Construction of Enzyme-Responsive Micelles Based on Theranostic Zwitterionic Conjugated Bottlebrush Copolymers with Brush-on-Brush Architecture for Cell Imaging and Anticancer Drug Delivery

Bottlebrush copolymers with different chemical structures and compositions as well as diverse architectures represent an important kind of material for various applications, such as biomedical devices. To our knowledge, zwitterionic conjugated bottlebrush copolymers integrating fluorescence imaging and tumor microenvironment-specific responsiveness for efficient intracellular drug release have been rarely reported, likely because of the lack of an efficient synthetic approach. For this purpose, in this study, we reported the successful preparation of well-defined theranostic zwitterionic bottlebrush copolymers with unique brush-on-brush architecture. Specifically, the bottlebrush copolymers were composed of a fluorescent backbone of polyfluorene derivate (PFONPN) possessing the fluorescence resonance energy transfer with doxorubicin (DOX), primary brushes of poly(2-hydroxyethyl methacrylate) (PHEMA), and secondary graft brushes of an enzyme-degradable polytyrosine (PTyr) block as well as a zwitterionic poly(oligo (ethylene glycol) monomethyl ether methacrylate-co-sulfobetaine methacrylate) (P(OEGMA-co-SBMA)) chain with super hydrophilicity and highly antifouling ability via elegant integration of Suzuki coupling, NCA ROP and ATRP techniques. Notably, the resulting bottlebrush copolymer, PFONPN₉-g-(PHEMA₁₅-g-(PTyr₁₆-b-P(OEGMA₆-co-SBMA₆)₂)) (P₂) with a lower MW ratio of the hydrophobic side chains of PTyr and hydrophilic side chains of P(OEGMA-co-SBMA) could self-assemble into stabilized unimolecular micelles in an aqueous phase. The resulting unimolecular micelles showed a fluorescence quantum yield of 3.9% that is mainly affected by the pendant phenol groups of PTyr side chains and a drug-loading content (DLC) of approximately 15.4% and entrapment efficiency (EE) of 90.6% for DOX, higher than the other micelle analogs, because of the efficient supramolecular interactions of π–π stacking between the PTyr blocks and drug molecules, as well as the moderate hydrophilic chain length. The fluorescence of the PFONPN backbone enables fluorescence resonance energy transfer (FRET) with DOX and visualization of intracellular trafficking of the theranostic micelles. Most importantly, the drug-loaded micelles showed accelerated drug release in the presence of proteinase K because of the enzyme-triggered degradation of PTyr blocks and subsequent deshielding of P(OEGMA-co-SBMA) corona for micelle destruction. Taken together, we developed an efficient approach for the synthesis of enzyme-responsive theranostic zwitterionic conjugated bottlebrush copolymers with a brush-on-brush architecture, and the resulting theranostic micelles with high DLC and tumor microenvironment-specific responsiveness represent a novel nanoplatform for simultaneous cell image and drug delivery.     

Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450

Biotransformation of organophosphorus flame retardants (OPFRs) mediated by cytochrome P450 enzymes (CYPs) has a potential correlation with their toxicological effects on humans. In this work, we employed five typical OPFRs including tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(1-chloro-2-propyl) phosphate (TCIPP), tri(2-chloroethyl) phosphate (TCEP), triethyl phosphate (TEP), and 2-ethylhexyl diphenyl phosphate (EHDPHP), and performed density functional theory (DFT) calculations to clarify the CYP-catalyzed biotransformation of five OPFRs to their diester metabolites. The DFT results show that the reaction mechanism consists of Cα-hydroxylation and O-dealkylation steps, and the biotransformation activities of five OPFRs may follow the order of TCEP ≈ TEP ≈ EHDPHP > TCIPP > TDCIPP. We further performed molecular dynamics (MD) simulations to unravel the binding interactions of five OPFRs in the CYP3A4 isoform. Binding mode analyses demonstrate that CYP3A4-mediated metabolism of TDCIPP, TCIPP, TCEP, and TEP can produce the diester metabolites, while EHDPHP metabolism may generate para-hydroxyEHDPHP as the primary metabolite. Moreover, the EHDPHP and TDCIPP have higher binding potential to CYP3A4 than TCIPP, TCEP, and TEP. This work reports the biotransformation profiles and binding features of five OPFRs in CYP, which can provide meaningful clues for the further studies of the metabolic fates of OPFRs and toxicological effects associated with the relevant metabolites.     

Impact of the Acetaldehyde-Mediated Condensation on the Phenolic Composition and Antioxidant Activity of Vitis vinifera L. Cv. Merlot Wine

Acetaldehyde is a critical reactant on modifying the phenolic profile during red wine aging, suggesting that the acetaldehyde-mediated condensation can be responsible for the variation of antioxidant activity during the aging of this beverage. The present study employs exogenous acetaldehyde at six levels of treatment (7.86 ± 0.10–259.02 ± 4.95 mg/L) before the bottle aging of Merlot wines to encourage phenolic modification. Acetaldehyde and antioxidant activity of wine were evaluated at 0, 15, 30, 45, 60 and 75 days of storage, while monomeric and polymeric phenolics were analyzed at 0, 30 and 75 days of storage. The loss of acetaldehyde was fitted to a first-order reaction model, the rate constant (k) demonstrated that different chemical reaction happened in wines containing a different initial acetaldehyde. The disappearance of monomeric phenolics and the formation of polymeric phenolics induced by acetaldehyde could be divided into two phases, the antioxidant activity of wine did not alter significantly in the first phase, although most monomeric phenolics vanished, but the second phase would dramatically reduce the antioxidant activity of wine. Furthermore, a higher level of acetaldehyde could shorten the reaction time of the first phase. These results indicate that careful vinification handling aiming at controlling the acetaldehyde allows one to maintain prolonged biological activity during wine aging.     

Improved space time prewhitener for linear frequency modulation reverberation using fractional Fourier transform

This letter presents an improved space time prewhitening method for linear frequency modulation (LFM) reverberation. The proposed method transforms the reverberation to fractional Fourier domain to whiten using fractional Fourier transform. The linear varying frequency in LFM reverberation is focused on a stationary frequency, and the adjacent block signal is used as the reference signal of prewhitening. Finally, experiment results with real reverberation data verify that the proposed method improves the detection performance of active sonar in shallow sea significantly.     

Non-Invasive Detection of Anti-Inflammatory Bioactivity and Key Chemical Indicators of the Commercial Lanqin Oral Solution by Near Infrared Spectroscopy

Quality control methods of current traditional Chinese medicine (TCM) preparation is time-consuming and difficult to assess in terms of overall efficiency of the drug. A non-destructive rapid near-infrared spectroscopy detection system for key chemical components and biological activity of Lanqin oral solution (LOS), one of the best-selling TCM formulations, was established for comprehensive quality evaluation. Near infrared spectral scanning was carried out on 101 batches of commercial LOS under the penetrated vial state and traditional state. RAW 264.7 cells were cultured to detect the anti-inflammatory ability of LOS, and the reference concentrations of epigoitrin, geniposide, and baicalin were obtained by HPLC. The quantitative models were optimized by three kinds of variable selection methods. The correlation coefficients of prediction value of the models were greater than 0.94. The system also passed the external validation. The performance of the non-invasive models was similar to the traditional models. The established non-destructive system can be applied to the rapid quality inspection of LOS to avoid unqualified drugs from entering the market and ensure drug effectiveness. The biological activity index of LOS was introduced and predicted by NIRs for the first time, which provides a new idea about the quality control of TCM formulations.     

Enzymatic Synthesis of a Diastereomer of Neoabyssomicin Derivative Using the Diels-Alderase AbyU

Main observation and conclusion The enzyme AbyU catalyses a Diels-Alder (DA) reaction during abyssomicin C biosynthesis.In this study,AbyU is shown to convert t...     

Estimation of biophysical properties of cell exposed to electric field

Excitable media,such as cells,can be polarized and magnetized in the presence of an external electromagnetic field.In fact,distinct geometric deformation can be induced by the external electromagnetic field,and also the capacitance of the membrane of cell can be changed to pump the field energy.Furthermore,the distribution of ion concentration inside and outside the cell can also be greatly adjusted.Based on the theory of bio-electromagnetism,the distribution of field energy and intracellular and extracellular ion concentrations in a single shell cell can be estimated in the case with or without external electric field.Also,the dependence of shape of cell on the applied electronic field is calculated.From the viewpoint of physics,the involvement of external electric field will change the gradient distribution of field energy blocked by the membrane.And the intracellular and extracellular ion concentration show a certain difference in generating timevarying membrane potential in the presence of electric field.When a constant electric field is applied to the cell,distinct geometric deformation is induced,and the cell triggers a transition from prolate to spherical and then to oblate ellipsoid shape.It is found that the critical frequency in the applied electric field for triggering the distinct transition from prolate to oblate ellipsoid shape obtains smaller value when larger dielectric constant of the cell membrane and intracellular medium,and smaller conductivity for the intracellular medium are used.Furthermore,the effect of cell deformation is estimated by analyzing the capacitance per unit area,the density of field energy,and the change of ion concentration on one side of cell membrane.The intensity of external applied electric field is further increased to detect the change of ion concentration.And the biophysical effect in the cell is discussed.So the deformation effect of cells in electric field should be considered when regulating and preventing harm to normal neural activities occurs in a nervous system.     

Effect of additives on the structure and electrochemical performance of mesoporous nickel hydroxide

Nickel hydroxide mesoporous structures are synthesized by a simple method in the presence of different additives (oxalic acid, aminoacetic acid, and sulfosalicylic acid). Structural characterizations reveal that the additives can affect the crystal structure, increase the specific surface area, and reduce the pore size of the products. The electrochemical properties of the synthesized Ni(OH)₂ samples are dependent on their crystal phase, surface area, and pore size distribution. Mesoporous β-Ni(OH)₂ with poor crystallinity shows high specific capacitances at different current densities and excellent cycling ability. A highest specific capacitance of 1,693 F?g^?1 can be achieved at a scan rate of 5 mV?s^?1. The results suggest its potential application in electrochemical supercapacitors.     

Estimating ellipticity of a fiber core using two types of interferometry

In the present work two types of low-coherence interferometry are used to estimate the ellipticity of the core of an optical fiber in the cross section. Using the time-domain low-coherence interferometry the group-index difference between the degenerate high-order modes is measured. Because of the usage of a short fiber sample the group-index difference between the degenerate fundamental modes is too small to measure. Secondly, a frequency-domain low-coherence interferometry is presented in details. Since it is an all-fiber setup, longer fiber is allowed to be used. The high-order modes are filtered. The group-index difference between the degenerate fundamental modes is obtained. For each of the methods the experimental results are used to estimate the ellipticity of the fiber core in numerical simulations.