Optimization of Electrochemical Sensitivity in Anticancer Drug Quantification through ZnS@CNS Nanosheets: Synthesis via Accelerated Sonochemical Methodology.

Zinc sulfide/graphitic Carbon Nitride binary nanosheets were synthesized by using a novel sonochemical pathway with high electrocatalytic ability. The as- obtained samples were characterized by various analytical methods such as Transmission Electron Microscopy (TEM), Field emission scanning electron microscopy (FESEM), Energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction analysis (XRD), and X-ray photoelectron spectroscopy (XPS) to evaluate the properties of ZnS@CNS synthesized by this new route. Subsequently, the electrical and electrochemical performance of the proposed electrodes were characterized by using EIS and CV to establish an electroactive ability of the nanocomposites. The complete properties like structural and physical of ZnS@CNS were analyzed. As-prepared binary nanocomposite was applied towards the detection of anticancer drug (flutamide) by various electrochemical methods such as cyclic voltammetry (CV), differential pulse voltammetry (DPV) and amperometry. The glassy carbon electrode modified with a ZnS@CNS composite demonstrates a remarkable electrocatalytic efficiency for detecting flutamide in a pH 7.0 (PBS). The composite modified electrode shows synergistic effect of ZnS and CNS catalyst. The electrochemical sensing performance of the linear range was improved significantly due to high electroactive sites and rapid electron transport pathways. Crucially, the electrochemical method was successfully demonstrated in biological fluids which reveals its potential real-time applicability in the analysis of drug.

The High Stability and Selectivity of Electrochemical Sensor Using Low-Cost Diamond Nanoparticles for the Detection of Anti-Cancer Drug Flutamide in Environmental Samples.

In this study, a novel electrochemical sensor was created by fabricating a screen-printed carbon electrode with diamond nanoparticles (DNPs/SPCE). The successful development of the sensor enabled the specific detection of the anti-cancer drug flutamide (FLT). The DNPs/SPCE demonstrated excellent conductivity, remarkable electrocatalytic activity, and swift electron transfer, all of which contribute to the advantageous monitoring of FLT. These qualities are critical for monitoring FLT levels in environmental samples. Various structural and morphological characterization techniques were employed to validate the formation of the DNPs. Remarkably, the electrochemical sensor demonstrated a wide linear response range (0.025 to 606.65 µM). Additionally, it showed a low limit of detection (0.023 µM) and high sensitivity (0.403 µA µM-1 cm-2). Furthermore, the practicability of DNPs/SPCE can be successfully employed in FLT monitoring in water bodies (pond water and river water samples) with satisfactory recoveries.

Potentiation of flutamide-induced hepatotoxicity in mice by Xian-Ling-Gu-Bao through induction of CYP1A2.

ETHNOPHARMACOLOGICAL RELEVANCE: Xian-Ling-Gu-Bao (XLGB) Fufang is herbal formula widely used to treat osteoporosis and other bone disorders. Because of its commonality in the clinical use, there is a safety concern over the use of XLGB combined with other androgen deprivation therapy (ADT) drugs such as flutamide (FLU) that is associated with reduced bone density. To date, there have been no evaluations on the side effects of the drug-drug interaction between XLGB and FLU. AIM OF THE STUDY: The present study was designed to investigate the hepatotoxicity in the context of the combined treatment of XLGB and FLU in a mouse model, and to determine whether the metabolic activation of FLU through induction of CYP1A2 plays a role in the increased hepatoxicity caused by the combination of XLGB and FLU. MATERIALS AND METHODS: C57 mice were administered with either XLGB (6,160 mg/kg), FLU (300 mg/kg), or with the combination of the two drugs. Animals were treated with XLGB for 5 days before the combined administration of XLGB and FLU for another 4 days. The serum of mice from single or the combined administration groups was collected for biochemical analysis. The mouse liver was collected to examine liver morphological changes, evaluate liver coefficient, as well as determine the mRNA expression of P450 isozymes (Cyp1a2, Cyp3a11 and Cyp2c37). For metabolism analysis, mice were treated with XLGB, FLU, or the combination of XLGB and FLU for 24 h. The urine samples were collected for the analysis of FLU-NAC conjugate by UPLC-Q-Orbitrap MS. The liver microsomes were prepared from fresh livers to determine the activity of metabolizing enzyme CYP1A2. RESULTS: The combined treatment of XLGB and FLU caused loss of mice body weight and elicited significant liver toxicity as evidenced by an increased liver coefficient and serum lactate dehydrogenase (LDH) activity as well as pathological changes of fatty lesion of liver tissue. FLU increased hepatic expression of Cyp1a2 mRNA that was further elevated in the liver of mice when administered with both FLU and XLGB. Treatment of FLU resulted in an increase in the expression of Cyp3a11 mRNA that was negated when mice were co-treated with FLU and XLGB. No significant difference in Cyp2c37 mRNA expression was observed among the different treatment groups as compared to the control. Analysis of metabolic activity showed that the combined administration caused a synergic effect in elevating the activity of the CYP1A2 enzyme. Mass spectrometry analysis identified the presence of FLU reactive metabolite derived FLU-NAC conjugate in the urine of mice treated with FLU. Strikingly, about a two-fold increase of the FLU-NAC conjugate was detected when treated with both FLU and XLGB, indicating an elevated amount of toxic metabolite produced from FLU in the present of XLGB. CONCLUSION: FLU and XLGB co-treatment potentiated FLU-induced hepatoxicity. This increased hepatoxicity was mediated through the induction of CYP1A2 activity which in turn enhanced bioactivation of FLU leading to over production of FLU-NAC conjugate and oxidative stress. These results offer warnings about serious side effects of the FLU-XLGB interaction in the clinical practice.

Analysis of the binding modes of the first- and second-generation antiandrogens with respect to F876L mutation.

Androgen receptor (AR) is an important target for the treatment of prostate cancer, and mutations in the AR have an important impact on the resistance of existing drugs. In this work, we performed molecular dynamics simulations of the existing marketed antiandrogens flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, and its main metabolite ORM15341 in complex with the wild-type and F876L mutant AR. We calculated the residue-specific binding free energy contribution of the wild-type and mutant ARs with the AS-IE method and analyzed the hotspot residues and the binding free energy contributions of specific residues before and after the mutation. In addition, we analyzed the total binding obtained by adding residue binding energy contributions and compared the results with experimental values. The obtained residue-specific binding information should be very helpful in understanding the mechanism of drug resistance with respect to specific mutations and in the design of new generation drugs against possible new mutations.

Heterostructured bismuth oxide/hexagonal-boron nitride nanocomposite: A disposable electrochemical sensor for detection of flutamide.

Aquatic contamination from the accumulation of pharmaceuticals has induced severe toxicological impact to the ecological environment, especially from non-steroidal anti-inflammatory drugs (NSAIDs). Real-time monitoring of flutamide, which is a class of NSAIDs, is very significant in environmental protection. In this work, we have synthesized the hexagonal-h boron nitride decorated on bismuth oxide (Bi2O3/h-BN) based nanocomposite for the effective electrochemical detection of flutamide (FTM). The structural and morphological information of the heterostructured Bi2O3/h-BN nanocomposite was analyzed by using a sequence of characterization methods. Voltammetric techniques were used to evaluate the analytical performance of the Bi2O3/h-BN modified screen-printed carbon electrode (SPCE) for the FTM detection. The Bi2O3/h-BN modified SPCE displays a synergetic catalytic effect for the reduction of FTM due to large surface area, numerous active sites, fast charge transfer and abundant defects. The proposed electrochemical sensing platform demonstrates high selectivity, low detection limit (9.0 nM), good linear ranges (0.04-87 µM) and short response time for the detection of FTM. The feasibility of the electrochemical sensor has been proved by the successful application to determine FTM in environmental samples.

Synthesis of flutamide-conjugates.

In this paper, we designed and extended modification basing on the flutamide structure. A series of flutamide-conjugates were obtained with methyl bromoacetate and ethylenediamine. Through the synthesis of two conjugates with 3,5-bis(dodecyloxy)benzoate derivatives, these flutamide conjugates were tested for anticancer activity. Among the compounds tested, the flutamide-conjugates showed good inhibition activity against cancer cell lines U-251, PC-3 and K-562. The conjugates showed a better inhibitory effect than free flutamide and did not show activity against normal COS-7 monkey kidney fibroblast cells. It was also observed that the flutamide conjugates had an inhibitory effect against human colorectal adenocarcinoma HCT-15.

Development of Androgen-Antagonistic Coumarinamides with a Unique Aromatic Folded Pharmacophore.

First-generation nonsteroidal androgen receptor (AR) antagonists, such as flutamide (2a) and bicalutamide (3), are effective for most prostate cancer patients, but resistance often appears after several years due to the mutation of AR. Second-generation AR antagonists are effective against some of these castration-resistant prostate cancers, but their structural variety is still limited. In this study, we designed and synthesized 4-methyl-7-(N-alkyl-arylcarboxamido)coumarins as AR antagonist candidates and evaluated their growth-inhibitory activity toward androgen-dependent SC-3 cells. Coumarinamides with a secondary amide bond did not show inhibitory activity, but their N-methylated derivatives exhibited AR-antagonistic activity. Especially, 19b and 31b were more potent than the lead compound 7b, which was comparable to hydroxyflutamide (2b). Conformational analysis showed that the inactive coumarinamides with a secondary amide bond have an extended structure with a trans-amide bond, while the active N-methylated coumarinamides have a folded structure with a cis-amide bond, in which the two aromatic rings are placed face-to-face. Docking study suggested that this folded structure is important for binding to AR. Selected coumarinamide derivatives showed AR-antagonistic activity toward LNCaP cells with T877A AR, and they had weak progesterone receptor (PR)-antagonistic activity. The folded coumarinamide structure appears to be a unique pharmacophore, different from those of conventional AR antagonists.

Polyacrylamide-punicic acid conjugate-based micelles for flutamide delivery in PC3 cells of prostate cancer: synthesis, characterisation and cytotoxicity studies.

The aim of the present study was to synthesize a novel biopolymeric micelle based on punicic acid (PA) and polyacrylamide (PAM) for carrying chemotherapeutic drugs used in prostate cancer treatment. A polymer composite micelle was prepared by chemical conjugation between PAM and PA. The micelles were prepared by self-assembly via film casting followed by ultrasonication method. The successful production of PAMPA copolymeric micelles was confirmed using FTIR, 1H-NMR, and TEM. Then, flutamide was loaded in the designed nanomicelles and they were characterized. The cell cytotoxicity of the micelles was studied on PC3 cells of prostate cancer. The prepared nanomicelles showed the particle size of 88 nm, PDI of 0.246, zeta potential of -9 mV, drug loading efficiency of 94.5%, drug release of 85.6% until 10 hours in pH 7.4 and CMC of 74.13 µg/ml. The cell viability in blank nanocarriers was about 70% in PC3 cells at concentration of 25 µM. More significant cytotoxic effects were seen for flutamide loaded micelles at this concentration compared to the free drug. The results suggest that the PAMPA co-polymeric nanomicelles can be utilized as an effective carrier to enhance the cytotoxic effects of flutamide in prostate cancer.

Sonochemical synthesis and fabrication of perovskite type calcium titanate interfacial nanostructure supported on graphene oxide sheets as a highly efficient electrocatalyst for electrochemical detection of chemotherapeutic drug.

In green approaches for electrocatalyst synthesis, sonochemical methods play a powerful role in delivering the abundant surface areas and nano-crystalline properties that are advantageous to electrocatalytic detection. In this article, we proposed the sphere-like and perovskite type of bimetal oxides which are synthesized through an uncomplicated sonochemical procedure. As a yield, the novel calcium titanate (orthorhombic nature) nanoparticles (CaTiO3 NPs) decorated graphene oxide sheets (GOS) were obtained through simple ultrasonic irradiation by a high-intensity ultrasonic probe (Titanium horn; 50 kHz and 60 W). The GOS/CaTiO3 NC were characterized morphologically and chemically through the analytical methods (SEM, XRD, and EDS). Besides, as-prepared nanocomposites were modified on a GCE (glassy carbon electrode) and applied towards electrocatalytic and electrochemical sensing of chemotherapeutic drug flutamide (FD). Notably, FD is a crucial anticancer drug and also a non-steroidal anti-androgen chemical. Mainly, the designed and modified sensor has shown a wide linear range (0.015-1184 µM). A limit of detection was calculated as nanomolar level (5.7 nM) and sensitivity of the electrode is 1.073 µA µM-1 cm-2. The GOS/CaTiO3 modified electrodes have been tested in human blood and urine samples towards anticancer drug detection.

Degradation of the anticancer drug flutamide by solar photo-Fenton treatment at near-neutral pH: Identification of transformation products and in silico (Q)SAR risk assessment.

Flutamide (FLUT) is a non-steroidal drug mainly used in the treatment of prostate cancer and has been detected in the aquatic environment at ng L-1 levels. The environmental fate and effects of FLUT have not yet been studied. Conventional treatment technologies fail to completely remove pharmaceuticals, so the solar photo-Fenton process (SPF) has been proposed as an alternative. In this study, the degradation of FLUT, at two different initial concentrations in ultra-pure water, was carried out by SPF. The initial SPF conditions were pH0 5, [Fe2+]0 = 5 mg L-1, and [H2O2]0 = 50 mg L-1. Preliminary elimination rates of 53.4% and 73.4%. The kinetics of FLUT degradation could be fitted by a pseudo-first order model and the kobs were 6.57 × 10-3 and 9.13 × 10-3 min-1 t30W and the half-life times were 95.62 and 73.10 min t30W were achieved for [FLUT]0 of 5 mg L-1 and 500 µg L-1, respectively. Analysis using LC-QTOF MS identified thirteen transformation products (TPs) during the FLUT degradation process. The main degradation pathways proposed were hydroxylation, hydrogen abstraction, demethylation, NO2 elimination, cleavage, and aromatic ring opening. Different in silico (quantitative) structure-activity relationship ((Q)SAR) freeware models were used to predict the toxicities and environmental fates of FLUT and the TPs. The in silico predictions indicated that these substances were not biodegradable, while some TPs were classified near the threshold point to be considered as PBT compounds. The in silico (Q)SAR predictions gave positive alerts concerning the mutagenicity and carcinogenicity endpoints. Additionally, the (Q)SAR toolbox software provided structural alerts corresponding to the positive alerts obtained with the different mutagenicity and carcinogenicity models, supporting the positive alerts with more proactive information.

How does the high pressure affects the solubility of the drug within the polymer matrix in solid dispersion systems.

In this paper, we employed Broadband Dielectric Spectroscopy (BDS) in order to determine the effect of the high pressure on the solubility limits of the amorphous flutamide within Kollidon VA64 matrix. In order to achieve this goal, drug-polymer systems have been examined: (i) at ambient pressure and both isothermal and nonisothermal conditions by means of BDS as well as Differential Scanning Calorimetry (DSC), to validate proposed method; (ii) at high pressure conditions (20 and 50 MPa) and elevated temperatures (343 K, 353 K and 363 K) by means of dielectric spectroscopy. Our studies revealed that regardless of applied pressure the solubility of the flutamide within the co-polymer matrix increases with increasing temperature at isobar conditions. Moreover, our results clearly indicate that with increasing pressure the solubility of the drug within the polymer matrix is decreasing at isothermal conditions. Therefore, during the solubility limit studies one should consider the situation in which by increasing the pressure (at constant temperature) would achieve an effect similar to the lowering of the temperature (at constant pressure).

Structural Dynamics of Agonist and Antagonist Binding to the Androgen Receptor.

Androgen receptor (AR) is a steroid hormone nuclear receptor which upon binding its endogenous androgenic ligands (agonists), testosterone and dihydrotestosterone (DHT), alters gene transcription, producing a diverse range of biological effects. Antiandrogens, such as the pharmaceuticals bicalutamide and hydroxyflutamide, act as agonists in the absence of androgens and as antagonists in their presence or in high concentration. The atomic level mechanism of action by agonists and antagonists of AR is less well characterized. Therefore, in this study, multiple 1 µs molecular dynamics (MD), docking simulations, and perturbation-response analyses were performed to more fully explore the nature of interaction between agonist or antagonist and AR and the conformational changes induced in the AR upon interaction with different ligands. We characterized the mechanism of the ligand entry/exit and found that helix-12 and nearby structural motifs respond dynamically in that process. Modeling showed that the agonist and antagonist/agonist form a hydrogen bond with Thr877/Asn705 and that this interaction is absent for antagonists. Agonist binding to AR increases the mobility of residues at allosteric sites and coactivator binding sites, while antagonist binding decreases mobility at these important sites. A new site was also identified as a potential surface for allosteric binding. These results shed light on the effect of agonists and antagonists on the structure and dynamics of AR.

How can we improve the physical stability of co-amorphous system containing flutamide and bicalutamide? The case of ternary amorphous solid dispersions.

The article describes the preparation and characterization of binary mixtures of two antiandrogens used in prostate cancer treatment, i.e. flutamide (FL) and bicalutamide (BIC), as well as their ternary mixtures with either poly(methyl methacrylate-co-ethyl acrylate) (MMA/EA) or polyvinylpyrrolidone (PVP). The samples were converted into amorphous form to improve their water solubility and dissolution rate. Broadband dielectric spectroscopy and differential scanning calorimetry revealed that FL-BIC (65%) (w/w) does not tend to crystallize from the supercooled liquid state. We made the assumption that the drug-to-drug weight ratio should be maintained as in the case of monotherapy so we decided to investigate the system containing FL and BIC in 15:1 (w/w) ratio with 30% additive of polymers as stabilizers. Our research has shown that only in the case of the FL-BIC-PVP mixture the crystallization has been completely inhibited, both in glassy and supercooled liquid state, which was confirmed by X-ray diffraction studies. In addition, we performed solubility and dissolution rate tests, which showed a significant improvement in solubility of ternary system as compared to its crystalline counterpart. Enhanced physical stability and water solubility of the amorphous ternary system makes it promising for further studies.

Drug-polymer miscibility, interactions, and precipitation inhibition studies for the development of amorphous solid dispersions for the poorly soluble anticancer drug flutamide.

The major goal of this research was to successfully formulate solid dispersion (SD) of the poorly soluble anticancer drug flutamide (FLT) using various hydrophilic polymers. Furthermore, to get more insight into SD, solid-state studies (miscibility and molecular interaction) were correlated with solution study (precipitation inhibition, dissolution). Hydrophilic polymers like PVP K90, HPMC, Eudragit EPO, and PEG 8000 were used at different drug-to-polymer w/w ratios. Solid-state miscibility studies were carried out using modulated differential scanning calorimetry (MDSC). SDs were prepared using solvent-evaporation technique and characterized by powder X-ray diffraction (PXRD) and MDSC. Infrared, Raman spectroscopy and molecular modeling were used to investigate drug-polymer interactions in the dispersions. Precipitation inhibition studies were carried out at various FLT-hydrophilic polymer ratios. Precipitation inhibition studies showed that PEG 8000 has the highest efficiency, followed by PVP K90, while HPMC and EPO showed no effect on precipitation inhibition. In the solid-state, MDSC of the physical mixture (PM) suggested that FLT is miscible to a greater extent with EPO and PEG 8000. Characterization of the amorphous dispersions using MDSC and PXRD concluded that FLT transformed from crystalline to amorphous form in the presence of PVP K90 and PEG 8000. Spectroscopic results confirmed stronger interaction of FLT with PVP K90 and PEG 8000, thereby confirming the in-solution precipitation and molecular modeling binding energy results. Amorphous dispersions formulated with PVP and PEG were stable and showed higher dissolution, an important property necessary to improve the physicochemical properties and drug delivery of poorly soluble anticancer drug FLT.

Broadband dielectric spectroscopy as an experimental alternative to calorimetric determination of the solubility of drugs into polymer matrix: Case of flutamide and various polymeric matrixes.

In this paper we determined the solubility limits of the amorphous flutamide within the two different polymeric matrixes - poly vinylpyrrolidone and poly vinylacetate. In order to achieve this goal, series of broadband dielectric spectroscopy measurements were performed. As a result we found that the maximal amount of the drug that can be successfully dissolved within the PVAc (maintaining the non-supersaturated conditions) is equal to 35 wt% of the amorphous solid dispersion system. Interestingly enough similar results, in terms of solubility limits, were achieved utilizing significantly higher amount of the pharmaceutical - 71 wt% - in the PVP matrix. Accordingly, we established the following relationship in the solubility limits of the amorphous flutamide dispersed within examined polymer matrixes: PVP > PVAc. It is worth highlighting that in order to preserve the thermodynamic stability - one of the two contributors to the physical stability - drug loading in the amorphous solid dispersion system should not exceed its solubility limits. Hence, choosing appropriate amount of the polymer addition will determine if obtained system remains physically stable. Subsequently, we presented the "stability maps" for all investigated FL-based ASD systems from which one might predict the stabilization effect exerted by certain amount of polymer.

Chitosan-gold collapse gel/poly (bromophenol blue) redox-active film. A perspective for selective electrochemical sensing of flutamide.

Chitosan-gold collapse gel (CS-Au CG) was prepared by reducing chloroauric acid (HAuCl4) with a polysaccharide, chitosan (CS), in the absence of chemical and physical agents. CS-Au CG was used for the first time as a suitable nano-biocomposite sensing film for efficient one-step electrochemical deposition of poly (bromophenol blue) (PBPB) redox mediator through amino-hydroxyl reaction to prepare a novel anti-androgen drug flutamide (FLU) sensor using glassy carbon electrode (GCE). The effect of electropolymerization cycle, scan rate, pH, and concentration of CS-Au CG/PBPB film on electrochemical behavior of FLU molecules was investigated. The excellent synergetic effect of CS-Au CG/PBPB film showed substantially enhanced electrocatalytic activity for FLU due to the halogen-nitro synthon molecular recognition processes. The selectivity of CS-Au CG/PBPB film sensor for FLU was discussed in detail. The fabricated electrochemical sensor exhibited good linearity in the ranges of 0.01-1245 µM. And also superior sensitivity (0.63 µAµM-1 cm-2) along with low limit of detection (4.8 nM) was obtained for FLU determination. The CS-Au CG/PBPB film showed an excellent selectivity, good reproducibility, and stability. In addition, the proposed sensor was successfully used to analysis of FLU drug in human urine and human blood serum samples with satisfactory results.

Electrochemical determination of anticancer drug, flutamide in human plasma sample using a microfabricated sensor based on hyperbranchedpolyglycerol modified graphene oxide reinforced hollow fiber-pencil graphite electrode.

Flutamide (FLT) is a non-steroidal anti-androgen drug that has a specific anti-androgenic activity so that it is used in the treatment of prostate cancer. FLT may also be used to treat excess androgen levels in women. A sensitive electrochemical sensor based on hyperbranchedpolyglycerol functionalized- graphene oxide developed, using ionic liquid mediated hollow fiber-pencil graphite electrode (HF/HBP-GO/PGE) as a working electrode for determination of an anticancer drug, flutamide (FLT. In this design, a two centimeter piece of porous polypropylene hollow fiber membrane was impregnated with ionic liquid (1-Pentyl-3-methylimidazoliumbromide), and a graphite rod modified with hyperbranchedpolyglycerol/graphene oxide (HBP-GO), was located inside the fiber lumen. The modified electrode exhibits sorption activity, high sensitivity, stability and applicability over a wide range of concentration of FLT. The morphology and the electrochemical properties of the modified electrode were characterized by scanning electron microscopy (SEM) and cyclic voltammetry (CV). The effect of the amount of graphene oxide (GO), scan rate, pH, concentration of ionic liquid, extraction time and agitation rate on electrochemical behavior of flutamide molecules was investigated. The square wave voltammetric method showed a linear behavior over the drug concentration range 0.1-110 µM. The limit of detection (LOD) and the limit of quantification (LOQ) were found to be 0.029 µM and 0.099 µM, respectively. The proposed sensor was applied for determination of FLT in human plasma sample with satisfactory results.

Flutamide-Loaded Zein Nanocapsule Hydrogel, a Promising Dermal Delivery System for Pilosebaceous Unit Disorders.

Zein is a naturally occurring corn protein having similarity to skin keratin. Owing to its hydrophobicity and biodegradability, zein nanocarriers are promising drug delivery vehicles for hydrophobic dermatological drugs. In this study, zein-based nanocapsules (ZNCs) were exploited for the first time as dermal delivery carriers for flutamide (FLT), an antiandrogen used for the management of pilosebasceous unit disorders. FLT-loaded ZNC of appropriate particle size and negative surface charge were prepared by nanoprecipitation method. The dermal permeation and skin retention of FLT from ZNCs were studied in comparison to corresponding nanoemulsion (NE) and hydroalcoholic drug solution (HA). ZNCs showed a significantly lower permeation flux compared to NE and HA while increasing the skin retention of FLT. Confocal laser scanning microscopy (CLSM) demonstrated the follicular localization of the fluorescently labeled NCs. The incorporation of NCs in chitosan gel or Carbomer® 934 gel was studied. Carbomer® gel increased the skin retention of FLT compared to chitosan gel. Accordingly, Carbomer® hydrogel embedding FLT-loaded ZNCs is a promising inexpensive, biocompatible dermal delivery nanocarrier for localized therapy of PSU disorders suitable for application on oily skin.

Combination of 1H nuclear magnetic resonance spectroscopy and principal component analysis to evaluate the lipid fluidity of flutamide-encapsulated lipid nanoemulsions.

The lipid fluidity of various lipid nanoemulsions (LNEs) without and with flutamide (FT) and containing one of two neutral lipids, one of four phosphatidylcholines as a surfactant, and sodium palmitate as a cosurfactant was investigated by the combination of 1H nuclear magnetic resonance (NMR) spectroscopy and principal component analysis (PCA). In the 1H NMR spectra, the peaks from the methylene groups of the neutral lipids and surfactants for all LNE preparations showed downfield shifts with increasing temperature from 20 to 60 °C. PCA was applied to the 1H NMR spectral data obtained for the LNEs. The PCA resulted in a model in which the first two principal components (PCs) extracted 88% of the total spectral variation; the first PC (PC-1) axis and second PC (PC-2) axis accounted for 73 and 15%, respectively, of the total spectral variation. The Score-1 values for PC-1 plotted against temperature revealed the existence of two clusters, which were defined by the neutral lipid of the LNE preparations. Meanwhile, the Score-2 values decreased with rising temperature and reflected the increase in lipid fluidity of each LNE preparation, consistent with fluorescence anisotropy measurements. In addition, the changes of Score-2 values with temperature for LNE preparations with FT were smaller than those for LNE preparations without FT. This indicates that FT encapsulated in LNE particles markedly suppressed the increase in lipid fluidity of LNE particles with rising temperature. Thus, PCA of 1H NMR spectra will become a powerful tool to analyze the lipid fluidity of lipid nanoparticles. Graphical abstract ᅟ.

Anticancer Activity of Resorcinarene-PAMAM-Dendrimer Conjugates of Flutamide.

METHODS: The synthesis of conjugates of flutamide with resorcinarene-PAMAM-dendrimers as well as alkyl and ethyl phenyl chains in the lower part of the macrocycle as a nucleus and diethylenetriamines in the dendritic branches gives the opportunity to obtain conjugates in one step of synthesis with 16 and 64 flutamide moieties in the structure. RESULTS: The in vitro anticancer studies showed that the conjugates of flutamide are more active than the free flutamide and the flutamide derivatives, thus diminishing the amount of flutamide used. The resorcinarenedendrimer- flutamide conjugates with a high drug payload improve the activity of the drug. CONCLUSION: This is important in delivering a sufficient amount of flutamide and suggests that the dendrimer facilitates more of the drug being introduced into cells. It was also observed that the new conjugates are less toxic than the anti-androgens.