Pharmaceutical Sciences
Volume:28 Issue: 3, Jul 2022

Active targeting strategy in chemotherapy drug delivery aims to improve the therapeutic outcomes and minimize the side effects of chemotherapeutics. This review discusses utilizing ligands attached to gold nanoparticles (AuNPs) along with several specific ligands attached to AuNPs for active targeting in chemotherapy drug delivery. Antibodies, peptides, vitamins, DNA, polysaccharides, aptamers, and hormones showed active-targeting abilities as ligands attached to AuNPs. Active-targeting AuNPs enhanced cellular uptake and cytotoxicity in a specific cancer cell in vitro while reducing tumor growth in vivo by improving the photothermal, photodynamic and chemotherapy effects. Active-targeting ligands increased the internalization of AuNPs loaded onto the specific tumor site and minimized the accumulation in the normal site. AuNPs with active-targeting ligands such as antibodies, peptides, vitamins, DNA polysaccharides, aptamers, and hormones can improve the therapeutic outcomes of chemotherapeutics and can attenuate the toxicity effect in normal cells. For further research and development, researchers should be addressing AuNP characterization, drug–ligand disposition, active-targeting AuNP quantification, and target-AuNPs pertinence concerning the desired therapeutic outcomes.

Melissa officinalis (M. officinalis) is an herbal-based plant from the family of Lamiaceae and native to Europe and the Mediterranean region, widely used to cure various cancers. Phytochemical investigations proved different compounds such as polyphenolic compounds, flavonoids, and essential oil in the stem and leaves of M. officinalis as main ingredients contributing to different antitumor activity, including antiproliferation and antioxidant antiangiogenetic, antimigratory, antiapoptotic, and change in cell cycle profile of cancer cells. Herbal formulations with colorful ingredients use several types of these mentioned biological processes to display synergistic cancer treatment activities. M. officinalis extracts a wide range from water to ethanol using varied mechanisms to reduce the viability of cancer cells. Hence, scientists are currently interested in evaluating these extracts based on the medical plant to minimize the adverse effects of conventional anti-cancer drugs and discover these mechanisms to pave the way for future studies. This review aimed to discuss the recent studies that M. officinalis have used as an anti-cancer agent to investigate its potential effect on several types of cancer. Therefore, after a short introduction of M. officinalis, we will explain the several biological processes by which M. officinalis exert an anti-cancer effect.

As of recent, the appearance rate of several degenerative diseases and cancer influenced by oxidative stress continues to increase dramatically. Many compounds with high potential antioxidant activity have been explored and used extensively, i.e., as preventive or curative treatments. Stilbene and its derivates have high potential antioxidant activity contained in several botanical sources. To date, source exploration and antioxidant activity study of stilbene derivate has been reported. However, the nano-delivery of stilbene derivate meant to increase the antioxidant activity and stability is still a limited process. This review is devoted to brief and recent outlooks regarding the antioxidant activity and delivery system of the most frequently applied stilbene and its derivates, namely resveratrol and pterostilbene.

MicroRNAs (miRNAs) are known as a group of short noncoding ribonucleic acids (ncRNAs). Mainly, they can manage gene expression at the posttranscriptional level in the essential biological and physiological functions. Significantly, more than 50% of the discovered miRNAs genes are placed in cancer‐related genomic regions, which can act as oncomiR or oncosuppressor. In this regard, growing evidence recently demonstrated the deregulation of miR-4800 in human cancers and non-cancerous diseases. However, little information is available on the biological roles of miR-4800 in cancer initiation, development, and progression. Here, we reviewed the targeting sites and biogenesis functions of the miR‐4800 family in physiological and pathological processes like human cancers, particularly with a particular focusing on the validated specific targets.

Evidence suggests that dysregulation in AMPA-type glutamate receptors (AMPA-Rs) has been associated with the pathogenesis of Alzheimer’s disease (AD), especially during its early phase. Hence, the present study was performed to elucidate the impact of resveratrol (RV) on hippocampal expression of AMPA-Rs in a rat model of AD.

A rat model of cognitive deficits was developed by a stereotactic intracerebroventricular infusion of lipopolysaccharide (LPS) in male Wistar rats (n=24). The LPS+RV30 group (n=12) received intraperitoneal injections of RV (30 mg/kg) at 30 min, 12 h, and 24 h before LPS injection. Meanwhile, the model (LPS) and sham (SO) groups only were treated with the vehicle solution (normal saline containing 1% ethanol). One day after the LPS infusion, the mRNA expressions of AMPA-Rs subunits (Gria1-4) were evaluated by RT–PCR. In addition, hippocampal levels of lipid peroxidation, superoxide dismutase, and nitric oxide were assessed. Seven days after the LPS challenge, the remaining animals (n=6, each group) were subjected to the Y-maze task, and the expression and localization of GluA1-containing AMPA-Rs in their hippocampi were investigated immunohistochemically.

Pretreatment with RV prevented LPS-induced cognitive dysfunction in rats and enhanced their working memory performance. Moreover, RV could moderately prevent oxidant-antioxidant imbalance in rats’ hippocampi. RT-PCR results revealed that the hippocampal mRNA expression of the Gria1 was significantly reduced, while the expressions of Gria2 and Gria3 were increased in LPS-challenged rats. RV significantly modulated the alteration in the Gria1 mRNA expression; however, it could not influence the Gria2 and Gria3 mRNA expressions. The immunohistochemical assessment showed a significantly reduced immunoreactivity for GluA1- containing AMPA-Rs in all hippocampal subfields of the LPS group, and RV could effectively ameliorate the alteration.

This study is the first to report that RV could modulate GluA1-containing AMPA-Rs dysregulation in a rat AD model.

EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), as one of the polycyclic group proteins (PcGs), is an epigenetic regulator that plays a crucial role in the pathophysiology of hematologic malignancies through regulating cell differentiation. Also, it is well known that aberrant expression of specific transcription factors can be involved in the pathogenesis of various cancers. Herein, we aimed to suppress EZH2 expression in MOLT-4 cells, T-ALL (T cell acute lymphoblastic leukemia) cell line, and evaluate the role of EZH2 on the expression of transcription factors that regulate T cell maturation, differentiation, and apoptosis.

EZH2-siRNA was transfected into MOLT-4 cells, and the expression levels of EZH2, NOTCH1, TCF1, IKZF1, and NFATC1 were measured using real-time PCR. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was performed to study the effect of EZH2 knockdown on MOLT-4 cell viability. The apoptosis rate of EZH2-siRNA transfected cells was assessed by flow cytometry. The interaction of mentioned genes was investigated using STRING and GO (gene ontology).

Our results have shown that EZH2-siRNA transfection can substantially decrease EZH2 expression in MOLT-4 cells. Besides, EZH2 suppression can upregulate NOTCH1, TCF1, IKZF1, and NFATC1 expression levels. EZH2 knockdown does not affect the viability and apoptosis of MOLT-4 cells. The most remarkable protein-protein interaction of EZH2 has been with NOTCH1. Besides, GO analysis has demonstrated that EZH2, NOTCH1, TCF1, IKZF1, and NFATC1 were located within nucleoplasm and can regulate RNA polymerase II-mediated transcription.

MOLT-4 cells harbor increased expression of EZH2 in comparison with normal human T cells. EZH2 knockdown can upregulate the expression of the transcription factors involved in T cell differentiation. Thus, EZH2 can halt the differentiation of immature lymphoblastic T cells.

Fibroblast growth factors (FGFs) are involved in angiogenesis, wound healing and embryonic development. However, one of the causes of cancer cell growth in fibroblast-dependent cancers is FGF7 secreted by fibroblasts. Therefore, antibodies against FGF7 can be used for the treatment of these types of cancers.

In the previous studies, a phage displaying single domain antibody, D53, against human FGF7 has been identified using the phage display technique. In the present study, D53 was produced and purified in its isolated form. ELISA experiment was performed to evaluate the binding of D53 to FGF7. The mode of interaction of D53-FGF7 was explored using docking study and molecular dynamics (MD) simulations.

The expression and purification processes were verified using western blotting and SDS-PAGE analyses. ELISA experiment showed that D53 is able to recognize and bind FGF7. Docking study and MD simulations indicated that compared to dummy VH, D53 has more affinity towards FGF7.

The findings in the current study can be useful for the generation and the development of FGF7 inhibitors with a potential use in fibroblast-dependent cancers.

Thiolated hyaluronic acid (HA) with interesting properties, such as muco-adhesiveness, enzyme inhibitory, permeation enhancing, and release controlling properties can be applied for drug delivery in various diseases like mucositis. The purpose of this study was to evaluate the stability and toxicity of thiol modified HA by the aid of L-cysteine ethyl ester hydrochloride (Cys) named (HA-Cys) and allantoin (Alla) incorporated HA-Cys (HA-Cys-Alla) to reveal their potential for the future treatment of mucositis.

The HA modification and drug incorporation were investigated using FTIR spectroscopy. The evaluation of in vitro cytotoxicity on Caco-2 cell line by means of MTT assay and in vivo toxicity by measuring the hematological and biochemical parameters in rats were performed. The appearance stability of HA-Cys and HA-Cys-Alla was evaluated at room and refrigerator temperatures over time. In addition, the stability of HA-Cys and HA-Cys-Alla subjected to heating and cooling, freeze-thaw, centrifugal forces, as well as the pH stability under the above-mentioned conditions were also investigated.

The results indicated that the synthesized HA-Cys and HA-Cys-Alla with pseudo-plastic rheological behavior demonstrated excellent stability at refrigerator temperature. Although HA-Cys showed good stability, the HA-Cys-Alla revealed color change at room temperature. Moreover, despite no much resistance of HA-Cys and HA-Cys-Alla against the heating-cooling test, the samples exhibited good resistance against freeze-thaw and centrifugal forces. Also, convenient pH stability and high in vitro and in vivo biocompatibility were observed.

The low in vitro and in vivo toxicity and convenient stability of HA-Cys-Alla has introduced it as a proper candidate for future clinical applications.

In the setting of impaired liver function, estimation of glomerular filtration rate (GFR) using common creatinine-based equations is inaccurate. Recently, the Glomerular filtration Rate Assessment In Liver disease (GRAIL) model has been introduced to estimate GFR in liver transplantation. This study was conducted to compare vancomycin dose adjustment in liver transplant patients using Cockcroft-Gault (C-G) versus the GRAIL method.

In this pilot, randomized clinical trial, adult liver transplant recipients who were a candidate to receive intravenous vancomycin were enrolled. The level of kidney function was estimated using the GRAIL model and C-G equation in the intervention and control arms, respectively. Then, vancomycin maintenance doses were accordingly adjusted. At the steady state, peak and trough serum concentrations of vancomycin were collected for area under the concentration-time curve (AUC) calculation and pharmacokinetic comparisons.

Fifteen patients were enrolled in each arm of study. The mean daily dose of vancomycin was estimated insignificantly lower for individuals in the GRAIL arm than the C-G group (1550.00±544.45 mg versus 1750.00± 389.60 mg). Compared with the C-G group, a higher rate of patients in the GRAIL arm experienced below-target vancomycin trough concentrations (40.0% versus 13.3%), and a lower rate showed above target trough concentration (40.0% versus 66.7%). These differences did not reach statistical significance. Individuals in the GRAIL arm represented a significantly higher rate of below target vancomycin AUC/MIC than patients in the C-G arm (46.7% versus 6.7%) (P=0.049). No differences in clinical outcomes were observed between the two groups.

Using the GRAIL model for vancomycin dosing may result in less percent of patients with at target AUC/MIC compared to the C-G method and expose more patients at risk for vancomycin under dosing.

Benign Prostatic Hyperplasia (BPH), and Prostate Cancer (PCa) are androgen-dependent diseases. PPCa is associated with excessive signalling of the androgen receptor (AR) due to the binding of 5α-dihydrotestosterone (5α-DHT) and testosterone (T). BPH is related to high levels of 5α-DHT, biosynthesized from T by 5α-reductase (5RD5A). The inhibition of 5RD5A and the blockage of AR are targets for their treatment. In this study, the synthesis and determination of biological activity of the new N-cyclohexyl-3β-hydroxyandrosta-5,16- diene-17-carboxamide (6), N-cyclohexyl-3-oxoandrosta-4,6,16-triene-17-carboxamide (7), and N-cyclohexyl-3-oxoandrosta-4,16-diene-17-carboxamide (8) were carried out to find new drugs to improve these afflictions.

The synthesis of 6 to 8 was confirmed by spectroscopic and spectrometric analyses. Competitive binding assays determined the affinity of 6 to 8 to the AR. The inhibitory activity of 5RD5A isoform 2 (5RD5A2) (IC50) was established by the conversion of [3 H]-T to [3 H]-5α-DHT and it was compared with finasteride (FIN). The pharmacological effect of 6 to 8 was determined on the weight of the prostate and seminal vesicles glands of castrated hamsters treated with T, and on the diameter size of their flank organs.

Compounds 7 and 8 bound lightly (ca. 15 %) to AR. Comparing to FIN (IC50 = 8.5 nM), 6 to 8 (IC50 = 0.169, 0.105 and 0.155 nM, respectively) showed higher potency as inhibitors of 5RD5A2. Compound 6 decreased the prostate and seminal vesicles weight, as well as the hamsters’ diameter flank organs. However, 7 only decreased the diameter of flank organs. Surprisingly, 8 increased these pharmacological parameters.

Androstane-17-caboxamide 6 is a 5RD5A2 inhibitor that reduces the weight of androgen-dependent glands such as the prostate, suggesting it could be a lead for new drugs to treat BPH and PCa.

Sofosbuvir is a potent direct-acting antivirus agent that has been listed as a promising medicine for the treatment of all genotypes of hepatitis C virus. As antiviral drugs could be metabolized to their associated compounds and toxicologically and pharmacologically interfere with the parent drugs, identifying the therapeutic range of drugs would be notable.

In the current study, copper nanoclusters (Cu NCs) are synthesized during the reduction of copper nitrate with hydrazine hydrate in a protected media and used as a nanoprobe for the determination of sofosbuvir in plasma samples. Herein, synchronous fluorescence spectroscopy (SFS) is used for monitoring of fluorescence variation of nanoprobe owing to the excessive benefits compared with the traditional fluorescence.

SFS peak of Cu NCs has appeared at 355 nm with ∆λ=80 nm which is decreased in the presence of sofosbuvir. To optimize the reaction factors, a response surface methodology is used and in the optimized conditions, a linear concentration-response plot is obtained in a range of 0.05-6.0 µg mL−1 with a limit of detection of 0.0147 µg mL−1.

The developed method also reveals good repeatability and selectivity for sofosbuvir in plasma samples.

The present investigation aimed to prepare Vancomycin-loaded nanoparticles (VAN-NPs) using chitosan (CS) and tripolyphosphate (TPP) besides exploring the effects of changing CS/TPP ratio on the physicochemical properties, corneal permeation, and ocular delivery of the prepared NPs.

Different pre-formulations were prepared using the modified ionic gelation process, then were characterized in terms of size distribution. Optimized formulations were furtherly evaluated by some characteristic tools such as Fourier-transform infrared (FTIR) spectroscopy and thermogravimetric analysis (TGA). The in vitro antimicrobial efficacy and drug release amounts along with the Ex-vivo corneal permeation of NPs through the sheep cornea were investigated. Quantification was performed using high-performance liquid chromatography.

Spherical and uniformly distributed NPs were developed with a mean particle size varied between 215–290 nm. FTIR spectroscopy confirmed that the CS/TPP cross-linking has taken place without affecting the pharmacologically active moiety of the drug. The obtained zeta potential values were in the range of +34 to +37 mV, which could ensure the stability of formulations. TGA analysis indicated enhanced thermal stability for the encapsulated drug compared to the plain drug. Formulations indicated suitable antimicrobial efficacy while releasing more than 90% of the drug during 24 h. NPs offered a 10-fold enhancement in corneal permeation compared to the drug solution.

Although further in vivo evaluation is still required to completely confirm the efficacy of the formulations, the enhanced release and corneal permeation of the drug suggest that the prepared NPs are suitable for ocular delivery of VAN.

Carbamazepine (CBZ) is a BCS II class drug, having many challenges in solubility, flowability, and compactibility. The study focused on the improvement of solubility, flow behavior, and drug release of carbamazepine.

Low shear granulation (LSG), extrusion spheronization (ES), high shear granulation (HSG), fluid bed granulation (FBG), and hot melt granulation (HMG) methods were employed to prepare CBZ granules. Polyvinylpyrrolidone (PVP) K29/32, PVP K90, and Hydroxypropyl methylcellulose (HPMC) E5 were used as a binder. The drug to binder ratio was maintained in the proportion of 95:5. The nature of granules was analyzed by using X-ray Diffraction and Differential Scanning Calorimetry techniques. A powder flow tester was utilized to study the flow characteristics of the granules.

The HMG has successfully converted the crystalline structure of CBZ granules into an amorphous form. Dispersive and distributive mixing in the HMG has achieved better solid dispersion and fast drug release. The ES technique has reported the incompressible nature of the granules. PVP K90 and HPMC E5 were superior binders for imparting strength to the CBZ granules than PVP K29/32. The FBG has exhibited the free-flowing nature of granules due to their uniform and spherical shape.

The HMG and FBG were the most effective methods that have remarkably improved drug release, flow properties, and compactibility of CBZ granules.

Andrographolide is a phytoconstituent with anti-inflammatory activity, however, the compound’s poor oral bioavailability has hindered its effective formulation for oral administration. This study, therefore, aims to develop an ethosome for improving andrographolide penetration through the transdermal delivery system.

This study developed 3 ethosome formulas with different andrographolide-phospholipid weight ratios (1:8, 1:9 and 1:10), using the thin-layer dispersion-sonication method. Subsequently, the ethosomes were evaluated for particle size, polydispersity index, zeta potential, morphology, as well as entrapment efficiency, and incorporated into a gel dosage form. Subsequently, an in vitro penetration study was performed using Franz diffusion cells for 24 hours and the stability of the gels at 5 ± 2°C, 30 ± 2°C, and 40 ± 2°C, were studied for 3 months.

The results showed the optimal formula was E2, a 1:9 weight ratio formula of andrographolide and phospholipid. Based on the transmission electron micrograph, E2 possessed unilamellar, as well as spherical-shaped vesicles, and exhibited superior characteristics for transdermal delivery, with a particle size of 89.95 ± 0.75 nm, polydispersity index of 0.254 ± 0.020, a zeta potential of -39.3 ± 0.82 mV, and entrapment efficiency of 97.89 ± 0.02%. Furthermore, the cumulative andrographolide penetration and transdermal flux for the ethosomal gel of E2 (EG2) were 129.25 ± 4.66 µg/cm2 and 5.16 ± 0.10 µg/cm2 /hours, respectively. All the ethosomal gel formulations exhibited improved penetration enhancement of andrographolide, compared to the nonethosomal formulations. Also, the andrographolide levels in the ethosomal and nonethosomal gels after 3 months ranged from 98.13 to 104.19%, 97.93 to 104.01%, and 97.23 to 102.26% at storage temperatures of 5 ± 2°C, 30 ± 2°C/RH 65% ± 5%, and 40 ± 2°C/RH 75% ± 5%, respectively.

This study concluded that encapsulation into ethosome enhances andrographolide delivery through the skin.

Ethnobotanical investigations conducted in Turkey demonstrated that Jasminum fruticans L. extract and fruit juice had been used against parasites in animals. In this study, the possible antihelmintic activity of various J. fruticans extracts contributing to its traditional use, was relatively assessed. In addition, the antioxidant potentials and phytochemical composition of the extracts were investigated since there is a relationship between helminthiasis, oxidative stress and phenolic metabolites.

In this study, aerial parts of J. fruticans were subsequently extracted using n-hexane, ethyl acetate (EtOAc) and methanol (MeOH). In vivo anthelmintic activity of the extracts was compared with albendazole used as a reference in adult earthworms. Various methods, including free radical scavenging and metal-related activity assays, were used to assess the antioxidant capacity of the above-mentioned extracts. Assessment of phenolic composition was accomplished through total phenolic, phenolic acid, and flavonoid content assays as well as liquid chromatography-mass spectrometry (LC-MS/MS) using multiple reaction monitoring (MRM) scan modes. Further chlorogenic acid (3-O-caffeoylquinic acid) contents of extracts were quantified using high-performance thin-layer chromatography (HPTLC).

Between all tested extracts, MeOH extract at a quantity of 50.0 mg/mL, paralysed worms in 8.1 min and killed them in 12.8 min, showing a high anthelmintic effect similar to albendazole. Similarly, in vitro DPPH radical scavenging activity, cupric ion reduction and total antioxidant capacity experiments demonstrated that MeOH extract had significant antioxidant activity. Further phytochemical screening showed that MeOH extract was richer regarding phenolic metabolites. Chlorogenic acid, ferulic acid, caffeic acid and gallic acid were only detected in the MeOH extract.

Results justify and support the use of J. fruticans in traditional medicine as an anthelmintic agent. Furthermore, a positive correlation was found between the strong antioxidant capacity along with the phenolic composition determined in the MeOH extract and anthelmintic activity.