Harnessing Graphdiyne for Selective Cu2+ Detection: A Promising Tool for Parkinson's Disease Diagnostics and Pathogenesis.

Cu2+ accelerates the viral-like propagation of α-synuclein fibrils and plays a key role in the pathogenesis of Parkinson's disease (PD). Therefore, the accurate detection of Cu2+ is essential for the diagnosis of PD and other neurological diseases. The Cu2+ detection process is impeded by substances that have similar electrochemical properties. In this study, graphdiyne (GDY), a new kind of carbon allotrope with strong electron-donating ability, was utilized for the highly selective detection of Cu2+ by taking advantage of its outstanding adsorption capacity for Cu2+. Density functional theory (DFT) calculations show that Cu atoms are adsorbed in the cavity of GDY, and the absorption energy between Cu and C atoms is higher than that of graphene (GR), indicating that the cavity of GDY is favorable for the adsorption of Cu atoms and electrochemical sensing. The GDY-based electrochemical sensor can effectively avoid the interference of amino acids, metal ions and neurotransmitters and has a high sensitivity of 9.77 µA·µM-1·cm-2, with a minimum detectable concentration of 200 nM. During the investigating pathogenesis and therapeutic process of PD with α-synuclein as the diagnostic standard, the concentration of Cu2+ in cells before and after L-DOPA and GSH treatments were examined, and it was found that Cu2+ exhibits high potential as a biomarker for PD. This study not only harnesses the favorable adsorption of the GDY and Cu2+ to improve the specificity of ion detection but also provide clues for deeper understanding of the role of Cu2+ in neurobiology and neurological diseases.

Genetically encoded biocompatible anti-coagulant protein-coated coronary artery stents drive endothelialization.

In response to the critical demand for advancements in coronary artery stents, this study addresses the challenges associated with arterial recoil and restenosis post-angioplasty and the imperative to encourage rapid re-endothelialization for minimizing thrombosis risks. We employed an innovative approach inspired by mussel adhesion, incorporating placental anticoagulant protein (AnnexinV) on stent design. The introduction of a post-translationally modified catecholic amino acid L-3,4-dihydroxyphenylalanine (L-Dopa), mimicking mussel characteristics, allowed for effective surface modification of Stainless steel stents through genetic code engineering in AnnexinV (AnxDopa). The efficacy of AnxDopa was analyzed through microscale thermophoresis and flow cytometry, confirming AnxDopa's exceptional binding with phosphatidylserine and activated platelets. AnxDopa coated stainless steel demonstrates remarkable bio-, hemo-, and immuno-compatibility, preventing smooth muscle cell proliferation, platelet adhesion, and fibrin formation. It acts as an interface between the stent and biological fluid, which facilitates the anticoagulation and rapid endothelialization. Surface modification of SS verified through XPS analysis and contact angle measurement attests to the efficacy of AnxDopa mediated surface modification. The hydrophilic nature of the AnxDopa-coated surface enhanced the endothelialization through increased protein absorption. This approach represents a significant stride in developing coronary stents with improved biocompatibility and reduced restenosis risks, offering valuable contributions to scientific and clinical realms alike.

Quaternary Ammonium Assisted Synthesis of Melanin-like Poly(l-DOPA) Nanoparticles with a Boosted Photothermal Effect.

Poly(levodopa) nanoparticles (P(l-DOPA) NPs) are another kind of melanin mimetic besides well-established polydopamine nanoparticles (PDA NPs). Due to the presence of carboxyl groups, the oxidative polymerization of l-DOPA to obtain particles was not as efficient as that of dopamine. Several established methods toward P(l-DOPA) NP fabrication do not combine convenience, morphological regularity, size controllability, low cost, and adaptability to metal-free application scenarios. In this work, P(l-DOPA) NPs were successfully prepared in hot water with the assistant of organic quaternary ammonium, due to the extra physical cross-linking mediated by cations. The employed physical interactions could also be affected by quaternary ammonium structure (i.e., number of cation heads, length of alkyl chain) to achieve different polymerization acceleration effects. The obtained P(l-DOPA) NPs retained superior photothermal properties and outperformed PDA-based melanin materials. Furthermore, P(l-DOPA) NPs were used in photothermal tumor therapy and showed better efficacy. This study offers new insights into the synthesis of melanin-like materials, as well as new understanding of the interaction between quaternary ammonium and bioinspired polyphenolic materials.

Immobilized enzymatic membrane surfaces for biocatalytic organics removal and fouling resistance.

This research reported on the immobilization of environmentally friendly enzymes, such as horseradish peroxidase (HRP) and laccase (L), along with the hydrophilic zwitterionic compound l-DOPA on nano-filtration (NF) membranes. This approach introduced biocatalytic membranes, leveraging combined effects between membranes and enzymes. The aim was to systematically assess the efficacy of the enzymatic modified membrane (HRP-NF) in degrading colors in the wastewater, as well as enhancing the membrane resistance toward organic fouling. The enzymatic immobilized membrane demonstrated 96.3 ± 1.8% to 96.6 ± 1.9% removal of colors, and 65.2 ± 1.3% to 67.2 ± 1.3% removal of TOC. This result was underpinned by the insights obtained from the radical scavenger coumarin, which was employed to trap and confirm the formation of PRs through the reaction of enzymes and H2O2. Furthermore, membranes modified with enzymes exhibited significantly improved antifouling properties. The HRP-NF membrane experienced an 8% decline in flux, while the co-immobilized HRP-L-NF membrane demonstrated as low as 6% flux decline, contributed by the synergistic effect of increased hydrophilicity and biocatalytic effects. These findings confirmed that the immobilized enzymatic surface has added function of degrading contaminants in addition to separation function of nanofiltration membrane. These l-DOPA-immobilized enzymatic membranes offered a promising hybrid biocatalytic membrane to eliminate dyes and mitigate membrane fouling, which can be applied in many industrial and domestic water and wastewater treatment.

Spherical porous iron-nitrogen-carbon nanozymes derived from a tannin coordination framework for the preparation of L-DOPA by emulating tyrosine hydroxylase.

L-3,4-Dihydroxyphenylalanine (L-DOPA) is widely used in Parkinson's disease treatment and is therefore in high demand. Development of an efficient method for the production of L-DOPA is urgently required. Nanozymes emulating tyrosine hydroxylase have attracted enormous attention for biomimetic synthesis of L-DOPA, but suffered from heterogeneity. Herein, a spherical porous iron-nitrogen-carbon nanozyme was developed for production of L-DOPA. Tannic acid chelated with ferrous ions to form a tannin-iron coordination framework as a carbon precursor. Iron and nitrogen co-doped carbon nanospheres were assembled via an evaporation-induced self-assembly process using urea as a nitrogen source, F127 as a soft template, and formaldehyde as a crosslinker. The nanozyme was obtained after carbonization and acid etching. The nanozyme possessed a dispersive iron atom anchored in the Fe-N coordination structure as an active site to mimic the active center of tyrosine hydroxylase. The material showed spherical morphology, uniform size, high specific surface area, a mesoporous structure and easy magnetic separation. The structural properties could promote the density and accessibility of active sites and facilitate mass transport and electron transfer. The nanozyme exhibited high activity to catalyze the hydroxylation of tyrosine to L-DOPA as tyrosine hydroxylase in the presence of ascorbic acid and hydrogen peroxide. The titer of DOPA reached 1.2 mM. The nanozyme showed good reusability and comparable enzyme kinetics to tyrosine hydroxylase with a Michaelis-Menten constant of 2.3 mM. The major active species was the hydroxyl radical. Biomimetic simulation of tyrosine hydroxylase using a nanozyme with a fine structure provided a new route for the efficient production of L-DOPA.

Quantifying Intracellular Single Vesicular Catecholamine Concentration with Open Carbon Nanopipettes to Unveil the Effect of L-DOPA on Vesicular Structure.

Understanding the regulatory mechanisms of exocytosis is essential for uncovering the pathologies of neuronal disorders and developing related pharmaceuticals. In this work intracellular vesicle impact electrochemical cytometry (IVIEC) measurements with different-sized (50-500 nm radius) open carbon nanopipettes (CNPs) were performed to quantify the vesicular content and release kinetics of specific vesicle populations grouped by orifice sizes. Intracellular vesicles with radius below 100 nm were captured and narrowed between 50 and 100 nm. On the basis of this, single vesicular catecholamine concentrations in the intracellular environment were quantified as 0.23-1.1 M. Our results with L-3,4-dihydroxyphenylalanine (L-DOPA)-exposure indicate that L-DOPA regulates exocytosis by increasing the dense core size and vesicular content while catecholamine concentrations did not show obvious alterations. These were all achieved simultaneously and relatively noninvasively with open CNPs.

One-Pot Biocatalytic In Vivo Methylation-Hydroamination of Bioderived Lignin Monomers to Generate a Key Precursor to L-DOPA.

Electron-rich phenolic substrates can be derived from the depolymerisation of lignin feedstocks. Direct biotransformations of the hydroxycinnamic acid monomers obtained can be exploited to produce high-value chemicals, such as α-amino acids, however the reaction is often hampered by the chemical autooxidation in alkaline or harsh reaction media. Regioselective O-methyltransferases (OMTs) are ubiquitous enzymes in natural secondary metabolic pathways utilising an expensive co-substrate S-adenosyl-l-methionine (SAM) as the methylating reagent altering the physicochemical properties of the hydroxycinnamic acids. In this study, we engineered an OMT to accept a variety of electron-rich phenolic substrates, modified a commercial E. coli strain BL21 (DE3) to regenerate SAM in vivo, and combined it with an engineered ammonia lyase to partake in a one-pot, two whole cell enzyme cascade to produce the l-DOPA precursor l-veratrylglycine from lignin-derived ferulic acid.

Delivery of a system xc- inhibitor by a redox-responsive levodopa prodrug nanoassembly for combination ferrotherapy.

A comprehensive understanding of ferroptosis signaling pathways significantly contributes to the advances in cancer ferrotherapy. Herein, we constructed a self-assembled prodrug nanosystem targeting system xc-, a key regulator for ferroptosis, to amplify the therapeutic efficacy of cancer ferrotherapy. The prodrug nanosystem is assembled between sulfasalazine (SSZ, a ferroptosis resistance inhibitor) and disulfide-bridged levodopa (DSSD) that can chelate Fe2+ ions to form SSZ-Fe2+@DSSD, and the resulting nanoassembly can not only inhibit ferroptosis resistance, but also generate ROS in the tumor microenvironment. Whereas the prodrug nanosystem is stable in the physiological environment, it becomes unstable in the tumoral and intracellular reductive microenvironment, where the disulfide linkers are disrupted by high levels of glutathione (GSH), triggering the release of active Fe2+ and SSZ. Under the Fenton reaction, the released Fe2+ thus can induce ferroptosis, which is amplified by SSZ-mediated inhibition of ferroptosis resistance to synergistically improve the therapeutic efficacy of ferroptosis. Our study thus provides an innovative prodrug strategy to advance anticancer ferroptosis.

Effect of catechin and commercial preparation of green tea essence on the pharmacokinetics of l-dopa in rabbits.

The aim of this study was to investigate drug interactions of L-dopa/carbidopa with catechin and green tea essence in rabbits following the simultaneous administration via an intramuscular injection of catechin or via an intragastric route for green tea essence with L-dopa/carbidopa. The results indicated that catechin at doses of 10, 20 and 50 mg/kg increased the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t ) of L-dopa by about 69, 78 and 42%, respectively. The metabolic ratios of the AUC0-t for 3-O-methyldopa (3-OMD)/L-dopa significantly decreased by about 56, 68 and 76% (P < 0.05), respectively. In addition, a single dose of 5/1.25 mg/kg L-dopa/carbidopa was co-administrated with 150 mg/kg green tea essence via an intragastric route with an oral-gastric tube. Comparing the related pharmacokinetic parameters of L-dopa, the clearance and metabolic ratio of L-dopa decreased by 20 and 19% (P < 0.05), respectively. In conclusion, catechin and green tea essence can significantly affect the metabolism of L-dopa by the catechol-O-methyltransferase (COMT) metabolic pathway. Catechin can enhance L-dopa bioavailability, and both catechin and green tea essence decreased 3-OMD formation. Therefore, catechin and green tea essence may increase L-dopa efficacy for Parkinson's disease treatment.

Effectiveness of Long-Term Physiotherapy in Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Long-term physiotherapy is acknowledged to be crucial to manage motor symptoms for Parkinson's disease (PD) patients, but its effectiveness is not well understood. OBJECTIVE: This systematic review and meta-analysis aimed to assess the evidence regarding the effectiveness of long-term physiotherapy to improve motor symptoms and reduce antiparkinsonian medication dose in PD patients. METHODS: Pubmed, Cochrane, PEDro, and CINAHL were searched for randomized controlled trials before August 31, 2020 that investigated the effectiveness of physiotherapy for 6 months or longer on motor symptoms and levodopa-equivalent dose (LED) in PD patients with Hoehn and Yahr stage 1- 3. We performed random effects meta-analyses for long-term physiotherapy versus no/control intervention and estimated standard mean differences with 95% confidence intervals (CIs). Levels of evidence were rated by the Grading of Recommendation Assessment, Development and Evaluation approach. RESULTS: From 2,940 studies, 10 studies involving 663 PD patients were assessed. Long-term physiotherapy had favorable effects on motor symptoms in off medication state [- 0.65, 95% CI - 1.04 to - 0.26, p = 0.001] and LED [- 0.49, 95% CI - 0.89to - 0.09, p = 0.02]. Subgroup analyses demonstrated favorable effects on motor symptoms in off medication state by aerobic exercise [- 0.42, 95% CI - 0.64 to - 0.20, p < 0.001] and LED by multidisciplinary rehabilitation of primarily physiotherapy [- 1.00, 95% CI - 1.44 to - 0.56, p < 0.001]. Quality of evidence for aerobic exercise and multidisciplinary rehabilitation were low and very low. CONCLUSION: This review provided evidence that long-term physiotherapy has beneficial impact on motor symptoms and antiparkinsonian medication dose in PD patients and could motivate implementation of long-term physiotherapy.

Green Multi-Platform Solution for the Quantification of Levodopa Enantiomeric Excess in Solid-State Mixtures for Pharmacological Formulations.

The aim of the present work was to develop a green multi-platform methodology for the quantification of l-DOPA in solid-state mixtures by means of MIR and NIR spectroscopy. In order to achieve this goal, 33 mixtures of racemic and pure l-DOPA were prepared and analyzed. Once spectra were collected, partial least squares (PLS) was exploited to individually model the two different data blocks. Additionally, three different multi-block approaches (mid-level data fusion, sequential and orthogonalized partial least squares, and sequential and orthogonalized covariance selection) were used in order to simultaneously handle data from the different platforms. The outcome of the chemometric analysis highlighted the quantification of the enantiomeric excess of l-DOPA in enantiomeric mixtures in the solid state, which was possible by coupling NIR and PLS, and, to a lesser extent, by using MIR. The multi-platform approach provided a higher accuracy than the individual block analysis, indicating that the association of MIR and NIR spectral data, especially by means of SO-PLS, represents a valid solution for the quantification of the l-DOPA excess in enantiomeric mixtures.

L-DOPA Dioxygenase Activity on 6-Substituted Dopamine Analogues.

Dioxygenase enzymes are essential protein catalysts for the breakdown of catecholic rings, structural components of plant woody tissue. This powerful chemistry is used in nature to make antibiotics and other bioactive materials or degrade plant material, but we have a limited understanding of the breadth and depth of substrate space for these potent catalysts. Here we report steady-state and pre-steady-state kinetic analysis of dopamine derivatives substituted at the 6-position as substrates of L-DOPA dioxygenase, and an analysis of that activity as a function of the electron-withdrawing nature of the substituent. Steady-state and pre-steady-state kinetic data demonstrate the dopamines are impaired in binding and catalysis with respect to the cosubstrate molecular oxygen, which likely afforded spectroscopic observation of an early reaction intermediate, the semiquinone of dopamine. The reaction pathway of dopamine in the pre-steady state is consistent with a nonproductive mode of binding of oxygen at the active site. Despite these limitations, L-DOPA dioxygenase is capable of binding all of the dopamine derivatives and catalyzing multiple turnovers of ring cleavage for dopamine, 6-bromodopamine, 6-carboxydopamine, and 6-cyanodopamine. 6-Nitrodopamine was a single-turnover substrate. The variety of substrates accepted by the enzyme is consistent with an interplay of factors, including the capacity of the active site to bind large, negatively charged groups at the 6-position and the overall oxidizability of each catecholamine, and is indicative of the utility of extradiol cleavage in semisynthetic and bioremediation applications.

Site-Specific Biomimicry of Antioxidative Melanin Formation and Its Application for Acute Liver Injury Therapy and Imaging.

Biocompatible nano-antioxidants composed of natural molecules/materials, such as dopamine and melanin, are of great interest for diverse biomedical applications. However, the lack of understanding of the precise structure of these biomaterials and thus the actual dose of effective components impedes their advancement to translation. Herein, a strategy to mimic in situ melanin formation and explore its antioxidative applications is reported, by developing a PEGylated, phenylboronic-acid-protected L-DOPA precursor (PAD) that can self-assemble into well-defined nanoparticles (PADN). Exposure to oxidative species leads to deprotection of phenylboronic acids, transforming PADN to PEG-L-DOPA, which, similar to the biosynthetic pathway of melanin, can be oxidized and polymerized into an antioxidative melanin-like structure. With ultrahigh stability and superior antioxidative activity, the PADN shows remarkable efficacy in prevention and treatment of acute liver injury/failure. Moreover, the in situ structure transformation enables PADN to visualize damaged tissue noninvasively by photoacoustic imaging. Overall, a bioinspired antioxidant with precise structure and site-specific biological activity for theranostics of oxidative stress-related diseases is described.

Lack of Association Between GBA Mutations and Motor Complications in European and American Parkinson's Disease Cohorts.

BACKGROUND: Motor complications are a consequence of the chronic dopaminergic treatment of Parkinson's disease (PD) and include levodopa-induced dyskinesia (LIDs) and motor fluctuations (MF). Currently, evidence is on lacking whether patients with GBA-associated PD differ in their risk of developing motor complications compared to the general PD population. OBJECTIVE: To evaluate the association of GBA carrier status with the development of LIDS and MFs from early PD. METHODS: Motor complications were recorded prospectively in 884 patients with PD from four longitudinal cohorts using part IV of the UPDRS or MDS-UPDRS. Subjects were followed for up to 11 years and the associations of GBA mutations with the development of motor complications were assessed using parametric accelerated failure time models. RESULTS: In 439 patients from Europe, GBA mutations were detected in 53 (12.1%) patients and a total of 168 cases of LIDs and 258 cases of MF were observed. GBA carrier status was not associated with the time to develop LIDs (HR 0.78, 95%CI 0.47 to 1.26, p = 0.30) or MF (HR 1.19, 95%CI 0.84 to 1.70, p = 0.33). In the American cohorts, GBA mutations were detected in 36 (8.1%) patients and GBA carrier status was also not associated with the progression to LIDs (HR 1.08, 95%CI 0.55 to 2.14, p = 0.82) or MF (HR 1.22, 95%CI 0.74 to 2.04, p = 0.43). CONCLUSION: This study does not provide evidence that GBA-carrier status is associated with a higher risk of developing motor complications. Publication of studies with null results is vital to develop an accurate summary of the clinical features that impact patients with GBA-associated PD.

The Role of Melanin in the Biology and Ecology of Nematophagous Fungi.

Melanin is a heteropolymer formed by the polymerization of phenolic and indolic compounds. It occurs in organisms across all biological kingdoms and has a range different of functions, thus indicating its important evolutionary role. The presence of melanin offers several protective advantages, including against ultraviolet radiation, traumatic damage, oxidative stress, extreme temperatures, and pressure. For many species of fungi, melanin also participates directly in the process of virulence and pathogenicity. These organisms can synthesize melanin in two main ways: using a substrate of endogenous origin, involving 1,8-dihydroxynaphthalene (DHN); alternatively, in an exogenous manner with the addition of L-3, 4-dihydroxyphenylalanine (L-DOPA or levodopa). As melanin is an amorphous and complex substance, its study requires expensive and inaccessible technologies and analyses are often difficult to perform with conventional biochemical techniques. As such, details about its chemical structure are not yet fully understood, particularly for nematophagous fungi that remain poorly studied. Thus, this review presents an overview of the different types of melanin, with an emphasis on fungi, and discusses the role of melanin in the biology and ecology of nematophagous fungi.

Non-Invasive Sweat-Based Tracking of L-Dopa Pharmacokinetic Profiles Following an Oral Tablet Administration.

Levodopa (L-Dopa) is the "gold-standard" medication for symptomatic therapy of Parkinson disease (PD). However, L-Dopa long-term use is associated with the development of motor and non-motor complications, primarily due to its fluctuating plasma levels in combination with the disease progression. Herein, we present the first example of individualized therapeutic drug monitoring for subjects upon intake of standard L-Dopa oral pill, centered on dynamic tracking of the drug concentration in naturally secreted fingertip sweat. The touch-based non-invasive detection method relies on instantaneous collection of fingertip sweat on a highly permeable hydrogel that transports the sweat to a biocatalytic tyrosinase-modified electrode, where sweat L-Dopa is measured by reduction of the dopaquinone enzymatic product. Personalized dose-response relationship is demonstrated within a group of human subjects, along with close pharmacokinetic correlation between the finger touch-based fingertip sweat and capillary blood samples.

Proanthocyanidins isolated from the leaves of Photinia × fraseri block the cell cycle and induce apoptosis by inhibiting tyrosinase activity in melanoma cells.

Tyrosinase is considered a molecular marker of melanoma, and few natural antitumor drugs targeting tyrosinase have been identified. In this study, proanthocyanidins (PAs) were isolated from the leaves of Photinia × fraseri and their structures were characterized by high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and the effects of antityrosinase activity were investigated. The results showed that the basic structural units of PAs are composed of catechin and epicatechin and that oligomer is the main component. PAs exhibited better antityrosinase activity via chelation of copper ions and by disturbing o-quinone production. Furthermore, analyses of the cell cycle, apoptosis rate, and regulation of melanin protein expression revealed preliminarily that PAs could affect melanin production by downregulating microphthalmia transcription factor (MITF) expression and by inhibiting the activities of tyrosinase and tyrosinase related protein 1 (TRP-1), leading to cell cycle arrest and apoptosis of melanoma cells. Collectively, our study demonstrated that PAs are potential tyrosinase inhibitors and have good antimelanoma effects. These findings provide a theoretical support for the application of tyrosinase inhibitors and for further drug development.

L-Dopa release from mesoporous silica nanoparticles engineered through the concept of drug-structure-directing agents for Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease, the 2nd most common after Alzheimer's disease, the main effect of which is the loss of dopaminergic neurons. Levodopa or l-Dopa is an amino acid used in the treatment of PD that acts as the immediate precursor to dopamine. However, over time the efficacy of the medication gradually decreases requiring modified delivery methods. One of the major challenges for the medication to work is to achieve a gradual continuous supply of l-Dopa to the brain to minimise symptoms. Herein, mesoporous silica nanoparticles (MSNs) were engineered through the concept of drug-structure-directing agents (DSDAs) with inherent therapeutic activity. The DSDA used was l-Dopa drug modified by amidation with fatty acids to build anionic surfactants that were able to form micelles as templates for the assembly of inorganic precursors to form the silica framework. This templating route produced MSNs with tunable sizes ranging from 100 nm to 1 µm and with different shapes: spherical, with either solid structures with radial mesopores and porous shells, or hollow-shells with inside large void cavities; and elongated, characterized by long hollows covered by mesoporous shells. The concept of using DSDAs to synthesize drug nanocarriers can be used to avoid the surfactant removal and subsequent drug loading steps involved in the synthesis of conventional MSNs. We hypothesized that the l-Dopa released from MSN materials is mediated by the size and solubility of the DSDAs, and the surface chemical interactions between the DSDAs and MSN hosts. Different pHs (acidic and neutral) simulating gastrointestinal tract conditions were tested, and the results showed hardly any release for gastric conditions at pH 1.2, avoiding the premature release in the stomach typical of conventional MSNs, while for intestinal conditions of pH 7.4, the release of l-Dopa occurred in a continuous and sustained manner, which is well suited to the drug's application and delivery route, and matches well with achieving a sustained l-Dopa delivery to relief symptoms. This could open up new uses for MSNs synthesized by this approach to treat PD.

Species Difference in Hydrolysis of an Ester-type Prodrug of Levodopa in Human and Animal Plasma: Different Contributions of Alpha-1 Acid Glycoprotein.

Previously, we found that ONO-2160, an ester-type prodrug of levodopa (3-hydroxy-l-tyrosine), was mainly hydrolyzed in human plasma by α1-acid glycoprotein (AGP) with a partial contribution of albumin. In this study, we investigated whether ONO-2160 was hydrolyzed in the plasma of preclinical species (dog, rabbit, rat, and mouse) and humans and whether AGP and albumin are involved in its hydrolysis. ONO-2160 was hydrolyzed to some extent in the plasma of all tested species with the order of magnitude mouse > human > rabbit > rat > dog. Except for dogs, ONO-2160 was partially hydrolyzed by animal AGP and albumin. This indicated that, similar to albumin, AGP possesses esterase-like activity in mice, rats, and rabbits, as well as humans. A comparison of the values of intrinsic clearance per milliliter of plasma demonstrated that AGP was the major contributor to the hydrolysis of ONO-2160 in rabbit plasma, whereas albumin was primarily responsible for the hydrolysis of ONO-2160 in mouse plasma. This was confirmed by experiments using AGP-knockout mouse plasma. This study reports the first evidence for the existence of species differences in the hydrolysis of ONO-2160 in plasma related to the different contributions of AGP and albumin.

Structural Transformative Antioxidants for Dual-Responsive Anti-Inflammatory Delivery and Photoacoustic Inflammation Imaging.

We have synthesized a PEGylated, phenylboronic acid modified L-DOPA pro-antioxidant (pPAD) that can self-assemble into nanoparticles (pPADN) for the loading of a model glucocorticoid dexamethasone (Dex) through 1,3-diol/phenylboronic acid chemistry and hydrophobic interactions for more effective treatment of inflammation. Upon exposure to ROS, pPADN convert into the active form of L-DOPA, and a cascade of oxidative reactions transform it into antioxidative melanin-like materials. Concomitantly, the structural transformation of pPADN triggers the specific release of Dex, along with the acidic pH of inflammatory tissue. In a rat model of osteoarthritis, Dex-loaded pPADN markedly mitigate synovial inflammation, suppress joint destruction and cartilage matrix degradation, with negligible in vivo toxicity. Moreover, in situ structural transformation makes pPADN suitable for noninvasive monitoring of therapeutic effects as a photoacoustic imaging contrast agent.