Preparation and photophysical properties of quinazoline-based fluorophores

The donor–acceptor design is a classic method of synthesizing new fluorescent molecules. In this study, a series of new fluorescent compounds (1–10) were synthesized based on 2-(3,5-bis(trifluoromethyl)phenyl)-quinazoline acceptor and various amino donors. The fluorescent emissions of 1–10 cover the spectrum from 414 nm to 597 nm in cyclohexane solutions with various amino donors on 4- or 7-positions of quinazoline. Ultimately, compounds 1 and 2 presented the highest photoluminescence quantum yield (QY) over 80%, while compound 10 provided the largest Stokes shift (161 nm) in cyclohexane. Most of them have strong emissions in aggregated states such as in nanoparticles, in powders, in crystals and in films. Mechanochromic properties were observed for compounds 1, 2, 4 and 7. Furthermore, blue OLEDs were fabricated by using compound 2 or 7 as the active layer.

A series of new fluorescent compounds were synthesized based on 2-(3,5-bis(trifluoromethyl)phenyl)-quinazoline, with alterable emission, high quantum yield, mechanochromic properties and can be applied as an optoelectronic material for blue OLED.     

Hydrotalcite–PLGA composite nanoparticles for loading and delivery of danshensu

As one of the main pharmacodynamic components present in the water-soluble components of Salvia miltiorrhiza (Danshen), danshensu (DSS) is applicable to treating cardiovascular diseases. Nevertheless, such drawbacks as low water solubility and short half-life could reduce its bioavailability and restrict its clinical applicability. Therefore, it can be integrated into drug-carrying polymer microspheres, which is effective in improving the bioavailability of drugs. In this study, DSS was first embedded in a hydrotalcite (LDH) layer. Then, polylactic acid (PLGA) with excellent biocompatibility and biodegradability was coated on the surface. PLGA/DSS–LDH composite nanoparticles were prepared using the double emulsion (w/o/w) solvent evaporation method. As revealed by XRD and FTIR studies, success was achieved in embedding the drug DSS in the LDH layer, with the drug loading capacity of the LDH reaching 32.6%. A study was conducted on the encapsulation efficiency, surface morphology and in vitro drug release characteristics of PLGA/DSS–LDH. PLGA/DSS–LDH composite nanoparticles exhibited not only a high encapsulation efficiency but also a sustained release profile. The hemolysis assays demonstrated that the PLGA/DSS–LDH composite nanoparticles were ineffective in the induction of hemolysis, suggesting that PLGA/LDH composite nanoparticles can provide an effective controlled release drug system for pharmaceutics.

As one of the main pharmacodynamic components present in the water-soluble components of Salvia miltiorrhiza (Danshen), danshensu (DSS) is applicable to treating cardiovascular diseases.     

Sustained in vitro interferon-beta release and in vivo toxicity of PLGA and PEG-PLGA nanoparticles

Interferon-beta-1a (IFN-β-1a) can diminish the symptoms of relapsing-remitting multiple sclerosis. Herein, we prepared sustained drug delivery IFN-β-1a-loaded nanoparticles by a double emulsion solvent evaporation method. Bovine serum albumin (BSA) model drug was used to optimize the preparation of nanoparticles composed of four types of poly(lactic-co-glycolic acid) (PLGA) polymers and two pegylated PLGA (PEG-PLGA) polymers. Via optimization, selected PLGA and PEG-PLGA polymers were able to entrap IFN-β-1a with high encapsulation efficiency (>95%) and low size (145 nm and 163 nm, respectively). In vitro release kinetics of BSA and IFN-β showed similar tendency for PLGA and PEG-PLGA nanoparticles, respectively. Although the drug loaded nanoparticles did not show toxicity in hepatocyte cells, mild toxic effects such as pale kidney and pyelectasis were observed in the in vivo studies.

Interferon-beta-1a (IFN-β-1a) can diminish the symptoms of relapsing-remitting multiple sclerosis.     

pH-responsive polymeric nanoparticles with tunable sizes for targeted drug delivery

Biodegradable nanoparticles (NPs) have shown great promise as intracellular imaging probes, nanocarriers and drug delivery vehicles. In this study, we designed and prepared amphiphilic cellulose derivatives via Schiff base reactions between 2,3-dialdehyde cellulose (DAC) and amino compounds. Polymeric NPs were facilely fabricated via the self-assembly of the as-synthesized amphiphilic macromolecules. The size distribution of the obtained NPs can be tuned by changing the amount and length of the grafted hydrophobic side-chains. Anticancer drugs (DOX) were encapsulated in the NPs and the drug-loaded NPs based on cellulose derivatives were stable in neutral and alkaline environments for at least a month. They rapidly decomposed with the efficient release of the drug in acidic tumor microenvironments. These drug-loaded NPs have the potential for application in cancer treatment.

Novel nanoparticles for efficient drug delivery were designed and constructed using polymeric 2,3-dialdehyde cellulose (DAC). The drug DOX was encapsulated into nanoparticles and underwent thoroughly controlled release in acidic tumor microenvironments.     

Electrochemical detection of mercuric(ii) ions in aqueous media using glassy carbon electrode modified with synthesized tribenzamides and silver nanoparticles

This study reports the synthesis, characterization, and mercuric ion detection ability of novel tribenzamides having flexible and rigid moieties. N-{4-[2-(1,3-Benzoxazolyl)]phenyl}-3,5-N,N′-bis(4-alkyloxybenzoyl)benzamides (TBa-TBc) were synthesized from newly synthesized diamine, N-(1,3-benzoxazol-2-yl-phenyl)-3,5-diaminobenzamide (BODA) and p-alkoxybenzoic acids (p-ABA) by amidation reaction. Structural characterization of the synthesized compounds was done through spectroscopic techniques (FT-IR and NMR). The synthesized tribenzamides along with silver nanoparticles were used for modification of a glassy carbon electrode. Square wave anodic stripping voltammetry was carried out to test the performance of the modified electrode for mercuric ion detection. The designed sensor was found to demonstrate the qualities of sensitivity, selectivity, reproducibility and anti-interference ability. The sensing platform helped in detecting femtomolar concentrations of mercuric ions which are much below the level declared toxic by the World Health Organization.

This study reports the synthesis, characterization, and mercuric ion detection ability of novel tribenzamides having flexible and rigid moieties.     

PLGA/xylitol nanoparticles enhance antibiofilm activity via penetration into biofilm extracellular polymeric substances

Biofilms are gelatinous masses of microorganisms attached to wound surfaces. Previous studies suggest that biofilms generate resistance towards antibiotic treatments. It was reported that hydrogels containing xylitol and antibiotic combinations produced additive antibiofilm inhibition. However, hydrogel formulations lack specificity, due to which xylitol cannot penetrate into the biofilm matrix and gets easily degraded by bacterial beta lactamase enzymes. It was hypothesized that the incorporation of xylitol in PLGA (polylactic-co-glycolic acid) nanoparticles will enhance penetration into the EPS (extra polymeric substance) component of the biofilm matrix and potentially overcome the antibiotic resistance associated with the biofilms. The purpose of this study was to develop PLGA nanoparticles loaded with xylitol, which will enhance bacterial biofilm penetration. The nanoparticles were loaded with different amounts of xylitol (0.5–5% w/w) and characterized for physiochemical and drug release properties. The metabolic antibiofilm activity of the PLGA nanoparticles containing xylitol was demonstrated by an XTT assay using as references the cultures of Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) and the polymicrobial biofilms of both bacterial strains. Live/dead viability staining was also performed to investigate the viability ratio of bacterial cells present in the biofilms. The biofilm penetration study of the PLGA nanoparticles was assessed by combining the nanoparticles with conjugated concanavalin A (Con A)-fluorescein isothiocyanate (FITC) and by viewing using confocal laser scanning electron microscopy (CLSM). In conclusion, the PLGA nanoparticles loaded with xylitol were successfully developed and were found to promote the antibiofilm activity of xylitol in infected wounds.

Biofilms are gelatinous masses of microorganisms attached to wound surfaces.     

Mathematical modeling and parametrical analysis of the temperature dependency of control drug release from biodegradable nanoparticles

In this study we describe a mathematical analysis that considers the temperature effects of the controlled drug release process from biodegradable poly-d,l-lactide-co-glycolide (PLGA) nanoparticles. Temperature effects are incorporated and applied to two drug release models. The first one consists of a two-stage release process that considers only simultaneous contributions of initial burst and nanoparticle degradation–relaxation (BR model). The second one is a three release stage model that considers, additionally, a simultaneous drug diffusion (BRD model) step. In these models, the temperature dependency of the release parameters, initial burst constant, k_b, the rate of degradation–relaxation constant, k_r, time to achieve 50% of release, t_max, and effective diffusion coefficient constant (D_e), are determined using mathematical expressions analogous to the Arrhenius equation. The temperature dependent models are used to analyze the release of previously encapsulated Rhodamine 6G dye as a model drug in polyethylene glycol modified PLGA nanoparticles. The experimental data used to develop the mathematical model was obtained from release studies carried out in phosphate buffer pH 7.4 at 37 °C, 47 °C, and 57 °C. Multiphasic release behaviors with an overall increase rate associated with the incubation temperature were observed. The study incorporates a parametrical analysis that can evaluate diverse temperature variation effects of the controlled release parameters for the two models.

Temperature dependence of the main parameters involved in the drug release process from biodegradable nanoparticles.     

Preparation and in vitro characterization of valsartan-loaded ethyl cellulose and poly(methyl methacrylate) nanoparticles

Valsartan is an antihypertensive drug used primarily orally, however, due to its hydrophobic nature it has got low bio-availability thus requiring higher dosage/frequency and causing more side effects. The aim of our work was to prepare valsartan-loaded nanoparticles by using ethyl cellulose and poly(methyl methacrylate) polymers which can be administered orally and to investigate the preparation conditions and their significance as potential drug carriers for valsartan delivery by in vitro release studies. Ethyl cellulose and poly(methyl methacrylate) polymers were used for the preparation of nanoparticles by single emulsion-solvent evaporation technique. The formation of drug-loaded nanoparticles was designed by experimental design for size and encapsulation efficiency, in addition the prepared nanosuspensions were nano spray dried in order to gain a powder form that is easy to handle and store. Both of the nano spray dried formulations had an amorphous structure in contrast to the pure drug according to differential scanning calorimetry and X-ray diffraction analysis, which can be advantageous in drug absorption. The originally processed ethyl cellulose-valsartan nanoparticles increased the solubility of the drug in the model intestinal medium, while poly(methyl methacrylate)-valsartan nanoparticles enabled substantially prolonged drug release. The release kinetics of both types of nanoparticles could be described by the Weibull model.

Valsartan-loaded ethyl cellulose and poly(methyl methacrylate) nanoparticles were prepared and nano spray-dried. The active agent was structurally changed in the nanoparticles, which could be advantageous in the intestinal absorption.     

Comparison of drug release behavior of bacterial cellulose loaded with ibuprofen and propranolol hydrochloride

The aim of this study was to investigate the drug release behavior from bacterial cellulose (BC). Ibuprofen and propranolol hydrochloride were used as model drugs to represent low and highly water soluble drugs. The drug was loaded into the BC by immersing the partially swollen BC in a solution of drug concentrations ranging from 0.05 to 0.5 mg mL⁻¹ and then drying by two different methods: air-drying and freeze-drying. The results showed that the type of drug and the drying method influenced the drug loading efficiency and drug release behavior. For ibuprofen, high drug loading efficiency was found when loading the drug into BC at low concentration and vice versa for propranolol hydrochloride. The drug-loaded BC prepared by the freeze-drying method showed a sustained release regardless of drug type and drug-loaded amount. The sustained release followed the Higuchi and Korsmeyer–Peppas models. On the other hand, when using the air-drying method, BC loaded with ibuprofen showed immediate release at every drug-loaded amount. However, BC loaded with propranolol hydrochloride showed immediate release at the high drug-loaded amount but showed sustained release at the low drug-loaded amount. The release of drug from a drug-loaded BC prepared by air-drying method tended to follow first-order kinetics. In conclusion, the drug loading concentration and the drying method in the drug-loaded BC preparation influenced the drug release characteristics of the BC-based drug delivery system.

The aim of this study was to investigate the drug release behavior from bacterial cellulose (BC).     

Microfluidic assisted synthesis of PLGA drug delivery systems

Poly(lactic-co-glycolic acid) (PLGA) is a biocompatible and biodegradable polymer that recently attracted attention for use as part of drug delivery systems (DDS). In this context, there is an emerging need for a rapid, reliable and reproducible method of synthesis. Here, microfluidic systems provide great opportunities for synthesizing carriers in a tightly controlled manner and with low consumption of materials, energy and time. These miniature devices have been the focus of recent research since they can address the challenges inherent to the bulk system, e.g. low drug loading efficiency and encapsulation, broad size distribution and burst initial release. In this article, we provide an overview of current microfluidic systems used in drug delivery production, with a special focus on PLGA-based DDS. In this context, we highlight the advantages associated with the use of microchip systems in the fabrication of nanoparticles (NPs) and microparticles (MPs), e.g. in achieving complex morphologies. Furthermore, we discuss the challenges for selecting proper microfluidics for targeted DDS production in a translational setting and introduce strategies that are used to overcome microfluidics shortcomings, like low throughput for production.

Poly(lactic-co-glycolic acid) (PLGA) is a biocompatible and biodegradable polymer that recently attracted attention for use as part of drug delivery systems (DDS).     

Mechanistic formation of drug-encapsulated Janus particles through emulsion solvent evaporation

Janus particles are emerging as structurally unique drug carriers with the potential to deliver multiple drugs and agents. Although synthesis methods have been extensively explored to fabricate Janus particles, it remains a challenge to generate drug-loaded Janus particles through an economical, high throughput technique. Here, we report the formation of the first drug-loaded, micro-scale Janus particles prepared using a single-step emulsion solvent evaporation approach. Our results revealed that both the net charge of drug molecules (i.e. glibenclamide, tolbutamine, rapamycin and lidocaine) and polymer weight ratio (i.e. poly(lactic-co-glycolic) and polycaprolactone) were critical in determining the formation of Janus particles. The formation of drug-loaded Janus particles was proven to be thermodynamically-driven in accordance to the classical equilibrium spreading coefficient theory, which is strongly governed by interfacial tensions. Specifically, comparable interfacial tensions between the two interacting polymers with the water phase were identified to be key criteria to achieve the Janus particles hemispheric structure. Such interfacial tensions were amenable, and were found to be highly dependent on the interfacial charge density attributed to both drug and polymer ratio. Hereby, this study provides a mechanistic insight into the fabrication of drug-loaded Janus particles and paves an important path towards large-scale production of Janus particles using a simplified, single-step emulsion solvent evaporation strategy.

Janus particles are emerging as structurally unique drug carriers with the potential to deliver multiple drugs and agents.     

A comparison of acyl-moieties for noncovalent functionalization of PLGA and PEG-PLGA nanoparticles with a cell-penetrating peptide

Efficient intracellular drug delivery in nanomedicine strongly depends on ways to induce cellular uptake. Conjugation of nanoparticles (NPs) with cell-penetrating peptides (CPPs) is a known means to induce uptake via endocytosis. Here, we functionalized NPs consisting of either poly(d,l-lactide-co-glycolide) (PLGA) or polyethene glycol (PEG)-PLGA block-copolymer with a lactoferrin-derived cell-penetrating peptide (hLF). To enhance the association between the peptide and the polymer NPs, we tested a range of acyl moieties for N-terminal acylation of the peptide as a means to promote noncovalent interactions. Acyl moieties differed in chain length and number of acyl chains. Peptide-functionalized NPs were characterized for nanoparticle size, overall net charge, storage stability, and intracellular uptake. Coating particles with a palmitoylated hLF resulted in minimal precipitation after storage at −20C and homogeneous particle size (<200 nm). Palmitoyl-hLF coated NPs showed enhanced delivery in different cells in comparison to NPs lacking functionalization. Moreover, in comparison to acetyl-hLF, palmitoyl-hLF was also suited for coating and enhancing the cellular uptake of PEG-PLGA NPs.

Noncovalent functionalization with acylated cell-penetrating peptides achieves an efficient cellular uptake of PLGA and PEG-PLGA nanoparticles.      

Surface design and preparation of multi-functional magnetic nanoparticles for cancer cell targeting,therapy, and imaging

Recently, theranostic candidates based on superparamagnetic iron oxide nanoparticles (SPIONs) providing the combination of therapy and diagnosis have become one of the most promising system in cancer research. However, poor stability, premature drug release, lack of specific tumor cell targeting, and complicated multi-step synthesis processes still hinder them for potential clinical applications. In this research, the multi-functional magnetic nanoparticles (MNPs-DOX) were prepared via a simple assembly process for targeted delivery of doxorubicin (DOX) and enhanced magnetic resonance (MR) imaging detection. Firstly, the multi-functional copolymer coating, polyamidoamine (PAMAM), was designed and synthesized by Michael addition reaction, where N,N-bis(acryloyl)cystamine served as backbone linker, and DOX, dopamine (DA), and polyethylene glycol (PEG) acted as comonomers. The PAMAM was then directly assembled to the surface of SPIONs by the ligand exchange reaction with SPIONs forming the MNPs-DOX. The hydrophilic PEG moieties provide the nanoparticles with colloidal stability and good-dispersity in aqueous solution. Comparing with the quick release of free DOX, the drug release behavior of MNPs-DOX exhibited a sustained drug release. Because the chemical cleavage of disulfide in the polymer backbone, a high cumulative drug release up to 60% in GSH within 48 h was observed, rather than only 26% in PBS (pH 7.4) without GSH. The MR imaging detection experiment showed that the MNPs-DOX had an enhanced T₂ relaxivity of 126 mM⁻¹ S⁻¹ for MR imaging. The results of the cytotoxicity assays showed a remarkable killing effect of cancer cells by MNPs-DOX due to the FA tumor-targeting ligand, comparing with non-targeted drug molecules. All the results showed that the as prepared multi-functional magnetic nanoparticles may serve as a promising theranostic candidate for targeted anticancer drug delivery and efficient detection through MR imaging in medical application.

Multi-functional magnetic nanoparticles for targeted anticancer drug delivery and efficient MR imaging detection in theranostics.     

The influence of nanocarrier architectures on antitumor efficacy of docetaxel nanoparticles

To study the structural influence, hybrid amphiphilic copolymer (G2C₁₈) and linear amphiphilic copolymer (PEG₄₅C₁₈) were utilized to prepare docetaxel (DTX)-loaded nanoparticles through an antisolvent precipitation method. The different architectures of the hydrophilic portion affected the particle sizes significantly, and then induced the different antitumor activity. Compared with DTX/PEG₄₅C₁₈ nanoparticles, the antitumor efficacy of DTX/G2C₁₈ nanoparticles was significantly enhanced, the IC₅₀ value was 2.1-fold lower in vitro, and the inhibition rate was 1.3-fold higher in vivo. These results suggested that the antitumor activity was significantly affected by the architecture of the nanocarriers, and should be considered when nanocarriers are designed.

Nanocarrier branched structure affects the particle size of drug-loaded nanoparticles and further induces different antitumor efficacy.     

Co-delivery of paclitaxel and gemcitabine via a self-assembling nanoparticle for targeted treatment of breast cancer

Multi-functional nanoparticles can be used to improve the treatment index and reduce side effects of anti-tumor drugs. Herein, we developed a kind of multi-functional and highly biocompatible nanoparticle (NP) loaded with folic acid (FA), paclitaxel (PTX) and gemcitabine (GEM) via self-assembly to target cancer cells. The transmission electron microscopy (TEM) results showed that multi-functional FA targeting nanoparticles (MF-FA NPs) exhibited spherical morphology and favorable structural stability in aqueous solution. In addition, NPs (MF-FA NPs and MF NPs) exhibited comparable proliferation inhibition to breast cancer cell 4T1 compared with the pure drug. In in vivo antitumor studies, NPs showed an obviously enhanced anti-tumor efficacy compared with the pure drug. Furthermore, MF-FA NPs displayed higher tumor growth inhibition than MF NPs due to the specific targeting of FA to cancer cells. Consequently, the novel MF-FA NPs could be used as a potential chemotherapeutic formulation for breast cancer therapy.

Preparation of MF-FA nanoparticles and the release behavior of drugs in tumor cells.     

Lanthanide-doped mesoporous MCM-41 nanoparticles as a novel optical–magnetic multifunctional nanobioprobe

To research and develop potential multifunctional nanoprobes for biological application, lanthanide-doped MCM-41 (Ln-MCM-41, Ln = Gd/Eu) silica nanoparticles with excellent pore structure and optical–magnetic properties were synthesized via a facile and economical sol–gel method. The microstructure and pore distribution of Ln-MCM-41 nanoparticles were obviously affected by the Ln-doping. As the Ln/Si mole ratio increased, the specific surface area and total pore volume of Ln-MCM-41 nanoparticles rapidly decreased. However, the Ln-MCM-41 nanoparticles still retained the typical well-ordered mesoporous structure, and exhibited excellent drug release behavior. Moreover, the drug release rate of Ln-MCM-41 was remarkably pH-dependent and increased gradually upon decreasing pH. Additionally, these nanoparticles also exhibit considerable photoluminescence properties, living cells photoluminescence imaging in vitro, and paramagnetism behavior at room temperature due to the Ln³⁺-ions doping. Our research shows the possibility of our Ln-MCM-41 nanoparticles as multifunctional nanoprobes for application in bioseparation, bioimaging, and drug delivery.

Mesoporous Ln-MCM-41 nanoparticles with optical–magnetic dual-modal properties can be used as a multifunctional nanoprobe for application in bioseparation, optical–magnetic bioimaging, and drug delivery.     

Mechanistic insight into the catalytic hydrogenation of nonactivated aldehydes with a Hantzsch ester in the presence of a series of organoboranes: NMR and DFT studies

Mechanistic studies on the organoborane-catalyzed transfer hydrogenation of nonactivated aldehydes with a Hantzsch ester (diethyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) as a synthetic NADH analogue were performed by NMR experiments and DFT calculations. In the reaction of benzaldehyde with the Hantzsch ester, the catalytic activity of tris[3,5-bis(trifluoromethyl)phenyl]borane was superior to that of other borane catalysts, such as tris(pentafluorophenyl)borane, trifluoroborane etherate, or triphenylborane. Stoichiometric NMR experiments demonstrated that the hydrogenation process proceeds through activation of the aldehyde by the borane catalyst, followed by hydride transfer from the Hantzsch ester to the resulting activated aldehyde. DFT calculations for the hydrogenation of benzaldehyde with the Hantzsch ester in the presence of borane catalysts supported the reaction pathway and showed why the catalytic activity of tris[3,5-bis(trifluoromethyl)phenyl]borane is higher than that of the other boron catalysts. Association constants and Gibbs free energies in the reaction of boron catalysts with benzaldehyde or benzyl alcohol, which were investigated by ¹H NMR analyses, also indicated why tris[3,5-bis(trifluoromethyl)phenyl]borane is a superior catalyst to tris(pentafluorophenyl)borane, trifluoroborane etherate, or triphenylborane in the hydrogenation reaction.

Mechanistic studies on the organoborane-catalyzed transfer hydrogenation of nonactivated aldehydes with a Hantzsch ester as a synthetic NADPH analogue were performed by NMR experiments and DFT calculations.     

Synthesis and characterization of magnetic chitosan microspheres for drug delivery

A novel magnetic microsphere was prepared by simple microemulsion polymerization for protein drug delivery systems. The Fe₃O₄ magnetic nanoparticles were successfully encapsulated in chitosan microspheres, which endowed the chitosan microspheres with good magnetism. The drug loading performance results indicated that the prepared magnetic chitosan microspheres exhibited a superior drug loading capacity, and the drug loading amount reached 947.01 mg g⁻¹. Furthermore, the magnetic chitosan microspheres also showed a higher drug release rate (87.8%) and evident sustained-release performance in vitro. The magnetic microsphere carrier will be widely used in the biomedical field as a promising drug carrier.

A novel magnetic microsphere was prepared by the simple microemulsion polymerization for protein drug delivery systems. This magnetic microsphere exhibited good magnetism and superior drug loading capacity and evident sustained-release performance.