Grinding-Induced Water Solubility Exhibited by Mechanochromic Luminescent Supramolecular Fibers.

Most mechanochromic luminescent compounds are crystalline and highly hydrophobic; however, mechanochromic luminescent molecular assemblies comprising amphiphilic molecules have rarely been explored. This study investigated mechanochromic luminescent supramolecular fibers composed of dumbbell-shaped 9,10-bis(phenylethynyl)anthracene-based amphiphiles without any tetraethylene glycol (TEG) substituents or with two TEG substituents. Both amphiphiles formed water-insoluble supramolecular fibers via linear hydrogen bond formation. Both compounds acquired water solubility when solid samples composed of supramolecular fibers are ground. Grinding induces the conversion of 1D supramolecular fibers into micellar assemblies where fluorophores can form excimers, thereby resulting in a large redshift in the fluorescence spectra. Excimer emission from the ground amphiphile without TEG chains is retained after dissolution in water. The micelles are stable in water because hydrophilic dendrons surround the hydrophobic luminophores. By contrast, when water is added to a ground amphiphile having TEG substituents, fragmented supramolecular fibers with the same molecular arrangement as the initial supramolecular fibers are observed, because fragmented fibers are thermodynamically preferable to micelles as the hydrophobic arrays of fluorophores are covered with hydrophilic TEG chains. This leads to the recovery of the initial fluorescent properties for the latter amphiphile. These supramolecular fibers can be used as practical mechanosensors to detect forces at the mesoscale.

Benzo-Crown-Ether Functionalized O-BODIPY Probes for Cations - A Selective Fluorescent Probe for Ba2.

Herein, we report the synthesis and sensing characteristics of 4,4'-methoxy-substituted BODIPY fluorescent probes (O-BODIPYs) 3, 4 and 5 equipped with differently sized benzo-crown ethers (cf. Scheme 1, 3 (benzo-15-crown-5), 4 (benzo-18-crown-6) and 5 (benzo-21-crown7)). O-BODIPYs 3, 4 and 5 exhibited in comparison to their known F-BODIPY analogues 3a, 4a and 5a (cf. Scheme 1) an improved solubility in aqueous medium and higher fluorescence quantum yields. Fluorometric study in aqueous solutions of 3, 4 and 5 in the presence of different cations show cation induced fluorescence enhancements (FE). Compared to the benzo-crown ether substituted F-BODIPY analogues 3a, 4a and 5a, we found for the free O-BODIPYs 3, 4 and 5 higher fluorescence quantum yields (φf) but lower cation induced FEs. We show that in aqueous medium the fluorescence quenching process (OFF switching), a photoinduced electron transfer, in O-BODIPYs 3, 4 and 5 is less effective and consequently sensitive and selective ON switching of the fluorescence by cations, too. Albeit these observations the novel benzo-21-crown-7 equipped fluorescent probe 5 exhibits a good fluorometric Ba2+ selectivity and Ba2+ sensitivity in conjunction to their aqueous solubility.

Multi-component Crystal Strategy for Improving Water Solubility and Antifungal Activity of Climbazole.

PURPOSE: The primary problem with climbazole (CLB), a broad-spectrum imidazole antifungal drug, is its low water solubility. In order to increase its water solubility and antifungal activity, three new multi-component crystals were synthesized in this work, and the intermolecular interactions were systematically studied. This work helps to optimize the CLB product formulation and extend its application prospects. METHODS: In this work, three novel multi-component crystals, CLB-malonic acid (CLB-MA) salt, CLB-succinic acid (CLB-SA) cocrystal and CLB-adipic acid (CLB-AA) cocrystal, were successfully synthesized. And the crystal structure, thermodynamic properties, solubility, dissolution, hygroscopicity, and antifungal activity of the three multi-component crystals were fully characterized by single-crystal X-ray diffraction (SCXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic water vapor adsorption (DVS) and powder dissolution tests, etc. The molecular interactions and molecular stacking in multi-component crystals were studied by Hirshfeld surface (HS), molecular surface electrostatic potential (MEP), interaction region indication (IRI) and atom and molecule (AIM) techniques. RESULTS: The results show that the three multi-component crystals have good moisture resistance stability, and their water solubility is 6-22 times that of pure CLB. Meanwhile, the measurement of the minimum inhibitory concentration (MIC) proves that the cocrystal/salt has a stronger antifungal activity than climbazole. Quantum chemistry calculations of crystal structure visualized and quantified the interactions that exist in multi-component crystals, and explored the microscopic mechanisms underlying the different performance of multi-component crystals.

Synthesis, physicochemical characterization, and investigation of anti-inflammatory activity of water-soluble PEGylated 1,2,4-Triazoles.

A series of water-soluble PEGylated 1,2,4-triazoles 5-8 were successfully synthesized from methyl 5-(chloromethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates 1. All of the water-soluble PEGylated 1,2,4-triazoles were characterized by FT-IR and 1H NMR spectroscopy. The solubility, in vitro plasma stability, and anti-inflammatory activity were also determined and compared to original methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates. For SAR study, all PEGylated 1,2,4-triazoles 5-8 performed potential anti-inflammatory activity on LPS-induced RAW 264.7 cells (IC50 = 3.42-7.81 µM). Moreover, the western blot result showed PEGylated 1,2,4-triazole 7d performed 5.43 and 2.37 folds inhibitory activity over iNOS and COX-2 expressions. On the other hand, the cell viability study revealed PEGylated 1,2,4-triazoles 7 and 8 with PEG molecular weight more than 600 presented better cell safety (cell viability > 95 %). Through the solubility and in vitro plasma stability studies, PEGylated 1,2,4-triazoles 7a-d exhibited higher hydrophilicity and prolonged 2.01 folds of half-life in compound 7d. Furthermore, the in vivo anti-inflammatory and gastric safety results indicated PEGylated 1,2,4-triazole 7d more effectively decreased the inflammatory response in edema and COX-2 expression and exhibited higher gastric safety than Indomethacin. Following the in vitro and in vivo study results, PEGylated 1,2,4-triazole 7d possessed favorable solubility, plasma stability features, safety, and significant anti-inflammatory activity to become the potential water-soluble anti-inflammatory candidate.

Preparation and evaluation of fenbendazole methyl-ß-cyclodextrin inclusion complexes.

As an orally effective benzimidazole anthelmintic agent, fenbendazole was not only widely used in agriculture and animal husbandry to prevent and treat parasites, but also shows anti-cancer effects against several types of cancer, exhibits anti-cancer effects in paclitaxel and doxorubicin-resistant cancer cells. However, fenbendazole's poor in water solubility (0.3 µg/mL), limits its clinical applications. Even great efforts were made toward increasing its water solubility, the results were not significant to reach anti-cancer drug delivery requirement (5-10 mg/mL). Through single factor and orthogonal strategy, many complex conditions were designed and used to prepare the complexes, the inclusion complex with methyl-ß-cyclodextrin with 29.2 % of inclusion rate and 89.5% of inclusion yield can increase drug's water solubility to 20.21 mg/mL, which is the best result so far. Its structure was confirmed by differential scanning calorimetry, scanning electron microscopic image, 1D and 2D NMR spectra in D2O. In its in vitro pharmacokinetic study, fenbendazole was 75% released in 15 min., in its in vivo pharmacokinetic study, the bio-availabilities of fenbendazole, its major metabolic anthelmintic agent oxfendazole and its minor metabolic anthelmintic agent oxfendazole were increased to 138%, 149% and 169% respectively, which would allow for fewer drug doses to achieve the same therapeutic effect and suggest that the complex can be used as a potential anticancer agent.

Design, Synthesis, and Biological Evaluation of Water-Soluble Prodrugs of C5-Curcuminoid GO-Y030 Based on Reversible Thia-Michael Reaction.

Although curcumin and its analogs exhibit anticancer activity, they are still not used as anticancer drugs because of their water insolubility and extremely poor bioavailability. This study describes the development of water-soluble prodrugs of GO-Y030, a potent antitumor C5-curcuminoid, in an attempt to enhance its bioavailability. These prodrugs release the parent compound via a retro-thia-Michael reaction. To endow sufficient hydrophilicity onto GO-Y030 via a single thia-Michael reaction of an aqueous entity, we used a modified glycoconjugate with a thiol group. The water-solubilizing motif was installed on GO-Y030 by the thia-Michael reaction of propargyl-polyethylene glycol (PEG)-thiol and subsequent click chemistry (CuAAC) reaction with 1-glycosyl azide. Turbidity measurements revealed a significantly improved water solubility of the prodrugs, demonstrating that disaccharide conjugates were completely dissolved in water at 100 µM. Their cytotoxicity was comparable to that of the parent compound GO-Y030, indicating the gradual in situ release of GO-Y030. The release of GO-Y030 from GO-Y199 via the retro-thia-Michael reaction was demonstrated through a degradation study in water. Our retro-thia-Michael reaction-based prodrug system can be used for targeting cancer cells.

Merging Counter-Propagation and Back-Propagation Algorithms: Overcoming the Limitations of Counter-Propagation Neural Network Models.

Artificial neural networks (ANNs) are nowadays applied as the most efficient methods in the majority of machine learning approaches, including data-driven modeling for assessment of the toxicity of chemicals. We developed a combined neural network methodology that can be used in the scope of new approach methodologies (NAMs) assessing chemical or drug toxicity. Here, we present QSAR models for predicting the physical and biochemical properties of molecules of three different datasets: aqueous solubility, acute fish toxicity toward fat head minnow, and bio-concentration factors. A novel neural network modeling method is developed by combining two neural network algorithms, namely, the counter-propagation modeling strategy (CP-ANN) with the back-propagation-of-errors algorithm (BPE-ANN). The advantage is a short training time, robustness, and good interpretability through the initial CP-ANN part, while the extension with BPE-ANN improves the precision of predictions in the range between minimal and maximal property values of the training data, regardless of the number of neurons in both neural networks, either CP-ANN or BPE-ANN.

Randomly Methylated ß-Cyclodextrin Inclusion Complex with Ketoconazole: Preparation, Characterization, and Improvement of Pharmacological Profiles.

As a powerful imidazole antifungal drug, ketoconazole's low solubility (0.017 mg/mL), together with its odor and irritation, limited its clinical applications. The inclusion complex of ketoconazole with randomly methylated ß-cyclodextrin was prepared by using an aqueous solution method after cyclodextrin selection through phase solubility studies, complexation methods, and condition selection through single factor and orthogonal strategies. The complex was confirmed by FTIR (Fourier-transform infrared spectroscopy), DSC (differential scanning calorimetry), TGA (thermogravimetric analysis), SEM (scanning electron microscope images), and NMR (Nuclear magnetic resonance) studies. Through complexation, the water solubility of ketoconazole in the complex was increased 17,000 times compared with that of ketoconazole alone, which is the best result so far for the ketoconazole water solubility study. In in vitro pharmacokinetic studies, ketoconazole in the complex can be 100% released in 75 min, and in in vivo pharmacokinetic studies in dogs, through the complexation, the Cmax was increased from 7.56 µg/mL to 13.58 µg/mL, and the AUC0~72 was increased from 22.69 µgh/mL to 50.19 µgh/mL, indicating that this ketoconazole complex can be used as a more efficient potential new anti-fungal drug.

Development of barley proteins into peptides nanomicelles for encapsulation of hydrophobic bioactive ingredient.

BACKGROUND: As natural polymer materials, barley proteins have been utilized to fabricate nanocarriers to encapsulate and delivery hydrophobic bioactive ingredients. However, as a result of the high proportion of hydrophobic amino acids and structural rigidity, barley protein-based nanocarriers tend to aggregate easily and have a low loading capacity, which greatly limits their application. In the present study, barley proteins were enzymolyzed to fabricate nanomicelles and then applied to encapsulate hydrophobic bioactive ingredient. RESULTS: Self-assembled barley peptides could be obtained by controllable enzymolysis of barley proteins. The obtained barley peptides could self-assemble into nanomicelles (BPNMs) with a diameter of approximately 90 nm when the concentration was > 2.1 µg mL-1. Hydrophobic interaction, disulfide bonds and hydrogen bonds were involved in maintaining the structure of BPNMs. Six self-assembled peptides (QQPFPQ, QTPLPQ, QLPQIPE, QPFPQQPQLPH, QPFPQQPPFGL and QPFPQQPPFWQQQ) were identified and they were characterized by alternating arrangement of hydrophobic amino acids and hydrophilic amino acids. Moreover, BPNMs were utilized to encapsulate hydrophobic bioactive ingredient quercetin. When quercetin was encapsulated by BPNMs, its water solubility was significantly increased, being approximately 30-fold higher than free quercetin. Meanwhile, encapsulation of BPNMs could greatly increase quercetin stability. The interaction between BPNMs and quercetin occurred spontaneously, mainly driven by van der Waals forces and hydrogen bonds. CONCLUSION: In the present study, BPNMs were successfully developed and could be used as a promising delivery system to improve the water solubility and stability of hydrophobic bioactive ingredients. © 2024 Society of Chemical Industry.

Synthesis of Quarternized Chitosans and Their Potential Applications in the Solubility Enhancement of Indomethacin by Solid Dispersion.

This study was designed to synthesize quarternized chitosans (Q-CS) and explore their potential application in aqueous solubility enhancement of indomethacin (IND), a BCS class-II drug. Three different Q-CS; N,N,N-trimethyl chitosan chloride (TMC), N-(4-N'-methylpyridinylmethyl) chitosan chloride (mPyCS), and N-(4-N',N',N'-trimethylaminobenzyl) chitosan chloride (TmBzCS) were synthesized and characterized through various spectroscopic analysis. Q-CS-based solid-dispersion (SD) composites of IND (Q-CS-IND) were prepared using the spray-drying method and characterized through Fourier transform infrared (FTIR), scanning electron microscopy (SEM), differential-scanning calorimetry (DSC), and powder X-ray diffraction (P-XRD). The solubility and dissolution profiles of SD-composites of IND were evaluated and compared with physical mixtures (PM). The IND contents were quantified and validated in the composites using UV-Vis spectrophotometer. FTIR and NMR analysis showed the successful preparation of Q-CS. TMC was found with the highest yield (55.13%) and mPyCS with the highest degree of quaternization (DQ) (63.37%). FT-IR analysis of IND-Q-CS composites demonstrated chemical interaction between carbonyl moieties of IND with functional groups of Q-CS. DSC and PXRD analyses demonstrated the transformation of IND in SD composites from crystalline to an amorphous form. All the IND-Q-CS composites were observed with a significant increase in the solubility and dissolution rate of the drug (1996.0 µg/min) compared to PM (1306.8 µg/min), which is higher than pure IND (791.6 µg/min). The contents of IND in TMC, mPyCS, and TmBzCS composites were 97.69-99.92%, 97.66-100.25%, and 97.18-100.11% respectively. Overall, the findings encourage the applications of Q-CS derivatives for increasing IND water solubility and warrant further in vivo biological profiling of IND composites.

Accounting for Cloud Nucleation Activation Mechanism of Secondary Organic Matter from α-Pinene Oxidation Using Experimentally Retrieved Water Solubility Distributions.

Activation of cloud droplets of aerosol particles from biogenic precursors plays a critical role in Earth's climate system. However, the molecular-level understanding of the cloud condensation nuclei (CCN) activation process for secondary organic matter (SOM) is still lacking. Here, we reduced the gap by segregating SOM from α-pinene based on water solubility. The chemical composition and CCN activity of the solubility-segregated fractions of SOM were measured. The results demonstrated for the first time by laboratory experiment that highly oxygenated compounds such as hydroperoxides and highly oxygenated organic molecules are important contributors for the CCN activity of α-pinene SOM. Meanwhile, relatively less water-soluble species were also abundant. Analysis based on the Köhler theory demonstrated that less water-soluble compounds in SOM remain undissolved during the cloud activation process, suggesting that the traditional single-parameter parameterization for CCN activation would not be sufficient for representing the process. In combination with the recent developments in SOM formation chemistry, the present study helps in understanding the interactions between the biosphere and climate.

Environmental Hazard Screening of Heterocyclic Polyaromatic Hydrocarbons: Physicochemical Data and In Silico Models.

Heterocyclic polyaromatic hydrocarbons (heterocyclic PAHs) are frequently found in the environment yet, compared to homocyclic PAHs, little attention has been paid to their environmental behavior and a comprehensive hazard assessment has not been undertaken. Surprisingly, the physicochemical data necessary to perform at least a screening-level assessment are also limited. To address this, we began by experimentally determining the physicochemical properties of heterocyclic PAHs, namely, water solubility (Sw), n-octanol-water partition coefficients (Kow), and organic carbon-water partition coefficients (Koc). The physicochemical data obtained in this study allowed for the development of clear structure-property relationships and evaluation of the predictive power of in silico models including conductor-like screening model for realistic solvation, the poly-parameter linear solvation energy relationship, and the quantitative structure-property relationship. Finally, heterocyclic and homocyclic PAHs were evaluated in terms of persistence, bioaccumulation, mobility, and toxicity to perform a screening-level comparative hazard assessment by integrating the data and evidence from multiple sources.

Enhancement of debitterness, water-solubility, and neuroprotective effects of naringin by transglucosylation.

Naringin found in citrus fruits is a flavanone glycoside with numerous biological activities. However, the bitterness, low water-solubility, and low bioavailability of naringin are the main issues limiting its use in the pharmaceutical and nutraceutical industries. Herein, a glucansucrase from isolated Leuconostoc citreum NY87 was used for trans-α-glucosylattion of naringin by using sucrose as substrate. Two naringin glucosides (O-α-D-glucosyl-(1'''' → 6″) naringin (compound 1) and 4'-O-α-D-glucosyl naringin (compound 2)) were purified and determined their structures by nuclear magnetic resonance. The optimization condition for the synthesis of compound 1 was obtained at 10 mM naringin, 200 mM sucrose, and 337.5 mU/mL at 28 °C for 24 h by response surface methodology method. Compound 1 and compound 2 showed 1896- and 3272 times higher water solubility than naringin. Furthermore, the bitterness via the human bitter taste receptor TAS2R39 displayed that compound 1 was reduced 2.9 times bitterness compared with naringin, while compound 2 did not express bitterness at 1 mM. Both compounds expressed higher neuroprotective effects than naringin on human neuroblastoma SH-SY5Y cells treated with 5 mM scopolamine based on cell viability and cortisol content. Compound 1 reduced acetylcholinesterase activity more than naringin and compound 2. These results indicate that naringin glucosides could be utilized as functional material in the nutraceutical and pharmaceutical industries. KEY POINTS: • A novel O-α-D-glucosyl-(1 → 6) naringin was synthesized using glucansucrase from L. citreum NY87. • Naringin glucosides improved water-solubility and neuroprotective effects on SH-SY5Y cells. • Naringin glucosides showed a decrease in bitterness on bitter taste receptor 39.

Arctigenin derivatives improve exercise performance in mice: synthesis and biological evaluation.

Arctigenin (ARG) has potent antifatigue activity, but its clinical application has been restricted for its poor water solubility. In this study, seven ARG derivatives containing different amino acids coupled via an ethoxy linker were synthesized, and tested for their solubility, as well as activities to improve exercise performance in mice. All of the derivatives showed improved solubility compared to that of ARG. Derivative Z-A-6 exhibited the highest activity, showing that the mice ran a 4.88-fold greater distance in the running wheel test and swam a 2.86-fold greater time in the swimming test than those in the blank control group. Z-A-6 treatment increased the plasma superoxide dismutase and catalase concentrations as well as reduced lactic acid and blood urea nitrogen accumulation during exercise. Z-A-6 treatment enhanced the phosphorylation of adenosine monophosphate-activated protein kinase, and no acute toxicity was observed. The results will contribute to the development of potential antifatigue agents.

A Novel Amphotericin B Hydrogel Composed of Poly(Vinyl Alcohol)/Borate Complex for Ophthalmic Formulation.

In this study, we developed a water-soluble complex-hydrogel viscosity-controlled formulation of amphotericin B (AmB). AmB is insoluble in water, but borax makes it soluble by forming a complex with AmB. Borax also forms complexes with poly(vinyl alcohol) (PVA) to produce viscous hydrogels. Furthermore, boric acid interacts with mucin expressed in corneal epithelial cells. Accordingly, by utilizing these properties of borax simultaneously, we prepared a water-soluble AmB complex-hydrogel with poly(vinyl alcohol)/borate (PVA-B-AmB), which is suitable for eye drops. PVA-B-AmB was easily prepared by simply mixing aqueous AmB solution dissolved in borax, PVA solution, and water. The 11B-NMR results suggested that PVA-B-AmB existed by bonding PVA and AmB via boronic acid. PVA-B-AmB (gel ratio = 0.55) has a viscosity of 18.3 ± 0.5 mPa·s and is suitable for ophthalmic formulations. This formulation exhibited sustained release of AmB of approximately 45% at 24 h. It was also shown that this formulation interacts with mucin. These results suggest that PVA-B-AmB can be used as a water-soluble AmB preparation suitable for ophthalmic use.

Synthesis and anti-HIV activity of non-nucleoside reverse-transcriptase inhibitor DB02 phosphate derivatives based on water-soluble optimization.

To improve the water solubility of anti-human immunodeficiency virus (HIV) agent DB02, an excellent non-nucleoside reverse-transcriptase inhibitor (NNRTI) obtained in our previous efforts, we designed and synthesized four phosphate derivatives of DB02 based on the molecular model of DB02 with RT. Here, the antiviral activity of these four derivatives was detected, leading to the discovery of compound P-2, which possessed a superior potency to the lead compound DB02 against wild-type HIV-1 and a variety of HIV-resistant mutant viruses significantly. Furthermore, the water solubility of P-2 was nearly 17 times higher than that of DB02, and the pharmacokinetic test in rats showed that P-2 demonstrate significantly improved oral bioavailablity of 14.6%. Our study showed that the introduction of a phosphate ester group at the end of the C-2 side chain of DB02 was beneficial to the improvement of its antiviral activity and pharmacokinetic properties, which provided a promising lead for the further development of S-DACOs type of NNRTIs.

Non-Steroidal Anti-Inflammatory Drugs Loaded to Micelles for the Modulation of Their Water Solubility.

The low water solubility of aspirin (ASPH) is well known, creating research challenges regarding both its composition and its delivery. Therefore, the development of new aspirin-based formulations that are water soluble is a research, technological, and financial issue. With the aim to improve the water solubility of ASPH, the micelle of formula SLS@ASPH (SLS = Sodium Lauryl Sulfate) was formed. The Critical Micelle Concentration (CMC) of SLS in the presence of ASPH was determined by ultrasonic velocity, complementary, and transient birefringence measurements. The SLS@ASPH was characterized by the melting point (m.p.), attenuated total reflection spectroscopy (FT-IR-ATR), and X-ray fluorescence spectroscopy (XRF) in a solid state and in a solution by ultraviolet-visible (UV-Vis) and 1H NMR spectroscopies. The SLS/ASPH molar ratio was determined to be 5/1 in SLS@ASPH. The inhibitory activity of SLS@ASPH towards lipoxygenase (LOX), an enzyme that takes part in the inflammation mechanism, was studied. The inhibitory activity of SLS@ASPH against LOX is 3.5-fold stronger than that of free SLS. The in vitro toxicity of the SLS@ASPH was tested on immortalized human keratinocyte (HaCaT) cells.

Development of Phytochemical Delivery Systems by Nano-Suspension and Nano-Emulsion Techniques.

The awareness of the existence of plant bioactive compounds, namely, phytochemicals (PHYs), with health properties is progressively expanding. Therefore, their massive introduction in the normal diet and in food supplements and their use as natural therapeutics to treat several diseases are increasingly emphasized by several sectors. In particular, most PHYs possessing antifungal, antiviral, anti-inflammatory, antibacterial, antiulcer, anti-cholesterol, hypoglycemic, immunomodulatory, and antioxidant properties have been isolated from plants. Additionally, their secondary modification with new functionalities to further improve their intrinsic beneficial effects has been extensively investigated. Unfortunately, although the idea of exploiting PHYs as therapeutics is amazing, its realization is far from simple, and the possibility of employing them as efficient clinically administrable drugs is almost utopic. Most PHYs are insoluble in water, and, especially when introduced orally, they hardly manage to pass through physiological barriers and scarcely reach the site of action in therapeutic concentrations. Their degradation by enzymatic and microbial digestion, as well as their rapid metabolism and excretion, strongly limits their in vivo activity. To overcome these drawbacks, several nanotechnological approaches have been used, and many nanosized PHY-loaded delivery systems have been developed. This paper, by reporting various case studies, reviews the foremost nanosuspension- and nanoemulsion-based techniques developed for formulating the most relevant PHYs into more bioavailable nanoparticles (NPs) that are suitable or promising for clinical application, mainly by oral administration. In addition, the acute and chronic toxic effects due to exposure to NPs reported so far, the possible nanotoxicity that could result from their massive employment, and ongoing actions to improve knowledge in this field are discussed. The state of the art concerning the actual clinical application of both PHYs and the nanotechnologically engineered PHYs is also reviewed.

Rhenium(I) Block Copolymers Based on Polyvinylpyrrolidone: A Successful Strategy to Water-Solubility and Biocompatibility.

A series of diphosphine Re(I) complexes Re1-Re4 have been designed via decoration of the archetypal core {Re(CO)2(N^N)} through the installations of the phosphines P0 and P1 bearing the terminal double bond, where N^N = 2,2'-bipyridine (N^N1), 4,4'-di-tert-butyl-2,2'-bipyridine (N^N2) or 2,9-dimethyl-1,10-phenanthroline (N^N3) and P0 = diphenylvinylphosphine, and P1 = 4-(diphenylphosphino)styrene. These complexes were copolymerized with the corresponding N-vinylpyrrolidone-based Macro-RAFT agents of different polymer chain lengths to give water-soluble copolymers of low-molecular p(VP-l-Re) and high-molecular p(VP-h-Re) block-copolymers containing rhenium complexes. Compounds Re1-Re4, as well as the copolymers p(VP-l-Re) and p(VP-h-Re), demonstrate phosphorescence from a 3MLCT excited state typical for this type of chromophores. The copolymers p(VP-l-Re#) and p(VP-h-Re#) display weak sensitivity to molecular oxygen in aqueous and buffered media, which becomes almost negligible in the model physiological media. In cell experiments with CHO-K1 cell line, p(VP-l-Re2) and p(VP-h-Re2) displayed significantly reduced toxicity compared to the initial Re2 complex and internalized into cells presumably by endocytic pathways, being eventually accumulated in endosomes. The sensitivity of the copolymers to oxygen examined in CHO-K1 cells via phosphorescence lifetime imaging microscopy (PLIM) proved to be inessential.

The Use of Cyclodextrin Inclusion Complexes to Increase the Solubility and Pharmacokinetic Profile of Albendazole.

Albendazole is the preferred deworming drug and has strong insecticidal effects on human and animal helminth parasites, showing remarkable activity against hepatocellular carcinoma and colorectal cancer cells. However, it is classified as being in class II in the Biopharmaceutics Classification System due to its poor water solubility (0.2 mg/L) and high permeability, which make the clinical application of albendazole impractical. Through complexation with methyl-ß-cyclodextrin, as the best result so far, albendazole's water solubility was increased by 150,000 times, and albendazole could be 90% released during the first 10 min. In an in vivo pharmacokinetic study, the Cmax and Tmax of the active metabolized sulfoxide were changed from 2.81 µg/mL at 3 h to 10.2 µg/mL at 6 h and the AUC0-48 was increased from 50.72 h⁎µg/mL to 119.95 h⁎µg/mL, indicating that the inclusion complex obtained can be used as a new oral therapeutic anti-anthelmintic and anti-tumor agent formulation.