Chemical Delivery Research Articles

Corrigendum: Multifunctional Nanoprobes for Nanoscale Chemical Imaging and Localized Chemical Delivery at Surfaces and Interfaces

Corrigendum: Multifunctional Nanoprobes for Nanoscale Chemical Imaging and Localized Chemical Delivery at Surfaces and Interfaces

Gold nanoparticles electroporation enhanced polyplex delivery to mammalian cells.

Nonviral methods have been explored as the replacement of viral systems for their low toxicity and immunogenicity. However, they have yet to reach levels competitive to their viral counterparts. In this paper, we combined physical and chemical methods to improve the performance of polyplex delivery of DNA and small interfering RNA. Specifically, gold nanoparticles (AuNPs) were used to carry polyplex (a chemical approach) while electroporation (a physical approach) was applied for fast and direct cytosolic delivery. In this hybrid approach, cationic polymer molecules condense and/or protect genetic probes as usual while AuNPs help fix polycations to reduce their cytotoxicity and promote the transfection efficiency of electroporation. AuNPs of various sizes were first coated with polyethylenimine, which were further conjugated with DNA plasmids or small interfering RNA molecules to form AuNPs-polyplex. The hybrid nanoparticles were then mixed with cells and introduced into cell cytosol by electroporation. The delivery efficiency was evaluated with both model anchor cells (i.e., NIH/3T3) and suspension cells (i.e., K562), together with their impact on cell viability. We found that AuNP-polyplex showed 1.5∼2 folds improvement on the transfection efficiency with no significant increase of toxicity when compared to free plasmid delivery by electroporation alone. Such a combination of physical and chemical delivery concept may stimulate further exploration in the delivery of various therapeutic materials for both in vitro and in vivo applications.

Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems.

Existing nanoscale chemical delivery systems target diseased cells over long, sustained periods of time, typically through one-time, destructive triggering. Future directions lie in the development of fast and robust techniques capable of reproducing the pulsatile chemical activity of living organisms, thereby allowing us to mimic biofunctionality. Here, we demonstrate that by applying programmed femtosecond laser pulses to robust, nanoscale liposome structures containing dopamine, we achieve sub-second, controlled release of dopamine – a key neurotransmitter of the central nervous system – thereby replicating its release profile in the brain. The fast delivery system provides a powerful new interface with neural circuits, and to the larger range of biological functions that operate on this short timescale.

A bivalent small molecule-drug conjugate directed against carbonic anhydrase IX can elicit complete tumour regression in mice

There is a pressing need for the development of innovative chemical drug delivery strategies in oncology, since conventional chemotherapeutic agents typically do not localise to solid tumours in vivo. It is widely accepted that bivalent antibody formats accumulate in tumours more strongly than monovalent ones and that they should thus be preferred for antibody-based pharmacodelivery approaches. For small molecule-drug conjugates this is less clear. Here, we show that a bivalent ligand against the tumour marker carbonic anhydrase IX leads to an improved tumour-targeting performance compared with the corresponding monovalent counterpart in the SKRC52 model of constitutively CAIX-positive renal cell carcinoma. A bivalent disulfide-linked small drug conjugate with the potent cytotoxic maytansinoid DM1 as the payload can mediate complete eradication of the same tumours, which are resistant to standard-of-care therapeutics, in a proportion of treated mice. In the A375 melanoma model, which preferentially expresses CAIX at sites distant to blood vessels, no measurable tumour accumulation could be observed. Our results suggest that the use of bivalent small molecule ligand-drug conjugates against CAIX may represent an attractive chemical strategy for the treatment of constitutively CAIX-positive kidney cancer.

Preparation, transportation mechanisms and brain-targeting evaluation in vivo of a chemical delivery system exploiting the blood–cerebrospinal fluid barrier

In recent years, specific transportation mechanisms on the blood–brain barrier (BBB) are extensively employed for brain-targeted drug delivery via colloidal nanocarriers. However, in this study, we purposed to exploit the sodium-dependent vitamin C transporter 2 (SVCT2)-mediated transportation on the blood–cerebrospinal fluid barrier to enhance central nervous system penetration of the highly hydrophilic ibuprofen (IBU) by synthesizing a SVCT2-targeted chemical delivery system (CDS), ibuprofen-C6-O-ascorbic acid (IAA). The physicochemical parameters of IAA were determined, and the transporter-mediated transportation mechanism of IAA was explored on a BBB monolayer mode. The overall brain targeting effect of IAA was assayed on mice by measuring the biodistribution of IBU after i.v. administration and calculating the pharmacokinetic parameters and targeting indexes. Results showed that lipophilicity and solubility of IAA was conspicuously improved compared with IBU. At the physiological pH, IAA was stable while in brain homogenates it was easily degraded. Transport studies on the BBB monolayer mode revealed that IAA displayed higher transepithelial permeability than IBU via SVCT2. The biodistribution study in vivo demonstrated that the overall targeting efficiency of IAA was 1.77-fold greater than that of the IBU. In conclusion, the synthetic IAA might be a promising brain-targeted CDS for smuggling small-molecule hydrophilic pharmaceuticals into the brain.

New developments in redox chemical delivery systems by means of 1,4-dihydroquinoline-based targetor: Application to galantamine delivery to the brain

The therapeutic efficiency of palliative treatments of AD, mostly based on acetylcholinesterase (AChE) inhibitors, is marred by serious adverse effects due to peripheral activity of these AChE inhibitors. In the literature, a redox-based chemical delivery system (CDS) has been developed to enhance drugs distribution to the brain while reducing peripheral side effects. Herein, we disclose two new synthetic strategies for the preparation of 1,4-dihydroquinoline/quinolinium salt redox-based systems particularly well designed for brain delivery of drugs sensitive to alkylation reactions. These strategies have been applied in the present case to the AChE inhibitor galantamine with the aim of alleviating adverse effects observed with cholinergic AD treatment. The first strategy is based on an intramolecular alkylation reaction as key step, whilst the second strategy relies on a useful coupling between galantamine and quinolinium salt key intermediate. In the course of this work, polymer-supported reagents and a solid-phase synthesis approach revealed to be highly helpful to develop this redox-based galantamine CDS.

Numerical energetic and exergetic analysis of CI diesel engine performance for different fuels of hydrogen, dimethyl ether, and diesel under various engine speeds

The current study addresses engine specification and second thermodynamic law analysis of the CI diesel engine fueled with hydrogen, DME, and diesel at six engine speeds. The 3-D simulation was first carried out and then the results were exploited to calculate availability through a developed in-house code. Availability analysis was performed separately for chemical and thermo-mechanical availability to highlight each fuel'0s capacity in chemical and mechanical efficiency delivery. The results indicate that hydrogen fuel prevails in chemical and thermo-mechanical availability, indicated power, and mean effective in-cylinder pressure under all crank angle and engine speeds. Temperature distribution has more extensive and intensified region developed across the cylinder, although hydrogen demonstrated the lowest ISFC (indicated specific fuel consumption) value. With regard to engine speed, 2000 rpm shows overall better IP (indicated power), IMEP (indicated mean effective pressure), chemical and thermo-mechanical availability, irrespective of fuel type. The mean irreversibility rate for PMC (pre-mixed combustion) and MCC (mixing controlled combustion) combustion phase shows a different trend. Furthermore, hydrogen fueled engine demonstrates the highest temperature distribution of 2736 K and the wall heat flux to the amount of 29160 W. The variance of chemical availability for Hydrogen from 1500 to 4000 rpm decreases by crank-angle evolution from 43.3% to 10.1% corresponding to 10–40°CA after top dead center.

Out‐of‐Water Constitutional Self‐Organization of Chitosan–Cinnamaldehyde Dynagels

An investigation of the constitutional adaptive gelation process of chitosan/cinnamaldehyde (C/Cy) dynagels is reported. These gels generate timely variant macroscopic organization across extended scales. In the first stage, imine-bond formation takes place "in-water" and generates low-ordered hydrogels. The progressive formation of imine bonds further induces "out-of-water" increased reactivity within interdigitated hydrophobic self-assembled layers of Cy, with a protecting environmental effect against hydrolysis and that leads to the stabilization of the imine bonds. The hydrophobic swelling due to Cy layers at the interfaces reaches a critical step when lamellar self-organized hybrids are generated (24 hours). This induces an important restructuration of the hydrogels on the micrometric scale, thus resulting in the formation of highly ordered microporous xerogel morphologies of high potential interest for chemical separations, drug delivery, and sensors.

Biomimetic Approach for Liquid Encapsulation with Nanofibrillar Cloaks

Technologies that are able to handle microvolumes of liquids, such as microfluidics and liquid marbles, are attractive for applications that include miniaturized biological and chemical reactors, sensors, microactuators, and drug delivery systems. Inspired from natural fibrous envelopes, here, we present an innovative approach for liquid encapsulation and manipulation using electrospun nanofibers. We demonstrated the realization of non-wetting soft solids consisting of a liquid core wrapped in a hydrophobic fibrillar cloak of a fluoroacrylic copolymer and cellulose acetate. By properly controlling the wetting and mechanical properties of the fibers, we created final architectures with tunable mechanical robustness that were stable on a wide range of substrates (from paper to glass) and floated on liquid surfaces. Remarkably, the realized fiber-coated drops endured vortex mixing in a continuous oil phase at high stirring speed without bursting or water losses, favoring mixing processes inside the entrapped liquid volume. Moreover, the produced cloak can be easily functionalized by incorporating functional particles, active molecules, or drugs inside the nanofibers.

Ionic diffusion in silica sol–gel glasses

Non-Fickian ionic diffusion in porous silica xerogel glasses was examined experimentally and modeled with a concentration-dependent diffusion coefficient. Smaller pore sizes resulted in a decreased diffusion rate, increased hysteresis, and greater dependence on the nature of other ionic species present. The pH-dependent non-Fickian diffusional dynamics within the porous matrix was attributed to pH-dependent chemistry of the silica surface species. Protonation of the silica surface was found to dramatically increase the rate of proton diffusion within the pores. The observed hysteresis was attributed to a competition between entry into pore openings versus transport within the porous network. Factors that affect ionic diffusion kinetics in nanoscale porous materials are relevant to chemical sensor and dopant delivery applications of porous silica materials. • Non-Fickian diffusion kinetics were adequately modeled with a homogeneous diffusion model. • Ionic diffusion was dependent on both pore size and other cations in solution. • The hysteresis in proton diffusion was attributed to charge accretion at pore openings.

Design, synthesis, chemical and biological evaluation of brain targeted alkylating agent using reversible redox prodrug approach

The aim of the present work is to investigate the utility of redox chemical delivery prodrug approach for the targeted and sustained release of an alkylating anticancer agent in the brain. The N-methyl-1,4-dihydronicotinate ester of an alkylating nitrogen mustard NM-CDS (4) was synthesized in three step reactions. Structures of all the synthesized compounds were confirmed by UV, IR, (1H&13C) NMR and CHN elemental studies. In vitro chemical oxidation studies with silver nitrate of NM-CDS (4) indicated that it can be readily converted into its corresponding quaternary salt (3) with half life of 8min. In vitro biological oxidation studies showed facile oxidation in biological media and rate of oxidation followed pseudo first-order kinetics with reasonable half-lives of 32.5min in rat blood, 24.2min in human blood and 19.4min in brain homogenate. The in vivo studies on Sprague–Dawley rats were performed. The NM-CDS (4) at a dose of 40mg/kg, was injected into rats. At selected time intervals, blood samples and the brains were collected and analyzed by UV spectrophotometer. The results demonstrated that NM-CDS (4) was able to cross the blood–brain barrier (BBB) at detectable concentration, oxidized to its active quaternary salt (Q-salt) (3) and sustained there for some period of time. The in silico ADME descriptors required for CNS activity were determined by computational, online (Molinspiration) and QikProp 3.2 software (Schrodinger, USA) that further indicated that NM-CDS (4) has a good potential to cross the BBB and show CNS antitumor activity.

The role of intrinsic pathway in apoptosis activation and progression in Peyronie’s disease

Peyronie’s disease (PD) is a connective tissue disorder where formation of fibrous plaques in tunica albuginea (TA) and erectile tissue can result in penile deformity, pain, and erectile dysfunction. Fibrosis, its major pathological manifestation, arises from fibroblast proliferation and accumulation of extracellular matrix; PD progresses with formation of plaques or even ectopic calcification having the appearance of scar tissue, which prevent TA expansion during erections. The mechanisms underpinning PD are unclear, and relatively little is known about the disease itself. To date corrective surgery is the sole effective treatment. A greater understanding of PD pathophysiology at the molecular level has the potential to help develop novel medical therapeutic approaches. The aim of this study was to investigate the activation of the apoptotic intrinsic apoptotic pathway in plaques from PD patients. Tunica albuginea from either PD and control patients were assessed for the expression of bax, bcl-2, caspase 9 and 3 using immunohistochemistry, and by measurement of apoptotic cells using TUNEL assay. Bax overexpression was observed in metaplasic bone tissue, in fibroblasts and in myofibroblast of plaques from PD patients. Little or no bcl-2 immunostaining was detected in samples from either patients or controls. Caspase 3 immunostaining was very strong in fibrous tissue, in metaplasic bone osteocytes and in primary ossification center osteoblasts. Moderate caspase 9 immunostaining was seen in fibrous cells plaques and in osteocytes and osteoblasts of primary ossification centers from PD patients. Control samples were negative for caspase 9 immunostaining. In PD patients the TUNEL immunoassay showed intense immunostaining of fibroblasts and myofibroblasts, the absence of apoptotic cells in metaplasic bone tissue and on the border between fibrous and metaplasic bone tissue. Apoptotic cell death occurs in stabilized PD plaques and is partly induced by the intrinsic mitochondrial pathway. The present findings can have clinical implications and may help devise improved treatment strategies. A therapeutic approach aimed at enhancing apoptosis-inducing molecules would at least help delay the progression of PD. Identification of target molecules for gene construct or biological or chemical reagent delivery to target sites could contribute to induce PD plaque stabilization.

Design of Quartz Chemical Delivery Parts for High Temperature Vacuum Chambers Based on Simulation Results

Many of today’s technologies and research techniques depend on process and methods in high and ultra-high vacuum. High temperature vacuum chambers require creative design and use of exotic materials in design to achieve quality performance. In order to obtain good performance, the temperature and gas delivery on the vacuum chamber surface must be uniformly distributed. In this work, a new funnel for high-temperature vacuum chamber was successfully designed and tested using computer-based simulation techniques. The funnel was made of quartz crystal due to the ability to absorb temperature, properties of low gas permeability and low temperature coefficient. In order to mitigate O-rings from high temperature failure and to reduce non-uniformity effect during temperature delivery, a new quartz funnel was developed. The simulation and experimental results show that uniformity distributions in temperature of vacuum chamber surface were obtained with new funnel design

Physical and Chemical Stimuli-Responsive Drug Delivery Systems: Targeted Delivery and Main Routes of Administration

In the area of drug delivery, novel tools and technological approaches have captured the attention of researchers in order to improve the performance of conventional therapeutics and patient compliance to pharmacological therapy. Stimuli-responsive drug delivery systems (DDS) appear as a promising approach to control and target drug delivery. When these DDS are administered, the drug release is activated and then modulated through some action or external input and facilitated by the energy supplied externally. The stimuli responsible to activate the drug release can be classified into three types according to their nature or the type of energy applied: physical (e.g. magnetic field, electric field, ultrasound, temperature and osmotic pressure); chemical (e.g. pH, ionic strength and glucose); and biological (enzymes and endogenous receptors). The present review gives an overview of the most significant physical and chemical stimuliresponsive DDS and elucidates about their current and relevant applications in controlled and targeted drug delivery attending different routes of administration.

Preparation and Characterization of Flexible Optical Composite Films Based on Bragg-Structured Interferometer

AbstractThree types of functionalized flexible optical composite films based on Bragg structure porous silicon interferometerhave been successfully fabricated by casting a toluene solution of polystyrene onto the free-standing porous silicon. Theoptical properties of composite films are measured. Surface functionalization of porous silicon is determined by FT-IRmeasurement. Reflectance and transparence properties of composite films are measured for the possible application oftunable optical filter and indicate that the transmission peak occurred at the identical location where the reflection peakappeared.Key words: Composite, Transparency, Reflection, Surface Functionalization 1. Introduction The development of nanometer scale technology is ofgreat interest, because conventional lithographic methodis too complex to fabricate. Since the discovery ofporous silicon (PSi) [1] , it has been intensively investi-gated for a variety of applications such as chemical andbiological sensors, medical diagnostics, and drug deliv-ery

Transgenic Hybrid Poplar for Sustainable and Scalable Production of the Commodity/Specialty Chemical, 2-Phenylethanol

Fast growing hybrid poplar offers the means for sustainable production of specialty and commodity chemicals, in addition to rapid biomass production for lignocellulosic deconstruction. Herein we describe transformation of fast-growing transgenic hybrid poplar lines to produce 2-phenylethanol, this being an important fragrance, flavor, aroma, and commodity chemical. It is also readily converted into styrene or ethyl benzene, the latter being an important commodity aviation fuel component. Introducing this biochemical pathway into hybrid poplars marks the beginnings of developing a platform for a sustainable chemical delivery system to afford this and other valuable specialty/commodity chemicals at the scale and cost needed. These modified plant lines mainly sequester 2-phenylethanol via carbohydrate and other covalently linked derivatives, thereby providing an additional advantage of effective storage until needed. The future potential of this technology is discussed. MALDI metabolite tissue imaging also established localization of these metabolites in the leaf vasculature.

3D Energetic Metal–Organic Frameworks: Synthesis and Properties of High Energy Materials

Metal–organic frameworks (MOFs) have attracted great attention because of their intriguing molecular topologies and potential applications in chemical separation, gas storage, drug delivery, catalysis and chemical sensor technology. Particularly, MOFs could also be potential energetic materials because of their high densities and high heats of detonation. For example, Hope-Weeks and co-workers recently reported two hydrazine-perchlorate 1D MOFs [(Ni(NH2NH2)5(ClO4)2)n (NHP), and (Co(NH2NH2)5(ClO4)2)n (CHP)] with linear polymeric structures, which were regarded as possibly the most powerful metal-based energetic materials known to date, with heats of detonation comparable with that of hexanitrohexaazaisowutzitane (CL-20; about 1.5 kcalg ). Unfortunately, these coordination polymers were highly sensitive to impact deriving from their low rigidity characteristic of such linear polymeric structures, which makes practical use infeasible. In order to decrease the sensitivities, the same authors also used a hydrazine derivative (hydrazine-carboxylate) as the ligand to construct MOFs with 2D sheet structures [((Co2(N2H4)4(N2H3CO2)2)(ClO4)2·H2O)n (CHHP) and ((Zn2(N2H4)3(N2H3CO2)2)(ClO4)2·H2O)n (ZnHHP)], which showed a considerable reduction to the sensitivity, however, concomitantly their heats of detonation decreased (Figure 1). Despite these advances, current coordination frameworks are only limited to be a 1D or 2D structure. Compared with 1D linear and 2D layered structures, three-dimensional (3D) frameworks possess more complicated connection modes, which could further enhance structural reinforcement, hence improve the stabilities and energetic properties. A lot of 3D MOFs have been synthesized with interesting magnetic, catalytic, and luminescent properties, some of them incorporate a variety of energetic moities such as nitrate anions (NO3 ), perchlorate anions (ClO4 ) into the 3D frameworks. However, their potential applications as energetic materials have not been disclosed or discussed; relevant data about energetic properties are also missing in the literature. Additionally, both reported 1D and 2D energetic MOFs based on the perchlorate anions, have been scrutinized by the US Environmental Protection Agency (EPA) because they promote thyroid dysfunction and are teratogenic. Continuing our interest in finding new highly energetic, eco-friendly energetic materials, we explore the preparation of halogen-free energetic 3D MOFs, for which two polymers [Cu(atrz)3(NO3)2]n (1) and [Ag(atrz)1.5(NO3)]n (2) were designed by replacing the hydrazine ligand with 4,4’-azo1,2,4-triazole (atrz). Here, we chose to use atrz as a ligand for the following reasons: 1) as a nitrogen-rich heterocyclic backbone, atrz possesses a high nitrogen content (N%= Figure 1. Energetic MOFs with different topologies.

Dual system for the central nervous system targeting and blood‐brain barrier transport of a selective prolyl oligopeptidase inhibitor

Less than 2% of all potential neurotherapeutics cross the blood-brain barrier (BBB). Here, we sought to build a construct with the capacity to cross this barrier, to behave as a chemical delivery system, and, once inside the central nervous system, to be transformed and then act as an enzyme inhibitor. With all this in mind, here, we describe the entire process to obtain such a compound, from the initial candidate selection to preparation of the compound library and posterior evaluation and final selection of the most promising candidates in terms of selectivity, serum stability, and BBB-transport.

Reversible redox system-based drug design, synthesis, and evaluation for targeting nitrogen mustard across brain

Target drug delivery of nitrogen mustard anticancer agents for a brain tumor is still a challenge due to their high hydrophilicity, poor physicochemical properties, and toxicity to normal tissues. The present study is, therefore, an attempt to investigate the possibility of improving the targeting potential and sustained release of nitrogen mustard alkylating agent to brain by employing reversible redox chemical delivery system approach. Various redox derivatives CDS-L-M (4a–c) based on dihydropyridine ↔ quaternary pyridinium ion redox system were synthesized and characterized by IR, (1H and 13C)-NMR, and CHN elemental studies. The potential of these CDS derivatives (4a–c) to penetrate the blood–brain barrier was computed through an online software program and the values analyzed lay between the ranges those are required for good brain penetration. The results of storage stability study, in vitro chemical oxidation (silver nitrate) and pharmacokinetic studies in human blood, rat blood and brain homogenate for all CDS-L-M (4a–c) demonstrated that all derivatives could be oxidized into corresponding quaternary salts at an adequate rate, which suggested that brain targeting could be possible with more stable CDS-L-M (4c). The in vivo study on rats showed that administration of the CDS-L-M (4c) resulted in the sustained level of the corresponding salt (3c) in the brain, while blood levels of the oxidized metabolite rapidly fell. The in vitro NBP alkylating activity of quaternary salt (3c) of CDS-L-M (4c) was comparable to the known drug chlorambucil among all the synthesized derivatives.

Pre- and post-fire pollutant loads in an urban fringe watershed in Southern California

Post-fire runoff has the potential to be a large source of contaminants to downstream areas. However, the magnitude of this effect in urban fringe watersheds adjacent to large sources of airborne contaminants is not well documented. The current study investigates the impacts of wildfire on stormwater contaminant loading from the upper Arroyo Seco watershed, burned in 2009. This watershed is adjacent to the Greater Los Angeles, CA, USA area and has not burned in over 60 years. Consequently, it acts as a sink for regional urban pollutants and presents an opportunity to study the impacts of wildfire. Pre- and post-fire storm samples were collected and analyzed for basic cations, trace metals, and total suspended solids. The loss of vegetation and changes in soil properties from the fire greatly increased the magnitude of storm runoff, resulting in sediment-laden floods carrying high concentrations of particulate-bound constituents. Post-fire concentrations and loads were up to three orders of magnitude greater than pre-fire values for many trace metals, including lead and cadmium. A shift was also observed in the timing of chemical delivery, where maximum suspended sediment, trace metal, and cation concentrations coincided with, rather than preceded, peak discharge in the post-fire runoff, amplifying the fire's impacts on mass loading. The results emphasize the importance of sediment delivery as a primary mechanism for post-fire contaminant transport and suggest that traditional management practices that focus on treating only the early portion of storm runoff may be less effective following wildfire. We also advocate that watersheds impacted by regional urban pollutants have the potential to pose significant risk for downstream communities and ecosystems after fire.