During the past few decades, the novel biotherapeutic agents such as peptides and proteins have been contributed to the treatment of several diseases. However, their oral absorption is significantly ...limited due to their poor delivery through the intestinal mucosa. Therefore, the feasible approaches are needed for improving the oral bioavailability of biodrugs. Recently, cell-penetrating peptides (CPPs) such as HIV-1 Tat, penetratin and oligoarginine are considered as a useful tool for the intracellular delivery of therapeutic macromolecules. Hence, it was expected that the ability of CPPs may be applicable to enhance the absorption of biodrugs through intestinal epithelial membrane. CPPs are likely to become powerful tools for overcoming the low permeability of therapeutic peptides and proteins through the intestinal membrane, the major barrier to their oral delivery. Further advantage of this promising strategy is that this successful intestinal absorption could be achieved by more convenient methodology, coadministration of CPP with drugs via intermolecular interaction among them. Hereafter, the further establishment of delivery system based on CPPs is required to realize the development of the oral forms of therapeutic peptides and proteins. The aim here is to introduce our vision focusing on oral biodrug delivery by the use of CPPs as potential peptide carrier in order to provide new information in the design and development of new oral delivery systems for novel biotherapeutics.
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In previous studies we showed that the complexation hydrogels based in poly(methacrylic acid-g-ethylene glycol) P(MAA-g-EG) rapidly release insulin in the intestine owing to their pH-dependent ...complexation properties; they also exhibit a high insulin-loading efficiency, enzyme-inhibiting properties, and mucoadhesive characteristics. Cell-penetrating peptides (CPPs), such as oligoarginines hexa-arginine (R6), comprising six arginine residues, have been employed as useful tools for the oral delivery of therapeutic macromolecules. The aim of our study was to investigate the combination strategy of using P(MAA-g-EG) hydrogels with R6-based CPPs to improve the intestinal absorption of insulin. A high efficiency of loading into crosslinked P(MAA-g-EG) hydrogels was observed for insulin (96.1±1.4%) and R6 (46.6±3.8%). In addition, immediate release of the loaded insulin and R6 from these hydrogels was observed at pH 7.4 (80% was released in approximately 30 min). Consequently, a strong hypoglycemic response was observed (approximately 18% reduction in blood glucose levels) accompanied by an improvement in insulin absorption after the co-administration of insulin-loaded particles (ILP) and R6-loaded particles (ALP) into closed rat ileal segments compared with that after ILP administration alone. These results indicate that the combination of P(MAA-g-EG) hydrogels with CPPs may be a promising strategy for the oral delivery of various insulin preparations as an alternative to conventional parenteral routes.
The development of bacterial resistance to antibiotics is an increasing public health issue that worsens with the formation of biofilms. Quorum sensing (QS) orchestrates the bacterial virulence and ...controls the formation of biofilm. Targeting bacterial virulence is promising approach to overcome the resistance increment to antibiotics. In a previous detailed in silico study, the anti-QS activities of twenty-two β-adrenoreceptor blockers were screened supposing atenolol as a promising candidate. The current study aims to evaluate the anti-QS, anti-biofilm and anti-virulence activities of the β-adrenoreceptor blocker atenolol against Gram-negative bacteria Serratia marcescens, Pseudomonas aeruginosa, and Proteus mirabilis. An in silico study was conducted to evaluate the binding affinity of atenolol to S. marcescens SmaR QS receptor, P. aeruginosa QscR QS receptor, and P. mirabilis MrpH adhesin. The atenolol anti-virulence activity was evaluated against the tested strains in vitro and in vivo. The present finding shows considerable ability of atenolol to compete with QS proteins and significantly downregulated the expression of QS- and virulence-encoding genes. Atenolol showed significant reduction in the tested bacterial biofilm formation, virulence enzyme production, and motility. Furthermore, atenolol significantly diminished the bacterial capacity for killing and protected mice. In conclusion, atenolol has potential anti-QS and anti-virulence activities against S. marcescens, P. aeruginosa, and P. mirabilis and can be used as an adjuvant in treatment of aggressive bacterial infections.
Silk fibroin (SF) is a natural polymeric biomaterial that is widely adopted for the preparation of drug delivery systems. Herein, we aimed to fabricate and characterize SF nanoparticles loaded with ...the selective estrogen receptor modulator; tamoxifen citrate (TC-SF-NPs) and to assess their in vitro efficacy against breast cancer cell lines (MCF-7 and MDA-MB-231). TC-loaded SF-NPs were characterized for particle size, morphology, entrapment efficiency, and release profile. In addition, we examined the in vitro cytotoxicity of TC-SF-NPs against human breast cancer cell lines and evaluated the anticancer potential of TC-SF-NPs through apoptosis assay and cell cycle analysis. Drug-loaded SF-NPs showed an average particle size of 186.1 ± 5.9 nm and entrapment efficiency of 79.08%. Scanning electron microscopy (SEM) showed the nanoparticles had a spherical morphology with smooth surface. Tamoxifen release from SF-NPs exhibited a biphasic release profile with an initial burst release within the first 6 h and sustained release for 48 h. TC-SF-NPs exerted a dose-dependent cytotoxic effect against breast cancer cell lines. In addition, flow cytometry analysis revealed that cells accumulate in G
0
/G
1
phase, with a concomitant reduction of S- and G
2
-M-phase cells upon treatment with TC-SF-NPs. Consequently, the potent anticancer activities of TC-SF-NPs against breast cancer cells were mainly attributed to the induction of apoptosis and cell cycle arrest. Our results indicate that SF nanoparticles may represent an attractive nontoxic nanocarrier for the delivery of anticancer drugs.
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 3
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.
Alveolar macrophages are the first line of defense against intruding pathogens and play a critical role in cancer immunology. The Toll-like receptor (TLR) family mediates an important role in ...recognizing and mounting an immune response against intruding microbes. TLR-9 is a member of the intracellular TLR family, which recognizes unmethylated CG motifs from the prokaryotic genome. Upon its activation, TLR-9 triggers downstream of the MyD-88-dependent transcriptional activation of NF-κB, and subsequently results in abundant inflammatory cytokines expression that induces a profound inflammatory milieu. The present exploratory investigation aimed at elucidating the potency of schizophyllan for entrapping ODN 1826 (SPG-ODN 1826)-mediated stimulation of TLR-9 in provoking an inflammatory-type response in murine alveolar macrophages. Schizophyllan (SPG), a representative of the β-glucan family, was used in the present study as a nanovehicle for endosomal trafficking of CpG ODN 1826. TEM analysis of SPG-ODN 1826 nanovehicles revealed that the prepared nanovehicles are spherical and have an average size of about 100 nm. Interestingly, SPG-ODN 1826 nanovehicles were competent in delivering their therapeutic payload within endosomes of murine alveolar macrophage (J774A.1) cells. Exposure of these nanovehicles within LPS stimulated J774A.1, resulted in a significant provocation of reactive oxygen species (ROS) (p < 0.01) in comparison to CpG ODN 1826 alone. Moreover, the formulated nanovehicles succeeded in generating a profound Th1-based cytokine profile constituted by enhanced expression of IFN-γ (p < 0.001) and IL-1β (p < 0.001) inflammatory cytokines. These findings clearly indicated the immunostimulatory potential of SPG-ODN 1826 nanovehicles for inducing the Th1-type phenotype, which would certainly assist in skewing M2 phenotype into the much-desired M1 type during lung cancer.
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 (
,
,
) and gram-positive (
) 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.
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.
The remarkable rise of antibiotic resistance among pathogenic bacteria poses a significant threat to human health. Nanoparticles (NPs) have recently emerged as novel strategies for conquering fatal ...bacterial diseases. Furthermore, antibiotic-functionalized metallic NPs represent a viable nano-platform for combating bacterial resistance. In this study, we present the use of vancomycin-functionalized gold nanoparticles (V-GNPs) to battle pathogenic bacterial strains. A facile one-pot method was adopted to synthesize vancomycin-loaded GNPs in which the reducing properties of vancomycin were exploited to produce V-GNPs from gold ions. UV-Visible spectroscopy verified the production of V-GNPs via the existence of a surface plasmon resonance peak at 524 nm, whereas transmission electron microscopy depicted a size of ~24 nm. Further, dynamic light scattering (DLS) estimated the hydrodynamic diameter as 77 nm. The stability of V-GNPs was investigated using zeta-potential measurements, and the zeta potential of V-GNPs was found to be -18 mV. Fourier transform infrared spectroscopy confirmed the efficient loading of vancomycin onto GNP surfaces; however, the loading efficiency of vancomycin onto V-GNPs was 86.2%. Finally, in vitro antibacterial studies revealed that V-GNPs were much more effective, even at lower concentrations, than pure vancomycin. The observed antibacterial activities of V-GNPs were 1.4-, 1.6-, 1.8-, and 1.6-fold higher against Gram-negative
,
, and
and Gram-positive
, respectively, compared to pure vancomycin. Collectively, V-GNPs represented a more viable alternative to pure vancomycin, even at a lower antibiotic dose, in conquering pathogenic bacteria.
The polar fractions of the
species are rich in bioflavonoid contents. Phytochemical study of the polar fraction of
aerial parts resulted in the isolation of cupressuflavone (CPF) as the major ...component in addition to another two bioflavonoids, amentoflavone and robustaflavone. Biflavonoids have various biological activities, such as antioxidant, anti-inflammatory, antibacterial, antiviral, hypoglycemic, neuroprotective, and antipsychotic effects. Previous studies have shown that the metabolism and elimination of biflavonoids in rats are fast, and their oral bioavailability is very low. One of the methods to improve the bioavailability of drugs is to alter the route of administration. Recently, nose-to-brain drug delivery has emerged as a reliable method to bypass the blood-brain barrier and treat neurological disorders. To find the most effective CPF formulation for reaching the brain, three different CPF formulations (A, B and C) were prepared as self-emulsifying drug delivery systems (SEDDS). The formulations were administered via the intranasal (IN) route and their effect on the spontaneous motor activity in addition to motor coordination and balance of rats was observed using the activity cage and rotarod, respectively. Moreover, pharmacokinetic investigation was used to determine the blood concentrations of the best formulation after 12 h. of the IN dose. The results showed that formulations B and C, but not A, decreased the locomotor activity and balance of rats. Formula C at IN dose of 5 mg/kg expressed the strongest effect on the tested animals.
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