cell lines. Cell cycle analysis and apoptosis mechanism were studied. The nanoemulsion was created using deionized water, 1.5% Span 20, 1.5% Tween 80, 1.5% coconut oil, and 0.5% Metformin in an ultrasonicator to produce a homogenous solution. The anticancer activities of the metformin-loaded coconut nanoemulsion were highly improved compared to non-formulated metformin with IC50s of 8.3 ± 0.1 µg/ml, 12 ± 1.5 µg/ml, 2.685 ± 0.3 µg/ml for MCF-7, HepG2, and HCT-116 cell lines, respectively. There was a 76.5 ± 2.3 and 78.3 ± 3.2% increase in the number of apoptotic cells of MCF-7 and HepG2 cells after nanoemulsion treatment. This formula may be considered a new anticancer medication.

Ocular Delivery of Bimatoprost-Loaded Solid Lipid Nanoparticles for Effective Management of Glaucoma.

Glaucoma is a progressive optic neuropathy characterized by a rise in the intraocular pressure (IOP) leading to optic nerve damage. Bimatoprost is a prostaglandin analogue used to reduce the elevated IOP in patients with glaucoma. The currently available dosage forms for Bimatoprost suffer from relatively low ocular bioavailability. The objective of this study was to fabricate and optimize solid lipid nanoparticles (SLNs) containing Bimatoprost for ocular administration for the management of glaucoma. Bimatoprost-loaded SLNs were fabricated by solvent evaporation/ultrasonication technique. Glyceryl Monostearate (GMS) was adopted as solid lipid and poloxamer 407 as surfactant. Optimization of SLNs was conducted by central composite design. The optimized formulation was assessed for average particle size, entrapment efficiency (%), zeta potential, surface morphology, drug release study, sterility test, isotonicity test, Hen's egg test-chorioallantoic membrane (HET-CAM) test and histopathology studies. The optimized Bimatoprost-loaded SLNs formulation had an average size of 183.3 ± 13.3 nm, zeta potential of -9.96 ± 1.2 mV, and encapsulation efficiency percentage of 71.8 ± 1.1%. Transmission electron microscopy (TEM) study revealed the nearly smooth surface of formulated particles with a nano-scale size range. In addition, SLNs significantly sustained Bimatoprost release for up to 12 h, compared to free drug (p < 005). Most importantly, HET-CAM test nullified the irritancy of the formulation was verified its tolerability upon ocular use, as manifested by a significant reduction in mean irritation score, compared to positive control (1% sodium dodecyl sulfate; p < 0.001). Histopathology study inferred the absence of any signs of cornea tissue damage upon treatment with Bimatoprost optimized formulation. Collectively, it was concluded that SLNs might represent a viable vehicle for enhancing the corneal permeation and ocular bioavailability of Bimatoprost for the management of glaucoma.

Piperine-Loaded In Situ Gel: Formulation, In Vitro Characterization, and Clinical Evaluation against Periodontitis.

Periodontitis is an inflammatory disorder associated with dysbiosis and characterized by microbiologically related, host-mediated inflammation that leads to the damage of periodontal tissues including gingiva, connective tissues, and alveolar bone. The aim of this study was to develop an in situ gel consisting of piperine. Eight in situ gel formulations were designed by varying the concentration of deacylated gellan gum cross-linked with sodium tripolyphosphate, and poloxamer-407. The prepared gels were evaluated for gelation temperature, gelation time, viscosity, piperine-loading efficiency, and piperine release. Finally, the optimized formula was evaluated for anti-inflammatory effectiveness among human patients during a 14-day follow-up. The optimized in situ gel formulation exhibited a gelation temperature of 35 ± 1 °C, gelling of 36 ± 1 s, excellent syringeability, and piperine loading of 95.3 ± 2.3%. This formulation efficiently sustained in vitro drug release for up to 72 h. In vivo studies revealed an efficient sol-to-gel transformation of optimized in situ gel formulation at physiological conditions, permitting an efficient residence time of the formulation within a periodontitis pocket. Most importantly, a clinical study revealed that treatment with the optimized formulation elicited a significant reduction in the mean plaque score (p = 0.001), gingival index (p = 0.003), and pocket depth (p = 0.002), and exerted a potent anti-inflammatory potential, compared to the control group. Collectively, piperine-loaded in situ gel might represent a viable therapeutic approach for the management of gingival and periodontal diseases.

Ganetespib with Methotrexate Acts Synergistically to Impede NF-κB/p65 Signaling in Human Lung Cancer A549 Cells.

Among the various types of cancer, lung cancer accounts for the highest number of fatalities across the globe. A combination of different cancer chemotherapeutics is regarded as an effective strategy for clinical management of different cancers. Ganetespib (GAN) is a well-established hsp90 inhibitor with enhanced pharmacological properties in comparison with its first-generation counterparts. Previous preclinical studies have shown that GAN exerts significant effects against cancer cells; however, its therapeutic effects against non-small cell lung cancer (NSCLC) A549 cells, achieved by modulating the expression of the NF-κB/p65 signaling pathway, remains unexplored. In this study, the combinatorial effect of GAN and methotrexate (MTX) against lung carcinomas was investigated through both in silico and in vitro studies. A combinatorial treatment regimen of GAN/MTX exerted more significant cytotoxic effects (p < 0.001) against A549 cells than individual treatments. The GAN/MTX combination also instigated nuclear fragmentation followed by augmentation in intracellular ROS levels (p < 0.001). The elevated ROS in A549 cells upon exposure to GAN/MTX combinatorial regimen was concomitantly accompanied with a remarkable reduction in mitochondrial viability. In addition, it was observed that the GAN/MTX combination succeeded in elevating caspase-3 activity and downregulating the expression levels of anti-apoptotic mediators Bcl2 and survivin in NSCLC A549 cells. Most importantly, the GAN/MTX combinatorial regimen impeded the activation of the NF-kB/p65 signaling pathway via repression of the expression of E-cadherin and N-cadherin, which was confirmed by molecular docking studies. Collectively, these findings demonstrated the synergistic effect of the GAN/MTX combinatorial regimen in suppressing the growth of A549 cells by modulating the NF-κB/p65 signaling pathway.

In Vitro Cytotoxicity and In Vivo Antitumor Activity of Lipid Nanocapsules Loaded with Novel Pyridine Derivatives.

This study demonstrates high drug-loading of novel pyridine derivatives (S1-S4) in lipid- and polymer-based core-shell nanocapsules (LPNCs) for boosting the anticancer efficiency and alleviating toxicity of these novel pyridine derivatives. The nanocapsules were fabricated using a nanoprecipitation technique and characterized for particle size, surface morphology, and entrapment efficiency. The prepared nanocapsules exhibited a particle size ranging from 185.0 ± 17.4 to 223.0 ± 15.3 nm and a drug entrapment of >90%. The microscopic evaluation demonstrated spherical-shaped nanocapsules with distinct core-shell structures. The in vitro release study depicted a biphasic and sustained release pattern of test compounds from the nanocapsules. In addition, it was obvious from the cytotoxicity studies that the nanocapsules showed superior cytotoxicity against both MCF-7 and A549 cancer cell lines, as manifested by a significant decrease in the IC50 value compared to free test compounds. The in vivo antitumor efficacy of the optimized nanocapsule formulation (S4-loaded LPNCs) was investigated in an Ehrlich ascites carcinoma (EAC) solid tumor-bearing mice model. Interestingly, the entrapment of the test compound (S4) within LPNCs remarkably triggered superior tumor growth inhibition when compared with either free S4 or the standard anticancer drug 5-fluorouracil. Such enhanced in vivo antitumor activity was accompanied by a remarkable increase in animal life span. Furthermore, the S4-loaded LPNC formulation was tolerated well by treated animals, as evidenced by the absence of any signs of acute toxicity or alterations in biochemical markers of liver and kidney functions. Collectively, our findings clearly underscore the therapeutic potential of S4-loaded LPNCs over free S4 in conquering EAC solid tumors, presumably via granting efficient delivery of adequate concentrations of the entrapped drug to the target site.

Clinical Resistant Strains of Enterococci and Their Correlation to Reduced Susceptibility to Biocides: Phenotypic and Genotypic Analysis of Macrolides, Lincosamides, and Streptogramins.

Enterococci are troublesome nosocomial, opportunistic Gram-positive cocci bacteria showing enhanced resistance to many commonly used antibiotics. This study aims to investigate the prevalence and genetic basis of antibiotic resistance to macrolides, lincosamides, and streptogramins (MLS) in Enterococci, as well as the correlation between MLS resistance and biocide resistance. From 913 clinical isolates collected from King Khalid Hospital, Hail, Saudi Arabia, 131 isolates were identified as Enterococci spp. The susceptibility of the clinical enterococcal isolates to several MLS antibiotics was determined, and the resistance phenotype was detected by the triple disk method. The MLS-involved resistance genes were screened in the resistant isolates. The current results showed high resistance rates to MLS antibiotics, and the constitutive resistance to all MLS (cMLS) was the most prevalent phenotype, observed in 76.8% of resistant isolates. By screening the MLS resistance-encoding genes in the resistant isolates, the erythromycin ribosome methylase (erm) genes that are responsible for methylation of bacterial 23S rRNA were the most detected genes, in particular, ermB. The ereA esterase-encoding gene was the most detected MLS modifying-encoding genes, more than lnuA (adenylation) and mphC (phosphorylation). The minimum inhibitory concentrations (MICs) of commonly used biocides were detected in resistant isolates and correlated with the MICs of MLS antibiotics. The present findings showed a significant correlation between MLS resistance and reduced susceptibility to biocides. In compliance with the high incidence of the efflux-encoding genes, especially mefA and mefE genes in the tolerant isolates with higher MICs to both MLS antibiotics and biocides, the efflux of resistant isolates was quantified, and there was a significant increase in the efflux of resistant isolates with higher MICs as compared to those with lower MICs. This could explain the crucial role of efflux in developing cross-resistance to both MLS antibiotics and biocides.

Development and Characterization of Pullulan-Based Orodispersible Films of Iron.

Iron deficiency is the principal cause of nutritional anemia and it constitutes a major health problem, especially during pregnancy. Despite the availability of various non-invasive traditional oral dosage forms such as tablets, capsules, and liquid preparations of iron, they are hard to consume for special populations such as pregnant women, pediatric, and geriatric patients with dysphagia and vomiting tendency. The objective of the present study was to develop and characterize pullulan-based iron-loaded orodispersible films (i-ODFs). Microparticles of iron were formulated by a microencapsulation technique, to mask the bitter taste of iron, and ODFs were fabricated by a modified solvent casting method. Morphological characteristics of the microparticles were identified by optical microscopy and the percentage of iron loading was evaluated by inductively coupled plasma optical emission spectroscopy (ICP-OES). The fabricated i-ODFs were evaluated for their morphology by scanning electron microscopy. Other parameters including thickness, folding endurance, tensile strength, weight variation, disintegration time, percentage moisture loss, surface pH, and in vivo animal safety were evaluated. Lastly, stability studies were carried out at a temperature of 25 °C/60% RH. The results of the study confirmed that pullulan-based i-ODFs had good physicochemical properties, excellent disintegration time, and optimal stability at specified storage conditions. Most importantly, the i-ODFs were free from irritation when administered to the tongue as confirmed by the hamster cheek pouch model and surface pH determination. Collectively, the present study suggests that the film-forming agent, pullulan, could be successfully employed on a lab scale to formulate orodispersible films of iron. In addition, i-ODFs can be processed easily on a large scale for commercial use.

Nano-Conversion of Ineffective Cephalosporins into Potent One against Resistant Clinical Uro-Pathogens via Gold Nanoparticles.

Infections caused by resistant bacterial pathogens have increased the complications of clinicians worldwide. The quest for effective antibacterial agents against resistant pathogens has prompted researchers to develop new classes of antibiotics. Unfortunately, pathogens have acted more smartly by developing resistance to even the newest class of antibiotics with time. The culture sensitivity analysis of the clinical samples revealed that pathogens are gaining resistance toward the new generations of cephalosporins at a very fast rate globally. The current study developed gold nanoparticles (AuNPs) that could efficiently deliver the 2nd (cefotetan-CT) and 3rd (cefixime-CX) generation cephalosporins to resistant clinical pathogens. In fact, both CT and CX were used to reduce and stabilize AuNPs by applying a one-pot synthesis approach, and their characterization was performed via spectrophotometry, dynamic light scattering and electron microscopy. Moreover, the synthesized AuNPs were tested against uro-pathogenic resistant clinical strains of Escherichia coli and Klebsiella pneumoniae. CT-AuNPs characteristic SPR peak was observed at 542 nm, and CX-AuNPs showed the same at 522 nm. The stability measurement showed ζ potential as -24.9 mV and -25.2 mV for CT-AuNPs and CX-AuNPs, respectively. Scanning electron microscopy revealed the spherical shape of both the AuNPs, whereas, the size by transmission electron microscopy for CT-AuNPs and CX-AuNPs were estimated to be 45 ± 19 nm and 35 ± 17 nm, respectively. Importantly, once loaded onto AuNPs, both the cephalosporin antibiotics become extremely potent against the resistant strains of E. coli and K. pneumoniae with MIC50 in the range of 0.5 to 0.8 µg/mL. The findings propose that old-generation unresponsive antibiotics could be revived into potent nano-antibiotics via AuNPs. Thus, investing efforts, intellect, time and funds for a nano-antibiotic strategy might be a better approach to overcome resistance than investing the same in the development of newer antibiotic molecule(s).

Tailoring of Novel Bile Salt Stabilized Vesicles for Enhanced Transdermal Delivery of Simvastatin: A New Therapeutic Approach against Inflammation.

Simvastatin (SMV), a cholesterol-lowering agent, has antioxidant and anti-inflammatory effects. Nevertheless, the oral use of SMV is linked with poor systemic bioavailability owing to its limited aqueous solubility and extensive first-pass metabolism. The aim of this study was to evaluate the feasibility of transdermal delivery of SMV using bile salt stabilized vesicles (bilosomes) for enhancing the anti-inflammatory potential of SMV. SMV-loaded bilosomes (SMV-BS) were prepared by the thin film hydration technique and optimized by 33 Box-Behnken design. The fabricated SMV-BS were assessed for vesicle size, entrapment efficiency (% EE) and cumulative drug release. The optimized formula was incorporated into HPMC gel and investigated for physical properties, ex vivo permeation, in vivo pharmacokinetic study and anti-inflammatory potential in inflamed paw edema rat model. The optimized SMV-BS showed vesicle size of 172.1 ± 8.1 nm and % EE of 89.2 ± 1.8%. In addition, encapsulating SMV within bilosomal vesicles remarkably sustained drug release over 12 h, compared to plain drug suspension. Furthermore, SMV-loaded bilosomal gel showed a three-fold enhancement in SMV transdermal flux, compared to plain drug suspension. Most importantly, the relative bioavailability of SMV-BS gel was ~2-fold and ~3-fold higher than those of oral SMV suspension and SMV gel, respectively. In carrageenan-induced paw edema model, SMV-BS gel induced a potent anti-inflammatory effect, as evidenced by a remarkable reduction in paw edema, which was comparable to that of the standard anti-inflammatory drug, indomethacin. Collectively, bilosomes might represent a plausible transdermal drug delivery system that could enhance the anti-inflammatory activity of SMV by boosting its skin permeation and its systemic bioavailability.

Biosynthesis of Silver Nanoparticles Using Commiphora mukul Extract: Evaluation of Anti-Arthritic Activity in Adjuvant-Induced Arthritis Rat Model.

Rheumatoid arthritis (RA) is a major global public health challenge, and novel therapies are required to combat it. Silver nanoparticles (AgNPs) have been employed as delivery vehicles of anti-inflammatory drugs for RA therapy, and it has been recently realized that AgNPs have anti-inflammatory action on their own. However, their conventional synthesis processes might result in cytotoxicity and environmental hazards. Instead, the use of natural products as a reducing and stabilizing agent in the biosynthesis of silver nanoparticles has arisen as an option to decrease the cytotoxic and environmental concerns associated with chemical synthesis of AgNPs. In this study, we challenged the efficacy of Commiphora mukul (guggul) aqueous extract as a reducing and/or capping agent for the biosynthesis of AgNPs. Guggul-mediated biosynthesized silver nanoparticles (G-AgNPs) were characterized via UV-vis spectroscopy, dynamic light scattering, and scanning electron microscopy. In addition, their anti-arthritic potential was evaluated in an adjuvant-induced arthritis (AIA) model. The fabricated NPs showed an absorption peak at 412 nm, corresponding to the typical surface plasmon resonance band of AgNPs. The synthesized G-AgNPs were nearly spherical, with a particle size of 337.6 ± 12.1 nm and a negative surface charge (−18.9 ± 1.8 mV). In AIA rat model, synthesized G-AgNPs exerted a potent anti-inflammatory action, as manifested by a remarkable reduction in paw volume (>40%) along with elicitation of a minimal arthritic score, compared to control rats. In addition, when compared to arthritic rats, treatment with G-AgNPs efficiently restored the activity of antioxidant enzyme, superoxide dismutase, and catalase, indicating the efficiency of synthesized G-AgNPs in alleviating the oxidative stress associated with RA. Finally, histological examination revealed comparatively lower inflammatory cells infiltration in ankle joint tissue upon treatment with G-AgNPs. Collectively, biosynthesized G-AgNPs might represent a plausible therapeutic option for the management of RA.

Vardenafil-Loaded Bilosomal Mucoadhesive Sponge for Buccal Delivery: Optimization, Characterization, and In Vivo Evaluation.

Vardenafil (VDF) is a relatively new phosphodiesterase-5 inhibitor that has limited oral bioavailability (≈15%). The objective of this study was to develop bilosome-based mucoadhesive buccal sponge for augmenting the oral bioavailability of VDF. VDF-loaded bilosomes were fabricated and optimized using a Box-Behnken design. The optimized VDF-loaded bilosomal formulation was assessed for surface morphology, particle size, thermal characteristics, and in vitro release. Afterwards, the optimized bilosomal formulation was incorporated into a cellulose-based matrix to obtain buccal sponge, which was evaluated for ex vivo permeation studies, in vivo oral bioavailability, and in vivo serum concentration of cyclic guanosine monophosphate (cGMP). The mean particle size and entrapment efficiency (%) of optimized bilosome formulation were 282.6 ± 9.5 nm and 82.95 ± 3.5%, respectively. In vitro release studies at pH 6.8 emphasized the potential of optimized bilosomal formulation to sustain VDF release for 12 h. Ex vivo permeation study using sheep buccal mucosa indicated significant enhancement in penetration of VDF from bilosomal buccal sponge compared to plain VDF gel. Pharmacokinetic study in Albino rats showed ~5 fold increase in relative bioavailability with bilosomal buccal sponge, compared to VDF suspension. In addition, VDF-loaded bilosomal buccal sponge triggered higher serum levels of cGMP, a biomarker of VDF in vivo efficacy, compared to oral VDF suspension. To sum up, bilosomes might represent a potential nanocarrier for buccal delivery of VDF, enhancing its oral bioavailability and therapeutic efficacy.

Delafloxacin-Capped Gold Nanoparticles (DFX-AuNPs): An Effective Antibacterial Nano-Formulation of Fluoroquinolone Antibiotic.

New antibiotics are seen as 'drugs of last resort' against virulent bacteria. However, development of resistance towards new antibiotics with time is a universal fact. Delafloxacin (DFX) is a new fluoroquinolone antibiotic that differs from existing fluoroquinolones by the lack of a protonatable substituent, which gives the molecule a weakly acidic nature, affording it higher antibacterial activity under an acidic environment. Furthermore, antibiotic-functionalized metallic nanoparticles have been recently emerged as a feasible platform for conquering bacterial resistance. In the present study, therefore, we aimed at preparing DFX-gold nano-formulations to increase the antibacterial potential of DFX. To synthesize DFX-capped gold nanoparticles (DFX-AuNPs), DFX was used as a reducing and stabilizing/encapsulating agent. Various analytical techniques such as UV-visible spectroscopy, TEM, DLS, FTIR and zeta potential analysis were applied to determine the properties of the synthesized DFX-AuNPs. The synthesized DFX-AuNPs revealed a distinct surface plasmon resonance (SPR) band at 530 nm and an average size of 16 nm as manifested by TEM analysis. In addition, Zeta potential results (-19 mV) confirmed the stability of the synthesized DFX-AuNPs. Furthermore, FTIR analysis demonstrated that DFX was adsorbed onto the surface of AuNPs via strong interaction between AuNPs and DFX. Most importantly, comparative antibacterial analysis of DFX alone and DFX-AuNPs against Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus and Bacillus subtilis) verified the superior antibacterial activity of DFX-AuNPs against the tested microorganisms. To sum up, DFX gold nano-formulations can offer a promising possible solution, even at a lower antibiotic dose, to combat pathogenic bacteria.

Phytosomes as a Plausible Nano-Delivery System for Enhanced Oral Bioavailability and Improved Hepatoprotective Activity of Silymarin.

Silymarin, a phyto-constituent derived from the plant Silybum marianum, has been widely acknowledged for its hepatoprotective activities. Nevertheless, its clinical utility is adversely hampered by its poor water-solubility and its limited oral bioavailability. The aim of this study was to investigate the efficacy of phospholipid-based phytosomes for enhancing the oral bioavailability of silymarin. The phytosomes were prepared using the solvent evaporation technique and were optimized using a full factorial design. The optimized silymarin phytosomal formulation was then characterized for particle size, surface morphology, aqueous solubility, and in vitro drug release. Furthermore, in vivo antioxidant activity, hepatoprotective activity and oral bioavailability of the optimized formula were investigated in a rat model. The prepared silymarin phytosomes were discrete particles with a porous, nearly smooth surface and were 218.4 ± 2.54 nm in diameter. In addition, the optimized silymarin phytosomal formulation showed a significant improvement in aqueous solubility (~360 µg/mL) compared to pure silymarin and manifested a higher rate and extent of silymarin release from the optimized formula in dissolution studies. The in vivo assessment studies revealed that the optimized silymarin phytosomal formulation efficiently exerted a hepatoprotective effect in a CCl4-induced hepatotoxicity rat model via restoring the normal levels of antioxidant enzymes and ameliorating cellular abnormalities caused by CCl4-intoxication. Most notably, as compared to pure silymarin, the optimized silymarin phytosomal formulation significantly improved silymarin oral bioavailability, as indicated by a 6-fold increase in the systemic bioavailability. Collectively, phytosomes might represent a plausible phospholipid-based nanocarrier for improving the oral bioavailability of phyto-constituents with poor aqueous solubility.

Inflammation targeted nanomedicines: Patents and applications in cancer therapy.

Evident role of inflammation in cancer development and progression prompted the application of anti-inflammatory medications as a therapeutic strategy. The major bottleneck for the anti-inflammatory drugs is targeted delivery to the cancerous cell. Nanotechnology has provided safe and effective way for targeted cancer therapy. However, the complex and heterogeneous traits of cancer, incomplete information on fate and behavior of nanomedicines in human body, and lack of large-scale commercial production have slowed down the pace of nanomedicines development. To shift the paradigm from conventional cancer therapeutics to anti-inflammatory nano-therapeutics, thorough understanding of the strategies, progress, success, challenges and future perspectives are needed. The present review highlights all these aspects in addition to innovations patented on them. In fact, patent plays a vital role in protection of innovations, and further translation of lab-scale outcomes into bedside medications. Thus, the review introspects and recognizes the glitches in successful clinical translation of anti-inflammatory nanomedicines.

Poly ε-Caprolactone Nanoparticles for Sustained Intra-Articular Immune Modulation in Adjuvant-Induced Arthritis Rodent Model.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder with synovitis and articular pathology as its primary expositions. Leflunomide (Lfd) is an anti-rheumatic drug that is effective in the treatment of RA, but displays severe side effects upon prolonged systemic administration. Local therapy might represent a promising strategy to treat rheumatoid arthritis without eliciting systemic adverse effects. In this study, leflunomide-loaded poly(ε-caprolactone) nanoparticles (Lfd-NPs) were prepared and assessed as a local drug delivery system capable of alleviating RA-associated inflammation. Lfd-NPs were optimized using the Quality by Design (QbD) approach, applying a 32 full factorial design. In vitro drug release from NPs was examined in simulated synovial fluid. In addition, the in vivo efficacy of Lfd-NPs was evaluated in the Adjuvant Induced Arthritis (AIA) rodent model. Sustained drug release in simulated synovial fluid was observed for up to 168 h. A gradual reduction in paw volume and knee diameter was observed over the course of treatment, indicating the regression of the disease. In addition, significant reductions in serum proinflammatory markers and cytokines, including the C-reactive protein (CRP), rheumatoid factor (RF), TNF-α, IL1-ß, and IL-6, were verified upon treatment with Lfd-NPs, suggesting the modulation of immune responses at the pathological site. Most importantly, no remarkable signs of toxicity were observed in Lfd-NP-treated animals. Collectively, intra-articularly administered Lfd-NPs might represent a potential therapeutic alternative to systemically administered drugs for the treatment of rheumatoid arthritis, without eliciting systemic adverse effects.

Cefotaxime Mediated Synthesis of Gold Nanoparticles: Characterization and Antibacterial Activity.

Cefotaxime (CTX) is a third-generation cephalosporin antibiotic with broad-spectrum activity against Gram negative and Gram positive bacteria. However, like other third-generation cephalosporin antibiotics, its efficacy is declining due to the increased prevalence of multidrug-resistant (MDR) pathogens. Recent advances in nanotechnology have been projected as a practical approach to combat MDR microorganisms. Therefore, in the current study, gold nanoparticles (AuNPs) were prepared using cefotaxime sodium, which acted as a reducing and capping agent, besides having well-established antibacterial activity. The synthesized cefotaxime-loaded gold nanoparticles (C-AuNPs) were characterized by UV-Visible spectroscopy, FTIR, TEM and DLS. In addition, the in vitro antibacterial activity of C-AuNPs was assessed against both Gram-positive and Gram-negative bacteria. UV-Visible spectroscopy verified the formation of C-AuNPs, while TEM and DLS verified their nano-size. In addition, CTX loading onto AuNPs was confirmed by FTIR. Furthermore, the colloidal stability of the synthesized C-AuNPs was ascribed to the higher net negative surface charge of C-AuNPs. Most importantly, the synthesized C-AuNPs showed superior antibacterial activity and lower minimum inhibitory concentration (MIC) values against Gram-negative (Escherichia coli, Klebsiella oxytoca, Pseudomonas aeruginosa) and gram-positive (Staphylococcus aureus) bacteria, compared with pure CTX. Collectively, CTX was successfully adopted, as reducing and capping agent, to synthesize stable, nano-sized spherical C-AuNPs. Furthermore, loading CTX onto AuNPs could efficiently restore and/or boost the antibacterial activity of CTX against resistant Gram-negative and Gram-positive bacteria.