Albumin Nanoparticles Increase the Efficacy of Doxorubicin Hydrochloride Liposome Injection Based on Threshold Theory.

One of the most significant reasons hindering the clinical translation of nanomedicines is the rapid clearance of intravenously injected nanoparticles by the mononuclear phagocyte system, particularly by Kupffer cells in the liver, leading to an inefficient delivery of nanomedicines for tumor treatment. The threshold theory suggests that the liver's capacity to clear nanoparticles is limited, and a single high dose of nanoparticles can reduce the hepatic clearance efficiency, allowing more nanomedicines to reach tumor tissues and enhance therapeutic efficacy. Building upon this theory, researchers have conducted numerous validation studies based on the same nanoparticle carrier systems. These studies involve the use of albumin nanoparticles to improve the therapeutic efficacy of albumin nanomedicines as well as polyethylene glycol (PEG)-modified liposomal nanoparticles to enhance the efficacy of PEGylated liposomal nanomedicines. However, there is no research indicating the feasibility of the threshold theory when blank nanoparticles and nanomedicine belong to different nanoparticle carrier systems currently. In this study, we prepared two different sizes of albumin nanoparticles by using bovine serum albumin. We used the marketed nanomedicine liposomal doxorubicin hydrochloride injection (trade name: LIBOD, manufacturer: Shanghai Fudan-zhangjiang Biopharmaceutical Co., Ltd.), as the representative nanomedicine. Through in vivo experiments, we found that using threshold doses of albumin nanoparticles still can reduce the clearance rate of LIBOD, prolong its time in vivo, increase the area under the plasma concentration-time curve (AUC), and also lead to an increased accumulation of the drug at the tumor site. Furthermore, evaluation of in vivo efficacy and safety further indicates that threshold doses of 100 nm albumin nanoparticles can enhance the antitumor effect of LIBOD without causing harm to the animals. During the study, we found that the particle size of albumin nanoparticles influenced the in vivo distribution of the nanomedicine at the same threshold dose. Compared with 200 nm albumin nanoparticles, 100 nm albumin nanoparticles more effectively reduce the clearance efficiency of LIBOD and enhance nanomedicine accumulation at the tumor site, warranting further investigation. This study utilized albumin nanoparticles to reduce hepatic clearance efficiency and enhance the delivery efficiency of nonalbumin nanocarrier liposomal nanomedicine, providing a new avenue to improve the efficacy and clinical translation of nanomedicines with different carrier systems.

Ultra-low current electrospray ionization of chloroform solution for the analysis of perfluorinated sulfonic acids.

RATIONALE: Femtoamp and picoamp electrospray ionization (ESI) characteristics of a nonpolar solvent were explored. The direct ESI mass spectrometry analysis of chloroform extract solution enabled rapid analysis of perfluorinated sulfonic acid analytes in drinking water. METHODS: Neat chloroform solvent and extracts were directly used in a typical wire-in ESI setup using micrometer emitter tips. Ionization currents were measured with femtoamp sensitivity while ramping the spray voltage from 0 to -5000 V. Methanol was used as a comparison to illustrate the characteristics of electrospraying chloroform. The effects of spray voltage and inlet temperature were studied. A liquid-liquid extraction workflow was developed to analyze perfluorooctanoate sulfonate (PFOS) in drinking water using an ion-trap mass spectrometer. RESULTS: The ionization onset of chloroform solution was 41 ± 17 fA at 300 V. The ionization current gradually increased with voltage while remaining below 100 pA when using voltages up to -5000 V. The ion signal of PFOS was significantly enhanced to improve the limit of detection (LoD) to 25 ppt in chloroform. Coupled with a liquid-liquid extraction workflow, LoD of 0.38-5.1 ppt and a quantitation range of 5-400 ppt were achieved for perfluorinated sulfonic compounds in 1-ml water samples. CONCLUSIONS: Femtoamp and picoamp modes expand the solvent compatibility range of ESI and can enable quantitative analysis in parts per trillion (ppt) concentrations.

Conducting and characterizing femto flow electrospray ionization.

Femto flow electrospray ionization (ESI) with flow rates ranging from 240 fL min-1 to the low pico level (<10 pL min-1) was conducted and measured using a submicron emitter tip and relay ESI configuration. Signature analyte ion current intensities and profiles were observed. The obtained flow rate and ionization current enabled size calculation for initial charged nanodroplets.

Measurement of the Proton Affinities of a Series of Mono- and Biradicals of Pyridine.

The proton affinity (PA) of a neutral molecule is defined as the negative of the enthalpy change for the gas-phase reaction between a proton and the neutral molecule to produce the (charged) conjugate acid of the molecule. PA is a fundamental property that is related to the structure of a molecule and affects its reactivity. Very few PA values are available for basic organic monoradicals and none for biradicals. Here, the PA values for several σ-type carbon-centered pyridine-based monoradicals and biradicals have been experimentally determined by monitoring proton transfer from the protonated mono- and biradicals to reference bases with known proton affinities as a function of time in Fourier-transform ion cyclotron resonance (FT-ICR) and linear quadrupole ion trap (LQIT) mass spectrometers. A procedure was developed for both instruments that permits differentiation between exo- and endothermic proton transfer reactions. The PA values of all the (bi)radicals studied were found to be lower than that of pyridine. This is rationalized based on the electron-withdrawing nature of the radical site(s). Thus, the PA values decrease in the order: pyridine > monoradicals > biradicals. The PA values of the monoradicals were also found to increase (making the protonated radicals less acidic) as the distance between the basic nitrogen atom and the radical site increases. Similar behavior was found for the biradicals, with one exception: 3,5-didehydropyridine has a larger PA (215.3 ± 3.3 kcal mol-1) than 3,4-didehydropyridine (PA = 213.4 ± 3.3 kcal mol-1) even though the latter biradical has one radical site farther away from the basic nitrogen atom. Quantum chemical calculations of the PAs of the (bi)radicals are in reasonably good agreement with the experimentally determined values. At the DFT (B3LYP), CCSD(T), and CASPT2 levels of theory, the mean unsigned errors are 2.3, 1.7, and 2.1 kcal mol-1.

Conversion of Ethanol via C-C Splitting on Noble Metal Surfaces in Room-Temperature Liquid-Phase.

Rh-catalyzed decomposition of ethanol into CO2 and CH4 via C-C bond splitting is reported in room-temperature liquid phase under atmospheric pressure. Mechanistic investigations show that C-C bond splitting of ethanol on the noble metal surface is rapid, and CO2 forms through the oxidation of α-CH xO and ß-CH x fragments after C-C bond splitting, while CH4 forms through the hydrogenation of ß-CH x utilizing H atoms from -OH, ß-CH x, and α-CH xOH fragments.

Compositional characterization of complex protopeptide libraries via triboelectric nanogenerator Orbitrap mass spectrometry.

RATIONALE: Understanding of the molecular processes that led to the first biomolecules on Earth is one of the key aspects of origins-of-life research. Depsipeptides, or polymers with mixed amide and ester backbones, have been proposed as plausible prebiotic precursors for peptide formation. Chemical characterization of depsipeptides in complex prebiotic-like mixtures should benefit from more efficient ion sources and ultrahigh-resolution mass spectrometry (UHR-MS) for elemental composition elucidation. METHODS: A sliding freestanding (SF) Triboelectric Nanogenerator (TENG) was coupled to glass nanoelectrospray emitters for the analysis of a depsipeptide library created using 11 amino acids and 3 alpha-hydroxy acids subjected to environmentally driven polymerization. The TENG nanoelectrospray ionization (nanoESI) source was coupled to an UHR Orbitrap mass spectrometer operated at 1,000,000 resolution for detecting depsipeptides and oligoesters in such libraries. Tandem mass spectrometry (MS/MS) experiments were performed on an Orbitrap Q-Exactive mass spectrometer. RESULTS: Our previous proteomics-like approach to depsipeptide library characterization showed the enormous complexity of these dynamic combinatorial systems. Here, direct infusion UHR-MS along with de novo sequencing enabled the identification of 524 sequences corresponding to 320 different depsipeptide compositions. Van Krevelen and mass defect diagrams enabled better visualization of the chemical diversity in these synthetic libraries. CONCLUSIONS: TENG nanoESI coupled to UHR-MS is a powerful method for depsipeptide library characterization in an origins-of-life context.

Robotic Surface Analysis Mass Spectrometry (RoSA-MS) of Three-Dimensional Objects.

Many technologies currently exist that are capable of analyzing the surface of solid samples under ambient or vacuum conditions, but they are typically limited to smooth, planar surfaces. Those few that can be applied to nonplanar surfaces, however, require manual sampling and a high degree of human intervention. Herein, we describe a new platform, Robotic Surface Analysis Mass Spectrometry (RoSA-MS), for direct surface sampling of three-dimensional (3D) objects. In RoSA-MS, a sampling probe is attached to a robotic arm that has 360° rotation through 6 individual joints. A 3D laser scanner, also attached to the robotic arm, generates a digital map of the sample surface that is used to direct a probe to specific ( x, y, z) locations. The sampling probe consists of a spring-loaded needle that briefly contacts the object surface, collecting trace amounts of material. The probe is then directed at an open port liquid sampling interface coupled to the electrospray ion source of a mass spectrometer. Material on the probe tip is dissolved by the solvent flow in the liquid interface and mass analyzed with high mass resolution and accuracy. The surface of bulky, nonplanar objects can thus be probed to produce chemical maps at the molecular level. Applications demonstrated herein include the examination of food sample surfaces, lifestyle chemistry, and chemical reactions on curved substrates. The modular design of this system also allows for modifications to the sampling probe and the ionization source, thereby expanding the potential of RoSA-MS for a great diversity of applications.

Triboelectric Nanogenerator (TENG) Mass Spectrometry of Falsified Antimalarials.

RATIONALE: An epidemic of low quality medicines continues to endanger patients worldwide. Detection of such "medicines" requires low cost, ambient ionization sources coupled to fieldable mass spectrometers for optimum sensitivity and specificity. With the use of triboelectric nanogenerators (TENGs), the charge required to produce gas-phase ions for mass analysis can be obtained without the need for high voltage electrical circuitry, simplifying and lowering the cost of next-generation mass spectrometry instruments. METHODS: A sliding freestanding (SF) TENG was coupled to a toothpick electrospray setup for the purposes of testing if falsified medicines could be fingerprinted by this approach. Extracts from both genuine and falsified medicines were deposited on the toothpick and the SF TENG actuated to generate electrical charges, resulting in gas-phase ions for both active pharmaceutical ingredients and excipients. RESULTS: Our previous work had shown that direct analysis in real-time (DART) ambient mass spectrometry can identify the components of multiple classes of falsified antimalarial medicines. Experiments performed in this study show that a simple extraction into methanol along with the use of a SF TENG-powered toothpick electrospray can provide similar detection capabilities, but with much simpler and rugged instrumentation, and without the need for compressed gases or high voltage ion source power supplies. CONCLUSIONS: TENG toothpick MS allows for rapid analyte ion detection in a safe and low-cost manner, providing robust sampling and ionization capabilities.

Atmospheric Pressure Drift Tube Ion Mobility-Orbitrap Mass Spectrometry: Initial Performance Characterization.

Atmospheric pressure drift tube ion mobility spectrometry (AP-DTIMS) was coupled with Fourier transform Orbitrap mass spectrometry. The performance capabilities of this versatile new arrangement were demonstrated for different DTIMS ion gating operation modes and Orbitrap mass spectrometer parameters with regard to sensitivity and resolving power. Showcasing the optimized AP-DTIMS-Orbitrap MS system, isobaric peptide and sugar isomers were successfully resolved and the identities of separated species validated by high-energy collision dissociation experiments.

Sizing sub-diffraction limit electrosprayed droplets by structured illumination microscopy.

Electrosprayed droplets are widely studied for their role in the formation of ions at atmospheric pressure. Most droplet measurement methods used today employ light scattering to infer information about an electrosprayed droplet's size. However, these methods fail to measure droplets smaller than about 400 nm in diameter due to constraints imposed by the diffraction limit of light. To overcome this limitation, a super resolution fluorescence microscopy-based method for determining the sizes of electrosprayed droplets has been developed. Solutions containing rhodamine B and different amounts of glycerol were paper sprayed and nanoelectrosprayed onto conductive microscope coverslips using a single, high voltage pulse. Images of the deposited droplets were collected using a super resolution microscope operating in 3D structured illumination microscopy mode (3D-SIM). The sizes of droplets were measured using a modified circular Hough transformation program in Matlab. On average, the diameters of paper sprayed droplets were between 500 nm and 2 µm while almost all nanoelectrosprayed droplets were smaller than 1 µm. The center of a paper spray plume exhibited larger droplets than those at the periphery, likely due to greater Coulombic repulsive forces acting on the smaller droplets to drive them outwards. The periphery also likely contained progeny droplets in addition to smaller parent droplets. It was possible to alter the sizes of nanoelectrosprayed droplets in several ways, including by changing the solvent composition and voltage applied to the emitter. Droplets consisting of high concentrations of glycerol were larger than droplets containing high concentrations of methanol, presumably due to the high surface tension of glycerol. Correspondingly, droplets became smaller when the voltage applied to the emitter was increased, likely due to the ability to overcome the surface tension of the solvent more easily. The smallest detectable droplets confidently measured with this method were 200 nm in diameter. This method demonstrates a new way of measuring the sizes of electrosprayed droplets with half the diameter of conventional droplet size measurement methods. Through further optimization, it may be possible to measure the sizes of electrosprayed droplets as small as the theoretical resolution limit of SIM (∼100 nm).

Hand-held portable desorption atmospheric pressure chemical ionization ion source for in situ analysis of nitroaromatic explosives.

A novel, lightweight (0.6 kg), solvent- and gas-cylinder-free, hand-held ion source based on desorption atmospheric pressure chemical ionization has been developed and deployed for the analysis of nitroaromatic explosives on surfaces in open air, offering portability for in-field analysis. A small, inexpensive, rechargeable lithium polymer battery was used to power the custom-designed circuitry within the device, which generates up to ±5 kV dc voltage to ignite a corona discharge plasma in air for up to 12 h of continuous operation, and allowing positive- and negative-ion mass spectrometry. The generated plasma is pneumatically transported to the surface to be interrogated by ambient air at a rate of 1-3.5 L/min, compressed using a small on-board diaphragm pump. The plasma source allows liquid or solid samples to be examined almost instantaneously without any sample preparation in the open environment. The advantages of low carrier gas and low power consumption (<6 W), as well as zero solvent usage, have aided in developing the field-ready, hand-held device for trigger-based, "near-real-time" sampling/ionization. Individual nitroaromatic explosives (such as 2,4,6-trinitrotoluene) can be easily detected in amounts as low as 5.8 pg with a linear dynamic range of at least 10 (10-100 pg), a relative standard deviation of ca. 7%, and an R(2) value of 0.9986. Direct detection of several nitroaromatic compounds in a complex mixture without prior sample preparation is demonstrated, and their identities are confirmed by tandem mass spectrometry fragmentation patterns.

On-demand ambient ionization of picoliter samples using charge pulses.

Relay electrospray ionization (rESI) from a capillary containing a sample solution (or from an array of such capillaries) is triggered by charge deposition onto the capillary. Suitable sources of primary ions, besides electrosprays, are plasma ion and piezoelectric discharge plasma sources. With no requirement for physical contact, high-throughput sample screening is enabled by rapidly addressing individual secondary (sample) capillaries. Sub-pL sample volumes can be loaded and sprayed. Polar analytes, including neurotransmitters, phosphopeptides, oligonucleotides, illicit drugs, and pharmaceutical compounds are successfully ionized by rESI with concentration sensitivities (0.1 ppb for acetylcholine) which are similar to nanoESI but absolute sensitivities are orders of magnitude better. Nonpolar analytes (steroids, alkynes) are ionized by rESI using an open-tube secondary capillary and injecting electrolytically generated metal cations from the primary electrospray.

Synthesis and catalytic reactions of nanoparticles formed by electrospray ionization of coinage metals.

Noble metals can be ionized by electrochemical corrosion and transported by electrospray ionization. Mass spectrometry (MS) showed solvated metal ions as the main ionic constituent of the sprayed droplets. Collection of the electrospray plume on a surface yielded noble metal nanoparticles (NPs) under ambient conditions. The NPs were characterized by several techniques. Under typical conditions, capped-nanoparticle sizes averaged 2.2 nm for gold and 6.5 nm for silver. The gold nanoparticles showed high catalytic activity in the reduction of p-nitrophenol by NaBH4 . Efficient catalysis was also observed by simply directing the spray of solvated Au(+) onto the surface of an aqueous p-nitrophenol/NaBH4 mixture. Organometallic ions were generated by spiking ligands into the spray solvent: for example, Cu(I) bipyridine cations dominated the spray during Cu electrocorrosion in acetonitrile containing bipyridine. This organometallic reagent was shown to be effective in the radical polymerization of styrene.

Using ambient ion beams to write nanostructured patterns for surface enhanced Raman spectroscopy.

Electrolytic spray deposition was used to pattern surfaces with 2D metallic nanostructures. Spots that contain silver nanoparticles (AgNP) were created by landing solvated silver ions at desired locations using electrically floated masks to focus the metal ions to an area as little as 20 µm in diameter. The AgNPs formed are unprotected and their aggregates can be used for surface-enhanced Raman spectroscopy (SERS). The morphology and SERS activity of the NP structures were controlled by the surface coverage of landed silver ions. The NP structures created could be used as substrates onto which SERS samples were deposited or prepared directly on top of predeposited samples of interest. The evenly distributed hot spots in the micron-sized aggregates had an average SERS enhancement factor of 10(8) . The surfaces showed SERS activity when using lasers of different wavelengths (532, 633, and 785 nm) and were stable in air.

Direct analysis of 4-methylimidazole in foods using paper spray mass spectrometry.

Rapid qualitative and quantitative analysis of 4-methylimidazole (4-MEI) in caramel and beverage samples is demonstrated using the paper spray form of ambient ionization mass spectrometry. The minimum level of pure 4-MEI detectable using multiple reaction monitoring (MRM) in a triple quadrupole instrument was 3 pg µL⁻¹ in neat solvent and 5 pg µL⁻¹ in a matrix containing caramel. This method was used to analyze 11 caramel samples for 4-MEI. After implementing effective quality control protocols, average relative standard deviations for paper spray triple quadrupole MS were less than 15% and the linear dynamic range was three orders of magnitude. Results obtained on three different days by two different analyst groups agreed closely. An ion trap tandem MS method of approximate quantitative analysis is also described and it gave similar precision to the triple quadrupole experiment when fluctuations in ion currents were cancelled by simultaneously isolating the analyte and internal standard and fragmenting both in an ion trap simultaneous MRM experiment. As another alternative, a rapid qualitative screening method based on the use of high-resolution measurements instead of tandem mass spectrometry using an Orbitrap was also tested and found to give a detection limit of 100 pg µL⁻¹.

In situ analysis of corrosion inhibitors using a portable mass spectrometer with paper spray ionization.

Paper spray (PS) ambient ionization is implemented using a portable mass spectrometer and applied to the detection of alkyl quaternary ammonium salts in a complex oil matrix. These salts are commonly used as active components in the formulation of corrosion inhibitors. They were identified in oil and confirmed by their fragmentation patterns recorded using tandem mass spectrometry (MS/MS). The cations of alkyl and benzyl-substituted quaternary ammonium salts showed characteristic neutral losses of CnH2n (n carbon number of the longest chain) and C7H8, respectively. Individual quaternary ammonium compounds were detected at low concentrations (<1 ng µL(-1)) and over a dynamic range of ∼5 pg µL(-1) to 500 pg µL(-1) (ppb). Direct detection of these compounds in complex oil samples without prior sample preparation or pre-concentration was also demonstrated using a home-built miniature mass spectrometer at levels below 1 ng µL(-1).

Gigaohm and Teraohm Resistors in Femtoamp and Picoamp Electrospray Ionization.

The femtoamp electrospray ionization (femtoESI) mode has been shown to exhibit unique characteristics that may facilitate ionization efficiency studies and experiments requiring low ion beam flux. Investigation of femtoESI was hindered by a tiny, applied voltage window of 10-100 V, beyond which ionization currents quickly jumped to nanoamps. This window was difficult to locate because the exact onset voltage fluctuates due to variations in ion source alignments. Large resistors (0.1-100 TΩ) in series effectively expanded the femtoESI applied voltage range, up to 1400 V. By swapping resistors, rapid alternation allows for the comparison of both ESI modes under the same alignment. In peptide mixtures, analytes with lower surface activity are suppressed in the nanoESI mode whereas the femtoESI mode shows signal enhancement of less surface-active species. For protein solutions, there is little change in the charge states generated but the femtoESI mode does show a decrease in the average charge state of protein peaks. Peptides and proteins analyzed in the femtoESI mode also tend to generate higher intensity sodiated peaks over protonated peaks at specific charge states compared with nanoESI mode operation.

Density of Surface States: Another Key Contributing Factor in Triboelectric Charge Generation.

The triboelectric nanogenerator (TENG) has been invented as a technology for harvesting mechanical energy, as well as for allocating quantized charge for scientific instruments. The charge generation of the TENG is mainly related to the triboelectric effect or contact electrification (CE) as usually described by the potential-well-electron-cloud model, while the triboelectric charge transfer is related to the difference in the occupied energy levels of electrons. However, in our experiment, we observed an abnormal triboelectric charge generation phenomena between ternary materials, which cannot be explained by the occupied energy level difference only. To address this issue, we proposed the model based on the density of surface states (DOSS) as another key contributing factor to the triboelectric charge generation. To demonstrate our model, we introduced an approach to measure the DOSS through applying external electric field between two triboelectric surfaces. Our experiments confirmed the contribution of the DOSS to the triboelectric charge generation, with the derived charge density consistent with the measured results, which verified our model. We also predicted that the FEP has the potential to achieve a high charge density of ∼5.6 × 10-4 C/m2, which is close to the reported maximum values. This study provides another key contributing factor to the triboelectric charge generation, which may provide a more complete model for guiding the material selection and modification to tailor the surface charge generated by the CE.

A paradigm shift fully self-powered long-distance wireless sensing solution enabled by discharge-induced displacement current.

The rapid development of the Internet of Things depends on wireless devices and their network. Traditional wireless sensing and transmission technology still requires multiple modules for sensing, signal modulation, transmission, and power, making the whole system bulky, rigid, and costly. Here, we proposed a paradigm shift wireless sensing solution based on the breakdown discharge­induced displacement current. Through that, we can combine the abovementioned functional modules in a single unit of self-powered wireless sensing e-sticker (SWISE), which features a small size (down to 9 mm by 9 mm) and long effective transmission distance (>30 m) when compared to existing wireless sensing technologies. Furthermore, SWISEs have functions of multipoint motion sensing and gas detection in fully self-powered manner. This work proposes a solution for flexible self-powered wireless sensing platforms, which shows great potential for implantable and wearable electronics, robotics, health care, infrastructure monitoring, human-machine interface, virtual reality, etc.

Nested-channel for on-demand alternation between electrospray ionization regimes.

On-demand electrospray ionization from different liquid channels in the same emitter was realized using filamented capillary and gas phase charge supply. The solution sub-channel was formed when back-filling solution to the emitter tip by capillary action along the filament. Gas phase charge carriers were used to trigger electrospray ionization from the solution meniscus at the tip. The meniscus at the tip opening may be fully filled or partially empty to generate electrospray ionization in main-channel regime and sub-channel regime, respectively. For emitters with 4 µm tip opening, the two nested electrospray (nested-ESI) channels accommodated ESI flow rates ranging from 50 pL min-1 to 150 nL min-1. The platform enabled on-demand regime alternations within one sample run, in which the sub-channel regime generated smaller charged droplets. Ionization efficiencies for saccharides, glycopeptide, and proteins were enhanced in the sub-channel regime. Non-specific salt adducts were reduced and identified by regime alternation. Surprisingly, the sub-channel regime produced more uniform responses for a peptide mixture whose relative ionization efficiencies were insensitive to ESI conditions in previous picoelectrospray study. The nested channels also allowed effective washing of emitter tip for multiple sampling and analysis operations.