Overcoming Hepatic Biotransformation Barrier of Gold Nanoparticles via Au-Se Bond for Enhanced In Vivo Active Targeting.

As a key metabolic function of the liver, the hepatic biotransformation process can alter the predesigned surface chemistry of nanoparticles in vivo, leading to hampered functionality and targeting ability. However, strategies to modulate the hepatic biotransformation of nanoparticles have been rarely explored. Herein, using indocyanine green (ICG)-conjugated gold nanoparticles that target liver hepatocytes as a model, we showed that merely changing the metal-ligand bond from gold-sulfur (Au-S) to gold-selenium (Au-Se) completely reshaped the hepatic biotransformation profiles of the nanoparticle as well as its targeting and transport behaviors in vivo. Compared with those of Au-S bond, Au-Se bond markedly slowed down nanoparticle biotransformation in liver sinusoids, enhanced ICG-mediated nanoparticle targeting to hepatocytes by 15-fold, and also altered nanoparticle intrahepatic transport, distribution, and clearance pathways. Moreover, we demonstrated that Au-Se bond could improve the active targeting of gold nanoparticles to hepatic tumors by reducing liver biotransformation-induced dissociation of targeting ligands. These discoveries not only deepen our understanding of nanoparticle biotransformation in the liver but also offer a strategy to overcome the biochemical barrier of hepatic biotransformation, providing guidance for the design and engineering of related nanomedicines by tuning their in vivo biotransformation profiles.

Early Detection and Noninvasive Staging of Kidney Dysfunction by a PEGylated Conventional Fluorophore via GFR-Sensitive Renal Transport.

Noninvasive fluorescence imaging of renal function is a valuable technique for understanding kidney disease progression and the development of renal medicine. This technique requires sensitive imaging probes for reporting renal dysfunction accurately at early stage. Herein, a molecularly engineered imaging probe (800CW-PEG45-COOH) was synthesized by simply PEGylating conventional near-infrared fluorophore IRDye800CW with NH2-PEG45-COOH (molecular weight ∼2100 Da) for early detection and staging of renal dysfunction through noninvasive real-time kidney imaging. 800CW-PEG45-COOH not only cleared through the kidney efficiently (>90% injection dosage at 24 h postinjection) but was also found to be freely filtered by glomeruli without renal tubular reabsorption and secretion. Despite this simple construction strategy, the transport of 800CW-PEG45-COOH within the kidneys was extremely sensitive to the alteration of the glomerular filtration rate (GFR), which enabled it to detect renal dysfunction much earlier than commonly used serum biomarkers and stage kidney function impairments (mild vs severe dysfunction) via imaging-based kidney clearance kinetics. This work not only provides a promising optical imaging probe for the noninvasive evaluation of kidney function but also highlights the utility of PEGylation in enhancing the performance of conventional organic dyes in biomedical applications.

Hepatic Biotransformation of Renal Clearable Gold Nanoparticles for Noninvasive Detection of Liver Glutathione Level via Urinalysis.

Renal clearable nanoparticles have been drawing much attention as they can avoid prolonged accumulation in the body by efficiently clearing through the kidneys. While much effort has been made to understand their interactions within the kidneys, it remains unclear whether their transport could be influenced by other organs, such as the liver, which plays a crucial role in metabolizing and eliminating both endogenous and exogenous substances through various biotransformation processes. Here, by utilizing renal clearable IRDye800CW conjugated gold nanocluster (800CW4-GS18-Au25) as a model, we found that although 800CW4-GS18-Au25 strongly resisted serum-protein binding and exhibited minimal accumulation in the liver, its surface was still gradually modified by hepatic glutathione-mediated biotransformation when passing through the liver, resulting in the dissociation of IRDye800CW from Au25 and biotransformation-generated fingerprint message of 800CW4-GS18-Au25 in urine, which allowed us to facilely quantify its urinary biotransformation index (UBI) via urine chromatography analysis. Moreover, we observed the linear correlation between UBI and hepatic glutathione concentration, offering us a noninvasive method for quantitative detection of liver glutathione level through a simple urine test. Our discoveries would broaden the fundamental understanding of in vivo transport of nanoparticles and advance the development of urinary probes for noninvasive biodetection.

Size-Dependent In Vivo Transport of Nanoparticles: Implications for Delivery, Targeting, and Clearance.

Understanding the in vivo transport of nanoparticles provides guidelines for designing nanomedicines with higher efficacy and fewer side effects. Among many factors, the size of nanoparticles plays a key role in controlling their in vivo transport behaviors due to the existence of various physiological size thresholds within the body and size-dependent nano-bio interactions. Encouraged by the evolving discoveries of nanoparticle-size-dependent biological effects, we believe that it is necessary to systematically summarize the size-scaling laws of nanoparticle transport in vivo. In this review, we summarized the size effect of nanoparticles on their in vivo transport along their journey in the body: begin with the administration of nanoparticles via different delivery routes, followed by the targeting of nanoparticles to intended tissues including tumors and other organs, and eventually clearance of nanoparticles through the liver or kidneys. We outlined the tools for investigating the in vivo transport of nanoparticles as well. Finally, we discussed how we may leverage the size-dependent transport to tackle some of the key challenges in nanomedicine translation and also raised important size-related questions that remain to be answered in the future.

Nucleus-targeting imaging and enhanced cytotoxicity based on naphthalimide derivatives.

Organelles possess critical biological effects in cellular processes. However, the relationship between organelle targeting and antitumour activity is a challenging issue. In this paper, a number of amide/acylhydrazine modified naphthalimide derivatives were designed and synthesized. Interestingly, amide modified naphthalimide derivatives NI-A-NH and NI-C-NH with (R)-piperdine and (S)-pyrrolidine functionalization exhibited enhanced cytotoxicity compared with acylhydrazine modified derivatives NI-A-2NH and NI-C-2NH. However, acylhydrazine modified derivatives NI-B-2NH and NI-D-2NH with (S)-piperdine and achiral piperdine conjugates possessed better cytotoxicity than NI-B-NH and NI-D-NH with amide modifications. Fluorescence imaging, DNA binding interactions and cell cycle analyses were further completed to clarify that the nucleus-targeting effects showed enhanced cytotoxic activity, strong DNA binding and the blocking of cells in S phase. These results provide a preliminary theoretical basis for the further design of organelle-targeting antitumour drugs.

Wear and Corrosion Resistance of Plasma Electrolytic Oxidation Coatings on 6061 Al Alloy in Electrolytes with Aluminate and Phosphate.

Phosphate and aluminate electrolytes were used to prepare plasma electrolytic oxidation (PEO) coatings on 6061 aluminum alloy. The surface and cross-section microstructure, element distribution, and phase composition of the PEO coatings were characterized by SEM, EDS, XPS, and XRD. The friction and wear properties were evaluated by pin-on-disk sliding tests under dry conditions. The corrosion resistance of PEO coatings was investigated by electrochemical corrosion and salt spray tests in acidic environments. It was found that the PEO coatings prepared from both phosphate and aluminate electrolytes were mainly composed of α-Al2O3 and γ-Al2O3. The results demonstrate that a bi-layer coating is formed in the phosphate electrolyte, and a single-layered dense alumina coating with a hardness of 1300 HV is realizable in the aluminate electrolyte. The aluminate PEO coating had a lower wear rate than the phosphate PEO coating. However, the phosphate PEO coating showed a better corrosion resistance in acidic environment, which is mainly attributed to the presence of an amorphous P element at the substrate/coating interface.

Influence of Cu2+ Ions on the Corrosion Resistance of AZ31 Magnesium Alloy with Microarc Oxidation.

The objectives of this study were to reduce the corrosion rate and increase the cytocompatibility of AZ31 Mg alloy. Two coatings were considered. One coating contained MgO (MAO/AZ31). The other coating contained Cu2+ (Cu/MAO/AZ31), and it was produced on the AZ31 Mg alloy via microarc oxidation (MAO). Coating characterization was conducted using a set of methods, including scanning electron microscopy, energy-dispersive spectrometry, X-ray photoelectron spectroscopy, and X-ray diffraction. Corrosion properties were investigated through an electrochemical test, and a H2 evolution measurement. The AZ31 Mg alloy with the Cu2+-containing coating showed an improved and more stable corrosion resistance compared with the MgO-containing coating and AZ31 Mg alloy specimen. Cell morphology observation and cytotoxicity test via Cell Counting Kit-8 assay showed that the Cu2+-containing coating enhanced the proliferation of L-929 cells and did not induce a toxic effect, thus resulting in excellent cytocompatibility and biological activity. In summary, adding Cu ions to MAO coating improved the corrosion resistance and cytocompatibility of the coating.

Unconstrained Monitoring Method for Heartbeat Signals Measurement using Pressure Sensors Array.

An unconstrained monitoring method for a driver's heartbeat is investigated in this paper. Signal measurement was carried out by using pressure sensors array. Due to the inevitable changes of posture during driving, the monitoring place for heartbeat measurement needs to be adjusted accordingly. An experiment was conducted to attach a pressure sensors array to the backrest of a seat. On the basis of the extreme learning machine classification method, driving posture can be recognized by monitoring the distribution of pressure signals. Then, a band-pass filter in heart rate range is adapted to the pressure signals in the frequency domain. Furthermore, a peak point array of the processed pressure frequency spectrum is derived and has the same distribution as the pressure signals. Thus, the heartbeat signals can be extracted from pressure sensors. Then, the correlation coefficient analysis of heartbeat signals and electrocardio-signals is performed. The results show a high level of correlation. Finally, the effects of driving posture on heartbeat signal extraction are discussed to obtain a theoretical foundation for measuring point real-time adjustment.