Synthesis and Characterization of a Luminescent Cyclic Poly(ethylene oxide)-Polypyridyl Ruthenium Complex.

We report the synthesis of a macrocyclic poly(ethylene oxide) (PEO) connected by one [Ru(bpy)3]2+ unit (where bpy = 2,2'-bipyridine), a photoactive metal complex that provides photosensitivity and potential biomedical applications to this polymer structure. The PEO chain provides biocompatibility, water solubility, and topological play. The macrocycles were successfully synthesized by copper-free click cycloaddition between a bifunctional dibenzocyclooctyne (DBCO)-PEO precursor and 4,4'-diazido-2,2'-bipyridine, followed by complexation with [Ru(bpy)2Cl2]. The cyclic product accumulated efficiently in MCF7 cancer cells and exhibited a longer fluorescence lifetime than its linear analogue, likely due to differences in the accessibility of the ligand-centered/intraligand states of Ru polypyridyls in both topologies.

Diosmin-Loaded Nanoemulsion-Based Gel Formulation: Development, Optimization, Wound Healing and Anti-Inflammatory Studies.

The wound-healing process is complex and prone to interruption or failure, which can result in the development of chronic wounds that never heal. This can be overcome by seeking prompt medical attention, which will reduce the likelihood of complications and speed up the healing of the cutaneous wound. It has been established that functionalized engineered biomaterials are a possible strategy for starting skin wound care. The purpose of the current study is to develop a diosmin (DSM)-loaded nanoemulsion (NE)-based gel formulation and to investigate its wound healing and anti-inflammatory activity on rats. The DSM-loaded NEs (F1-F17) were developed and optimized with the help of Box-Behnken Design Expert. The DSM-Nes were developed using lauroglycol 90 (LG90®) as oil, Tween-80 as surfactant and transcutol-HP (THP) as co-surfactant. The optimized Nes showed globule size (41 ± 0.07 nm), polydispersity index (PDI) (0.073 ± 0.008) and percentage of entrapment efficiency (%EE) (87 ± 0.81%). This optimized DSM-loaded NEs (F1) was further evaluated and incorporated into 1% carbopol 940 gel. F1-loaded gel was then characterized for drug content, spreadability, in vitro release, wound healing, and anti-inflammatory studies. The developed gel of DSM was found to show significantly better (p < 0.05) wound-healing and anti-inflammatory activity.

Nanocrystallization Improves the Solubilization and Cytotoxic Effect of a Poly (ADP-Ribose)-Polymerase-I Inhibitor.

Olaparib (OLA) is an anticancer agent that acts by inhibiting the poly (ADP-ribose)-polymerase-I (PARP-I). Due to its low solubility and low permeability, it has been placed as a BCS Class-IV drug and hence its clinical use is limited. In this study, we develop the nanocrystals of OLA as a way to improve its solubility and other performances. The OLA-NCs were prepared by antisolvent precipitation method through homogenization and probe sonication technique using a novel amphiphilic polymeric stabilizer (Soluplus®). Particle characterization resulted approximately 103.13 nm, polydispersity-index was 0.104 with positive zeta-potential of +8.67 mV. The crystal morphology by SEM of OLA-NCs (with and without mannitol) exhibited nano-crystalline prism-like structures as compared to the elongated OLA-pure. The DSC, XRD and FTIR were performed to check the interaction of Soluplus, mannitol and OLA did not exhibit any physical interaction among the OLA, Soluplus® and mannitol that is indicated by the presence of parent wave number peak. Two-fold increased solubility of OLA was found in PBS with Soluplus® from the NCs (69.3 ± 6.2 µgmL−1) as compared to pure drug (35.6 ± 7.2 µgmL−1). In vitro release of drug from OLA-NCs was higher (78.2%) at 12 h at pH 6.8 and relatively lower (53.1%) at pH 1.2. In vitro cellular cytotoxicity and anticancer effects were examined on MCF-7 cells. OLA-NCs were found effectively potent to MCF-7 cells compared with OLA-pure with approximately less than half IC50 value during MTT assay. Estimation of p53, Caspase-3 and Caspase-9 in MCF-7 cells indicated that OLA-NCs have significantly (p < 0.05) increased their expressions. After single oral dose in rats, 12 h plasma drug concentration-time profile indicated approximately 2.06-, 2.29-, 2−25- and 2.62-folds increased Cmax, AUC0-12 h, AUC0-∞ and AUMC0-∞, respectively, from the NCs as compared to OLA-pure. Storage stability indicated that the OLA-NCs was physically and chemically stable at 4 °C, 25 °C and 40 °C up to 6-months. Overall, OLA-NCs were deliberated; its potential feasibility to overwhelm the formulation challenges related to poorly soluble drugs and its future clinical applications.

Special Issue on "Function of Polymers in Encapsulation Process".

Encapsulation technology comprises enclosing active agents (core materials) within a homogeneous/heterogeneous matrix (wall material) at the micro/nano scale [...].

Encapsulation of Cerium Nitrate within Poly(urea-formaldehyde) Microcapsules for the Development of Self-Healing Epoxy-Based Coating.

In order to study the release of cerium nitrate in a self-healing epoxy-based coating, poly (urea-formaldehyde) (PUF) microcapsules containing cerium nitrate were synthesized. The effects of healing agent concentration and weight percent of microcapsules in the epoxy resin were studied through the incorporation of microcapsules within an epoxy-based coating. The prepared microcapsules were characterized using thermogravimetric analysis and Fourier transform infrared spectroscopy and confirmed the successful encapsulation of cerium nitrate within PUF capsules. The self-healing performance of the prepared epoxy coating was investigated in 0.6 M NaCl solution using electrochemical impedance spectroscopy (EIS) tests. The EIS results indicated the successful release of encapsulated cerium nitrate from PUF microcapsules once the damage occurred in the epoxy coating, which led to effective self-healing of the epoxy-based coating. The presence of chlorine and cerium ions in the solution led to the precipitation of cerium hydroxides and oxides in the scratched area as a passive layer which hindered the corrosion in the damaged area. In addition, the EIS results showed that the healing performance of the coatings depends on the weight percent of microcapsules and the concentration of the self-healing agent. The highest self-healing performance was achieved for the maximum amount of microcapsule incorporation (10 wt %), while the increase in the microcapsule percent led to a decrease in the adhesion of the coating to the substrate.

Enhanced Dissolution of Sildenafil Citrate Using Solid Dispersion with Hydrophilic Polymers: Physicochemical Characterization and In Vivo Sexual Behavior Studies in Male Rats.

Sildenafil citrate (SLC) is a frequently used medication (Viagra®) for the treatment of erectile dysfunction (ED). Due to its poor solubility, SLC suffers from a delayed onset of action and poor bioavailability. Hence, the aim of the proposed work was to prepare and evaluate solid dispersions (SDs) with hydrophilic polymers (Kolliphor® P188, Kollidon® 30, and Kollidon®-VA64), in order to enhance the dissolution and efficacy of SLC. The SLC-SDs were prepared using a solvent evaporation method (at the ratio drug/polymer, 1:1, w/w) and characterized by Differential Scanning Calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Scanning electron microscope (SEM), drug content, yield, and in vitro release studies. Based on this evaluation, SDs (SLC-KVA64) were optimized, with a maximum release of drug (99.74%) after 2 h for all the developed formulas. The SDs (SLC-KVA64) were further tested for sexual behavior activity in male rats, and significant enhancements in copulatory efficiency (81.6%) and inter-copulatory efficiency (44.9%) were noted in comparison to the pure SLC drug, when exposed to the optimized SLC-KVA64 formulae. Therefore, SD using Kollidon®-VA64 could be regarded as a potential strategy for improving the solubility, in vitro dissolution, and therapeutic efficacy of SLC.

Preparation of pH-Responsive Vesicular Deferasirox: Evidence from In Silico, In Vitro, and In Vivo Evaluations.

pH-sensitive nanocarriers can effectively deliver anticancer drugs to tumors and reduce the adverse effects of conventional chemotherapy. In this light, we prepared a novel pH-responsive deferasirox (DFX)-loaded vesicle and comprehensively performed in silico, in vitro, and in vivo studies to examine the properties of the newly synthesized formulation. Physiochemical assessment of the developed formulations showed that they have an average size (107 ± 2 nm), negative zeta potential (-29.1 ± 1.5 mV), high encapsulation efficiency (84.2 ± 2.6%), and a pH-responsive release. Using the molecular dynamics simulation, the structural and dynamic properties of ergosterol-containing niosomes (ST60/Ergo) in the presence of DFX molecules were analyzed and showed a good interaction between DFX and vesicle components. Cytotoxic assessment showed that niosomal DFX exhibited a greater cytotoxic effect than free DFX in both human cancer cells (MCF-breast cancer and Hela cervical cancer) and induced evident morphological features of apoptotic cell death. No marked difference between the ability of free and niosomal DFX was found in activating caspase-3 in Hela cells. Eight weeks of intraperitoneal administrations of free DFX at three doses caused a significant increase in serum biochemical parameters and liver lipid peroxidation. Treatment with 5 mg/kg dose of niosomal DFX caused a significant increase in serum creatinine (P < 0.05); however, other parameters remained unchanged. On the other hand, administration of niosomal DFX at the highest dose (10 mg/kg) significantly increased serum creatinine (P < 0.05), BUN, and serum liver enzymes compared to the control rats (P < 0.001). Based on the results, the application of pH-responsive DFX-loaded niosomes, as a novel drug delivery platform, may yield promising results in cancer treatment.

Gold nanoparticles endowed with low-temperature colloidal stability by cyclic polyethylene glycol in ethanol.

The colloidal stability of metal nanoparticles is tremendously dependent on the thermal behavior of polymer brushes. Neat polyethylene glycol (PEG) presents an unconventional upper critical solution temperature in ethanol, where phase segregation and crystallization coexist. This thermal behavior translated to a PEG brush has serious consequences on the colloidal stability in ethanol of gold nanoparticles (AuNPs) modified with PEG brushes upon cooling. We observed that AuNPs (13 nm diameter) stabilized with conventional linear PEG brushes (Mn = 6 and 11 kg mol-1) in ethanol suffer from reversible phase separation upon a temperature drop over the course of a few hours. However, the use of a polymer brush with cyclic topology as a stabilizer prevents sedimentation, ensuring the colloidal stability in ethanol at -25 °C for, at least, four months. We postulate that temperature-driven collapse of chain brushes promotes the interpenetration of linear chains, causing progressive AuNP sedimentation, a process that is unfavorable for cyclic polymer brushes whose topology prevents chain interpenetration. This study reinforces the notion about the importance of polymer topology on the colloidal stability of AuNPs.

Design of Olmesartan Medoxomil-Loaded Nanosponges for Hypertension and Lung Cancer Treatments.

Olmesartan medoxomil (OLM) is one of the prominent antihypertensive drug that suffers from low aqueous solubility and dissolution rate leading to its low bioavailability. To improve the oral bioavailability of OLM, a delivery system based on ethylcellulose (EC, a biobased polymer) nanosponges (NSs) was developed and evaluated for cytotoxicity against the A549 lung cell lines and antihypertensive potential in a rat model. Four OLM-loaded NSs (ONS1-ONS4) were prepared and fully evaluated in terms of physicochemical properties. Among these formulations, ONS4 was regarded as the optimized formulation with particle size (487 nm), PDI (0.386), zeta potential (ζP = -18.1 mV), entrapment efficiency (EE = 91.2%) and drug loading (DL = 0.88%). In addition, a nanosized porous morphology was detected for this optimized system with NS surface area of about 63.512 m2/g, pore volume and pore radius Dv(r) of 0.149 cc/g and 15.274 Å, respectively, measured by nitrogen adsorption/desorption analysis. The observed morphology plus sustained release rate of OLM caused that the optimized formulation showed higher cytotoxicity against A549 lung cell lines in comparison to the pure OLM. Finally, this system (ONS4) reduced the systolic blood pressure (SBP) significantly (p < 0.01) as compared to control and pure OLM drug in spontaneously hypertensive rats. Overall, this study provides a scientific basis for future studies on the encapsulation efficiency of NSs as promising drug carriers for overcoming pharmacokinetic limitations.

Lignin-Stabilized Doxorubicin Microemulsions: Synthesis, Physical Characterization, and In Vitro Assessments.

Encapsulation of the chemotherapy agents within colloidal systems usually improves drug efficiency and decreases its toxicity. In this study, lignin (LGN) (the second most abundant biopolymer next to cellulose on earth) was employed to prepare novel doxorubicin (DOX)-loaded oil-in-water (O/W) microemulsions with the aim of enhancing the bioavailability of DOX. The droplet size of DOX-loaded microemulsion was obtained as ≈ 7.5 nm by dynamic light scattering (DLS) analysis. The entrapment efficiency (EE) % of LGN/DOX microemulsions was calculated to be about 82%. In addition, a slow and sustainable release rate of DOX (68%) was observed after 24 h for these microemulsions. The cytotoxic effects of standard DOX and LGN/DOX microemulsions on non-malignant (HUVEC) and malignant (MCF7 and C152) cell lines were assessed by application of a tetrazolium (MTT) colorimetric assay. Disruption of cell membrane integrity was investigated by measuring intracellular lactate dehydrogenase (LDH) leakage. In vitro experiments showed that LGN/DOX microemulsions induced noticeable morphological alterations and a greater cell-killing effect than standard DOX. Moreover, LGN/DOX microemulsions significantly disrupted the membrane integrity of C152 cells. These results demonstrate that encapsulation and slow release of DOX improved the cytotoxic efficacy of this anthracycline agent against cancer cells but did not improve its safety towards normal human cells. Overall, this study provides a scientific basis for future studies on the encapsulation efficiency of microemulsions as a promising drug carrier for overcoming pharmacokinetic limitations.

Development of Sustained Release Baricitinib Loaded Lipid-Polymer Hybrid Nanoparticles with Improved Oral Bioavailability.

Baricitinib (BTB) is an orally administered Janus kinase inhibitor, therapeutically used for the treatment of rheumatoid arthritis. Recently it has also been approved for the treatment of COVID-19 infection. In this study, four different BTB-loaded lipids (stearin)-polymer (Poly(d,l-lactide-co-glycolide)) hybrid nanoparticles (B-PLN1 to B-PLN4) were prepared by the single-step nanoprecipitation method. Next, they were characterised in terms of physicochemical properties such as particle size, zeta potential (ζP), polydispersity index (PDI), entrapment efficiency (EE) and drug loading (DL). Based on preliminary evaluation, the B-PLN4 was regarded as the optimised formulation with particle size (272 ± 7.6 nm), PDI (0.225), ζP (-36.5 ± 3.1 mV), %EE (71.6 ± 1.5%) and %DL (2.87 ± 0.42%). This formulation (B-PLN4) was further assessed concerning morphology, in vitro release, and in vivo pharmacokinetic studies in rats. The in vitro release profile exhibited a sustained release pattern well-fitted by the Korsmeyer-Peppas kinetic model (R2 = 0.879). The in vivo pharmacokinetic data showed an enhancement (2.92 times more) in bioavailability in comparison to the normal suspension of pure BTB. These data concluded that the formulated lipid-polymer hybrid nanoparticles could be a promising drug delivery option to enhance the bioavailability of BTB. Overall, this study provides a scientific basis for future studies on the entrapment efficiency of lipid-polymer hybrid systems as promising carriers for overcoming pharmacokinetic limitations.

Cyclic Polyethylene Glycol as Nanoparticle Surface Ligand.

Cyclic polymers behave different than linear polymers due to the lack of end groups and smaller coil dimensions. Herein, we demonstrate that cyclic polyethylene glycol (PEG) can be used as an alternative of classical linear PEG ligands for gold nanoparticle (AuNP) stabilization. We observed that the brush height of cyclic PEG on AuNPs of diameter 4.4 and 13.2 nm increases identically as that of linear brushes with (Nσ1/2)0.7 (N, number of monomers in a chain and σ, grafting density) and that cyclic brushes are more stretched than their linear analogues when compared to their unperturbed dimensions. Such structural effect and the reduced footprint diameter in cyclic brushes with the entire chain in a concentrated polymer brush regime explains the distinct response of NPs to ionic strength and temperature, respectively, compared to linear analogues. These experiments are an important step in understanding the effect of polymer brush topology on colloidal properties.

Low-Energy Encapsulation of α-Tocopherol Using Fully Food Grade Oil-in-Water Microemulsions.

Encapsulation of active agents, such as vitamins and antioxidants, is one of the possibilities that allow their incorporation in beverages, food, or in pharmaceutical products. Simultaneously, encapsulation protects these active agents from oxidation, producing more stable active compounds. Formation of nanodroplets by spontaneously formed microemulsion (ME) offers, on one hand, a low-energy technology of encapsulation and, on the other hand, because of a small size of the droplets, it assures long-term stability even in harsher environments. In this study, oil-in-water MEs allowed the low-energy encapsulation of α-tocopherol (αToc) into an aqueous medium with the aid of fully food-grade ingredients, using isoamyl acetate as the dispersed oil phase, which was selected between three different types of oils. Both cosurfactant-free and cosurfactant-holder ME systems were formulated, in which Tween 20 and glycerol were employed as the surfactant and the cosurfactant, respectively. The ME monophasic area was determined through the construction of pseudoternary phase diagrams. The encapsulated αToc within 10-20 nm nanocapsules showed radical scavenging activity dependent on the encapsulated amount of αToc, as it was demonstrated by electron paramagnetic resonance spectroscopy. The radical scavenging activity slightly increased within the time investigated, indicating a slow release of the active compound from the nanodroplets, which is a promising result for their application, especially in pharmaceuticals.

Blocking probe as a potential tool for detection of single nucleotide DNA mutations: design and performance.

Developing strategies to detect single nucleotide DNA mutations associated with treatment decisions in cancer patients from liquid biopsies is a rapidly emerging area of personalized medicine that requires high specificity. Here we report how to design an easy enzyme-free approach that could create a platform for detection of L858R mutation of EGFR that is a predictive biomarker of tyrosine kinase treatment in many cancers. This approach includes the addition of blocking probes with the antisense ssDNA at different blocking positions and different concentrations such as to avoid re-annealing with the respective sense ssDNA. The successful blocking strategy was corroborated by fluorescence spectroscopy in solution using two distinct FRET pairs and quartz crystal microbalance with dissipation (QCM-D) measurements under comparable experimental conditions, as the hybridization rate-limiting step in both methods is the nucleation process. The efficiency of hybridization of each blocking probe was strongly dependent on its position particularly when the analyte possesses a secondary hairpin-structure. We tested the performance of blocking probes in combination with gold nanoparticles; the obtained results were in agreement with those of QCM-D. These findings could facilitate the development of better biosensors, especially those using probes containing secondary structure.

Facile synthesis of supramolecular ionic polymers that combine unique rheological, ionic conductivity, and self-healing properties.

A new family of supramolecular ionic polymers is synthesized by a simple method using (di-/tri-)carboxylic acids and (di-/tri-)alkyl amines. These polymers are formed by carboxylate and ammonium molecules that are weakly bonded together by a combination of ionic and hydrogen bonds, becoming solid at room temperature. The supramolecular ionic polymers show a sharp rheological transition from a viscoelastic gel to a viscous liquid between 30 and 80 °C. This sharp viscosity decrease is responsible for an unprecedented jump in ionic conductivity of four orders of magnitude in that temperature range. As a potential application, this chemistry can be used to develop polymeric materials with self-healing properties, since it combines properties from supramolecular polymers and ionomers into the same material.