Water-responsive gel extends drug retention and facilitates skin penetration for curcumin topical delivery against psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by erythema,scaling,and skin thickening.Topical drug application is recommended as the first-line treatment.Many formulation strategies have been developed and explored for enhanced topical psoriasis treatment.However,these preparations usually have low viscosity and limited retention on the skin surface,resulting in low drug delivery efficiency and poor patient satisfaction.In this study,we developed the first water-responsive gel(WRG),which has a distinct water-triggered liquid-to-gel phase transition property.Specifically,WRG was kept in a solution state in the absence of water,and the addition of water induced an immediate phase transition and resulted in a high viscosity gel.Curcumin was used as a model drug to investigate the potential of WRG in topical drug delivery against psoriasis.In vitro and in vivo data showed that WRG formulation could not only extend skin retention but also facilitate the drug permeating across the skin.In a mouse model of psoriasis,curcumin loaded WRG(CUR-WRG)effectively ameliorated the symptoms of psoriasis and exerted a potent anti-psoriasis effect by extending drug retention and facilitating drug penetration.Further mechanism study demonstrated that the anti-hyperplasia,anti-inflammation,anti-angiogenesis,anti-oxidation,and immunomodulation properties of curcumin were amplified by enhanced topical drug delivery efficiency.Notably,neglectable local or systemic toxicity was observed for CUR-WRG application.This study suggests that WRG is a promising formulation for topically psoriasis treatment.

Prognostic prediction and expression validation of NSD3 in pan-cancer analyses

Background:Nuclear receptor binding SET domain protein-3(NSD3)is a histone lysine methyltransferase and a crucial regulator of carcinogenesis in several cancers.We aimed to investigate the prognostic value and potential function of NSD3 in 33 types of human cancer.Methods:The data were obtained from The Cancer Genome Atlas.Kaplan-Meier analysis,CIBERSORT,gene set enrichment analysis,and gene set variation analysis were performed.The expression of NSD3 was measured using quantitative real-time polymerase chain reaction and western blot.Results:The expression of NSD3 was altered in pan-cancer samples.Patients with higher levels of NDS3 generally had shorter overall survival and disease-specific survival.Levels of NSD3 were positively correlated with DNA copy number variation(CNV)in pan-cancer.NSD3 expression was also associated with tumor mutation burden and microsatellite instability.The levels of immune-cell infiltration differed significantly between high and low NSD3 expression.NSD3 negatively correlated with levels of CD8+T cells.Functional enrichment analysis showed that while NSD3 expression was positively associated with several immune cell-related and histone methylation-related pathways,it was negatively correlated with cell metabolism-related,drug transport-related,and drug metabolismrelated pathways.NSD3 levels in the cell lines tested were significantly different.In U251 and NCI-H23 cells,silencing NSD3 inhibited cell proliferation and promoted apoptosis.Conclusions:NSD3 expression was changed in pan-cancer samples that was also verified in cell lines.NSD3 was associated with CNV and immune-cell infiltration.A poor prognosis was predicted in patients with high expression of NSD3.NSD3 might hence be a potential marker for predicting tumor prognosis.

Multi-User Connection Performance Assessment of NOMA Schemes for Beyond 5G

Non-orthogonal multiple access(NOMA)is proved to be useful to satisfy the requirements of beyond 5th generation such as massive multi-user connection.Here we compare the performances of two NOMA schemes:low code rate spreading(LCRS)scheme and interleaver division multiple access(IDMA)scheme.It is found that LCRS is superior to IDMA when number of users is small due to coding gain achieved.While IDMA is preferred when number of users is high because repetition applied in IDMA can suppress multi-user interference effectively.And interleaver is important in IDMA for randomizing the interference.Also,this paper evaluates the impact of channel decoder.It is observed that Log-MAP decoder has much better performance than that of Max-Log-MAP when number of users is large.Thus,it is recommended to use Log-MAP decoder in NOMA in high user overloading case.We also compared the performance of NOMA by using different type of channel codes.We find that NOMA using specific convolutional code has a better performance than that of using specific LDPC code when number of users is high.

Biochar-Induced Priming Effects in Young and Old Poplar Plantation Soils

The priming effect(PE)induced by biochar provides a basis for evaluating its carbon(C)sequestration potential in soils.A 60 days’laboratory incubation was conducted,which involved the amendment of biochar(1%of soil mass)produced from rice straw at 300℃(B300)and 500℃(B500)to young(Y)and old(O)poplar plantation soils,with the aim of studying the responses of biochar-induced PEs to poplar plantation ages.This incubation included six treatments:Y+CK(control),Y+B300,Y+B500,O+CK,O+B300,and O+B500.Carbon dioxide(CO_(2))emissions were significantly increased(p<0.05)in the B300 amended soils,while it was decreased in the B500 amended soils compared to the CK.The primed CO_(2) emissions were 2.35 times higher in the Y+B300 than the O+B300 treatments,which was measured to be 18.6 and 5.56 mg C·kg^(-1) with relative PEs of 12.4%and 3.35%,respectively.However,there was little difference between the primed CO_(2) emissions in Y+B500 and O+B500 treatments,which were measured to be-24.9 and-29.6 mg·C·kg^(-1) with relative PEs of-16.6%and-17.8%,respectively.Dissolved organic carbon(DOC)was significantly lower in the young poplar plantation soil than that in the old poplar plantation soil regardless of biochar amendment throughout the incubation,indicating greater C-limit of soil microorganisms in the young poplar plantation soil.Using ^(13)C isotope tracing,neither B300 nor B500 decreased native soil-derived DOC,which indicated that the negative B500-induced PEs were not due to a reduction in the availability of native soil-derived C.In conclusion,the response of biochar-induced PEs to poplar plantation age depends on biochar types while soil available C indirectly affects biochar-induced PEs.Further studies should focus on how the interactive effects between soil C availability and microbial community impacts biochar-induced PEs.

Fractal Uniform Circular Arrays Based Multi-Orbital-Angular-Momentum-Mode Multiplexing Vortex Radio MIMO

A radio wave driven by Orbital angular momentum(OAM) is called a vortex radio and has a helical wavefront. The differential helical wavefronts of several vortex radios are closely related to their topological charges or mode numbers. In physics, two or more radio waves with different mode numbers are orthogonal to their azimuth angles. With the development of radio communication technologies, some researchers have been exploring the OAM-based multi-mode multiplexing(multi-OAM-mode multiplexing) technologies in order to enhance the channel spectrum efficiency(SE) of a radio communication system by using the orthogonal properties of vortex radios. After reviewing the reported researches of OAM-based radio communication, we find that some breakthroughs have been made in the combination of OAM and traditional Multi-Input-Multi-Output(MIMO). However, the existing technology is not sufficient to support OAM-based MIMO system to achieve maximum the channel SE. To maximize the spectrum efficiency of OAM-based MIMO system, we present a reused multi-OAM-mode multiplexing vortex radio(RMMVR) MIMO system, which is based on fractal uniform cir-cular arrays(UCAs). The scheme described in this study can effectively combine multiOAM-mode multiplexing with MIMO spatial multiplexing. First, we present the generation of RMMVR MIMO signals. Second, under line-of-sight(LOS) propagation conditions, we derive the channels of the RMMVR MIMO system. Third, we separate the RMMVR MIMO signals using an orthogonal separation method based on full azimuth sampling. Finally, we introduce the method for calculating the channel capacity of the RMMVR MIMO system. Theoretical analysis shows that the scheme proposed in this study is feasible. Moreover, the simulation results show that spatial and mode diversity are obtained by exploiting fractal UCAs. However, to enhance the channel SE of RMMVR MIMO system, an interference cancellation method needs to be introduced for zero-mode vortex radios, and some methods of multi-OAM-mode beams convergence and mode power optimization strategy should be introduced in the future.

APO-Based Parallel Algorithm of Channel Allocation for Cognitive Networks

This article investigates channel allocation for cognitive networks, which is difficult to obtain the optimal allocation distribution. We first study interferences between nodes in cognitive networks and establish the channel allocation model with interference constraints. Then we focus on the use of evolutionary algorithms to solve the optimal allocation distribution. We further consider that the search time can be reduced by means of parallel computing, and then a parallel algorithm based APO is proposed. In contrast with the existing algorithms, we decompose the allocation vector into a number of sub-vectors and search for optimal allocation distribution of sub-vector in parallel. In order to speed up converged rate and improve converged value, some typical operations of evolutionary algorithms are modified by two novel operators. Finally, simulation results show that the proposed algorithm drastically outperform other optimal solutions in term of the network utilization.

Differences in Modified Morgan Phosphorus Levels Determined by Colorimetric and Inductively Coupled Plasma Methods

Phosphorus (P) fertilization is frequently needed for profitable crop production. Modified Morgan P (MMP) is a soil test P used to estimate plant available P in soils. The critical values of MMP for P fertilization and maintenance recommendations are based on the P concentrations measured by a common colorimetric molybdenum blue method although other P quantification methods have also been used for MMP measurements. In this study, we collected 120 surface soil samples of Caribou Sandy loam under potato cultivation or its rotation crops from Maine, USA, and 72 soil samples of Cecil sandy loam with cotton/corn crops under conventional tillage and no-till management with chemical and poultry litter fertilization in Georgia, USA. The MMP levels in all 192 dry samples were greater when they were measured by an inductively coupled plasma (ICP)-based method, compared to the corresponding data produced from colorimetry. Our results show the two sets of data were positively and significantly correlated (r = 0.93, P –1 with standard deviation of 12.9, compared to the average of colorimetric MMP level of 14.9 mg P kg–1 with standard deviation of 8.8. Based on the observations in this work, both colorimetric and ICP-based methods can be used for P fertilizer recommendation, but a conversion factor should be applied for ICP data as the current recommendation systems are based on colorimetric M&R data.

Decode-and-Forward Relay Based Bidirectional Wireless Information and Power Transfer

In this paper, we propose the decode-and-forward(DF) based bidirectional wireless information and power transfer(BWIPT) in two-hop relay systems, where the bidirectional relay can decode and forward information from the user to the access point(AP), and assist the wireless power transfer from the AP to the user. To maximize the information rate from the user to the AP, we derive the closed form expression of the optimal power splitting(PS) factor, and the time allocation scheme to obtain the optimal time switching(TS) factor. Simulation results show that for both PS and TS protocols, the proposed DF based bidirectional relay systems can improve the information rate as compared with the amplify-and-forward(AF) based bidirectional relay systems.

Soft-output stack algorithm with lattice-reduction for MIMO detection

A computationally efficient soft-output detector with lattice-reduction （LR） for the multiple-input multiple-output （MIMO） systems is proposed. In the proposed scheme, the sorted QR de- composition is applied on the lattice-reduced equivalent channel to obtain the tree structure. With the aid of the boundary control, the stack algorithm searches a small part of the whole search tree to generate a handful of candidate lists in the reduced lattice. The proposed soft-output algorithm achieves near-optimal perfor- mance in a coded MIMO system and the associated computational complexity is substantially lower than that of previously proposed methods.

Performance Analysis of Non-Identically Distributed FSO Systems with Dual- and Triple- Branch Based on MRC over Gamma-Gamma Fading Channels

In this work, the performance of free-space optical(FSO) communication system based on maximal ratio combining using binary phase shift keying subcarrier intensity modulation over Gamma-Gamma fading channels has been studied systematically. Under identically or non-identically distributed branches, the analytical expressions for the bit error rate function of signal-to-noise are derived by expressing the modified Bessel function of second kind with Meijer G-function for dualand triple-branch systems, respectively. In terms of H-fox function, the new expressions have more general forms and are more efficient for computation. It is found that the dual-and triple-branch systems significantly outperform the direct link system under weak, moderate and strong turbulence conditions. Monte Carlo simulation is also provided to confirm the accuracy of the proposed model.

An Energy-Efficient MAC Protocol for WSNs: Game-Theoretic Constraint Optimization with Multiple Objectives

In WSNs, energy conservation is the primary goal, while throughput and delay are less important. This re-sults in a tradeoff between performance (e.g., throughput, delay, jitter, and packet-loss-rate) and energy con-sumption. In this paper, the problem of energy-efficient MAC protocols in WSNs is modeled as a game-theoretic constraint optimization with multiple objectives. After introducing incompletely cooperative game theory, based on the estimated game state (e.g., the number of competing nodes), each node independ-ently implements the optimal equilibrium strategy under the given constraints (e.g., the used energy and QoS requirements). Moreover, a simplified game-theoretic constraint optimization scheme (G-ConOpt) is pre-sented in this paper, which is easy to be implemented in current WSNs. Simulation results show that G-ConOpt can increase system performance while still maintaining reasonable energy consumption.

A multi-center study on genetic variations in the fusion protein of respiratory syncytial virus from children with Acute Lower Respiratory Tract Infections in China during 2017-2021

Respiratory syncytial virus(RSV)is a significant cause of acute lower respiratory tract infection(ALRTI)in children underfive years of age.Between 2017 and 2021,396 complete sequences of the RSV F gene were obtained from 500 RSV-positive throat swabs collected from ten hospitals across nine provinces in China.In addition,151 sequences from China were sourced from GenBank and GISAID,making a total of 549 RSV F gene sequences subjected to analysis.Phylogenetic and genetic diversity analyses revealed that the RSV F genes circulating in China from 2017 to 2021 have remained relatively conserved,although some amino acids(AAs)have undergone changes.AA mutations with frequencies10%were identified at six sites and the p27 region:V384I(site I),N276S(site II),R213S(siteØ),and K124N(p27)for RSV A;F45L(site I),M152I/L172Q/S173 L/I185V/K191R(site V),and R202Q/I206M/Q209R(siteØ)for RSV B.Comparing mutational frequencies in RSV-F before and after 2020 revealed minor changes for RSV A,while the K191R,I206M,and Q209R frequencies increased by over 10%in RSV B.Notably,the nirsevimab-resistant mutation,S211N in RSV B,increased in frequency from 0%to 1.15%.Both representative strains aligned with the predicted RSV-F structures of their respective prototypes exhibited similar conformations,with low root-mean-square deviation values.These results could provide foundational data from China for the development of RSV mAbs and vaccines.

Tunnel bottleneck management with high-occupancy vehicle priority on intelligent freeways

Tunnels on freeways,as one of the critical bottlenecks,frequently cause severe congestion and passenger delay.To solve the tunnel bottleneck problem,most of the existing research can be divided into two types.One is to adopt variable speed limits(VSLs)to regulate a predetermined speed for vehicles to get through a bottleneck smoothly.The other is to adopt high-occupancy vehicle(HOV)lane management.In HOV lane management strategies,all traffic is divided into HOVs and low-occupancy vehicles(LOVs).HOVs are vehicles with a driver and one or more passengers.LOVs are vehicles with only a driver.This kind of research can grant priority to HOVs by providing a dedicated HOV lane.However,the existing research cannot both mitigate congestion and maximize passenger-oriented benefits.To address the research gap,this paper leverages connected and automated vehicle(CAV)technologies on intelligent freeways and develops a tunnel bottleneck management strategy with a dynamic HOV lane(DHL).The strategy bears the following features:1)enables tunnel bottleneck management at a microscopic level;2)maximizes passenger-oriented benefits;3)grants priority to HOVs even when the HOV lane is open to LOVs;4)allocates right-of-way segments for HOVs and LOVs in real time;and 5)performs well in a mixed-traffic environment.The proposed strategy is evaluated through comparison against the non-control baseline and a VSL strategy.Sensitivity analysis is conducted under different congestion levels and penetration rates.The results demonstrate that the proposed strategy outperforms in terms of passenger-oriented delay reduction and HOVs’priority level improvement.

Climatic Fluctuation of Marine Isotope Stage 9: A Case Study in the Southern Margin of the Chinese Loess Plateau

Marine Isotope Stages(MIS) 9 has been proposed as an analog for the present warm period. However, detailed studies of this geological time period are rare in loess-paleosol sequence. In the Chinese Loess Plateau(CLP), the corresponding stratum is the third paleosol layer(S3). Here, we report the terrestrial reconstruction of climatic fluctuations during MIS 9 by analyzing the paleo-climate indexes of S3 with high sampling density. Our results showed that:(1) During the period of MIS 9, the main climatic sub-cycle was 29 ka;(2) MIS 9 could be divided into five sections, MIS 9a, 9b, 9c, 9d, and 9e. Among them, MIS 9a, 9c, and 9e were warm stages, while MIS 9b and 9d were cool intervals;and 3) There were also three swift warm-wet events and one cool-dry event, which occurred around 332 –331, 324–323, 311–310, and 331–329 ka BP, respectively. The overall trend of paleo-climate fluctuation correlated approximately with SPECMAP, LR04 stack and Iberian margin deep-sea cores. This study suggested that the paleosol records in the southern margin of the CLP have global significance and contain more detailed climatic signals than marine deposits.

Influence of vegetation type and topographic position on volumetric soil water content dynamics and similarity among surface and deep soil layers

Clarifying the mechanisms governing volumetric soil water content(VSWC)dynamics in soil profiles is essential,as it can help to elucidate soil water transport processes and improve the prediction accuracy of soil hydrological processes.Using Spearman's rank correlation and wavelet coherence analysis methods,similarity in soil profile VSWC dynamics and factors governing VSWC soil profile dynamics in upslopes and downslopes under three vegetation types(evergreen forest[EG],secondary deciduous forest mixed with shrubs[SDFS],and deforested pasture[DP])at different time scales(hourly,daily,weekly,and monthly)and in different seasons were analyzed.The results revealed significant similarity in the VSWC of different soil depths(P<0.01),with the similarity decreasing in accordance with the increment in soil depth.Greater VSWC similarity was found in EG than SDFS and DP sites and in upslope than downslope areas at both forest sites.The average significant coherence area(SCA)of VSWC similarity among surface and deep soil layers varied with the time scale,which was in the order of monthly(58.6%)>weekly(42.8%)>daily(21.8%).The effects of soil properties(e.g.,texture,saturated hydraulic conductivity),rainfall,and potential evapotranspiration(ET_(p))on VSWC similarity were related to the time scale and season in which VSWC monitoring took place.Soil properties had apparent effects on VSWC similarity at longer time scales(i.e.,monthly),with a high SCA.In contrast,the effects of rainfall and ET_(p) on VSWC similarity were concentrated at weekly and daily scales,with a relatively low SCA.Rainfall and ET_(p) dominated VSWC dynamics in the summer and fall,respectively.These results imply the use of measured VSWC at one soil depth to predict the VSWC at other soil depths was a reliable method.While the in-fluence of time scale effects and seasonal variations on prediction accuracy of VSWC should be considered.

NaAlO_(2)硫酸法合成高质量拟薄水铝石

拟薄水铝石常应用于石油化工、环保等行业,是活性氧化铝的前驱体、分子筛、黏结剂等的重要原料。近年来,我国石油化工行业面临严峻挑战,原油劣质化、重质化,产品轻质化、清洁化和成本高等问题愈加突出,迫切需求拟薄水铝石的低成本生产制备方法。本工作采用NaAlO_(2)硫酸法结合动态调控pH合成了物相纯、具有特定孔结构的拟薄水铝石产品。通过XRD,BET,SEM,NMR等表征分析得出,硫酸法在pH=7、75℃下反应0.5 h可合成比表面积、孔容和平均孔径分别为341.01 m^(2)/g,0.41 cm^(3)/g,4.78 nm的γ-AlOOH,在极端合成条件会生成Al(OH)_(3)杂相。动态调控pH可以有效促进产品相纯化和孔结构改善。在70℃、NaAlO_(2)和Al_(2)(SO_(4))_(3)流速15 mL/min、反应10 min、老化10 min的条件下,杂相Al(OH)_(3)向γ-AlOOH转变,可将含有28.2%的Al(OH)3杂相经过摆动后降至3.1%,纯化后的γ-AlOOH结晶度增强,其中27Al以六配体形式存在,比表面积、孔容和平均孔径分别增加到358.88 m^(2)/g,0.70 cm^(3)/g和7.83 nm。

Influence of Long-Term Fertilization on Selenium Accumulation in Soil and Uptake by Crops

Continuous applications of organic and inorganic fertilizers can affect soil and food quality with respect to selenium （Se） concen- trations. A long-term （over 20 years） experimental field study, started in 1989, was conducted to investigate the changes in soil Se fractions and its uptake by crops, as affected by different fertilizer practices, in the North China Plain with an annual crop rotation of winter wheat and summer maize. The long-term experiment was arranged in a complete randomized block design consisting of 4 replications with 7 fertilizer treatments： 1） organic compost （OC）, 2） half organic compost plus half N-P-K chemical fertilizers （OC ＋ NPK）, 3） N-P-K fertilizers （NPK）, 4） N-P fertilizers （NP）, 5） P-K fertilizers （PK）, 6） N-K fertilizers （NK）, and 7） an un-amended control. Soil samples from the surface （20 cm） were collected in 1989, 1994, 1999, 2004 and 2009 to characterize Se and other soil properties. In 2009, the average soil Se concentrations in the treatments （149 ± 8 beg kg-1） were higher than those in the soil samples collected in 1989 at the beginning of the experiment （112 4- 4 beg kg-1）, and decreased in the order of OC 〉 OC ＋ NPK 〉 NPK NP 〉 PK NK 〉 control. Sequential extraction showed the oxidizable fraction （50.06%± 3.94%） was the dominant form of Se in the soil, followed by the residual fraction （24.12% ± 2.89%）, exchangeable fraction （15.09% ± 4.34%） and Fe-Mn oxides fraction （10.73%±4.04%）. With an increase of soil K, the exchangeable Se concentrations in the soil increased. The Se concentrations in the soil tillage layer （0-20 cm） were mainly related to soil organic carbon （SOC）, although different contributions came from atmospheric deposition, irrigation and fertilizers. With the accumulation of SOC, the uptakes of soil Se by two crops were inhibited. For the OC and OC ＋ NPK treatments, Se concentrations in wheat grains were lower than the critical standard of Se in stable food （100 μg kg·1]. Additionallv. Se concentrations in grains were also decreased by the deficiencies of major soil nutrients, especially P.

Enhanced thermal and frequency stability and decent fatigue endurance in lead-free NaNbO_(3) -based ceramics with high energy storage density and efficiency

Lead-free ceramic capacitors have the application prospect in the dielectric pulse power system due to the advantages of large dielectric constant,lower dielectric loss and good temperature stability.Never-theless,most reported dielectric ceramics have limitation of realizing large energy storage density(W_(rec))and high energy storage efficiency(h)simultaneously due to the low breakdown electric field(E_(b)),low maximum polarization and large remanent polarization(P_(r)).These issues above can be settled by raising the bulk resistivity of dielectric ceramics and optimizing domain structure.Therefore,we designed a new system by doping(Bi_(0.5)Na_(0.5))_(0.7)Sr_(0.3)TiO_(3) into 0.9NaNbO_(3)-0.1Bi(Ni_(0.5)Zr_(0.5))O_(3) ceramics,which simulta-neously obtained a higher bulk resistivity by decreasing the grain size and achieved a smaller P_(r) by optimizing domain structure,thus the better E_(b) of 530 kV/cm and W_(rec) of 6.43 J/cm^(3) were achieved,h was improved from 34%to 82%.Besides,the 0.4BNST ceramics show excellent temperature,frequency and fatigue stability under the conditions of 20-180℃,1-100 Hz and 104 cycles,respectively.Mean-while,superior power density(P_(D)=107 MW/cm^(3)),large current density(C_(D)=1070 A/cm^(2))and discharge speed(1.025 m s)were achieved in 0.4BNST ceramic.Finally,the charge-discharge performance displayed good temperature stability in the temperature range of 30℃-180℃.The above results indicated that the ceramics have potential practical value in the field of energy storage capacitor.

Versatile metasurface platform for electromagnetic wave tailoring

The emergence of metasurfaces provides a novel strategy to tailor the electromagnetic response of electromagnetic waves in a controlled manner by judicious design of the constitutive meta-atom.However,passive metasurfaces tend to perform a specific or limited number of functionalities and suffer from narrow-frequency-band operation.Reported reconfigurable metasurfaces can generally be controlled only in a 1D configuration or use p-i-n diodes to show binary phase states.Here,a 2D reconfigurable reflective metasurface with individually addressable meta-atoms enabling a continuous phase control is proposed in the microwave regime.The response of the meta-atom is flexibly controlled by changing the bias voltage applied to the embedded varactor diode through an elaborated power supply system.By assigning appropriate phase profiles to the metasurface through voltage modulation,complex beam generation,including Bessel beams,vortex beams,and Airy beams,is fulfilled to demonstrate the accurate phase-control capability of the reconfigurable metasurface.Both simulations and measurements are performed as a proof of concept and show good agreement.The proposed design paves the way toward the achievement of real-time and programmable multifunctional meta-devices,with enormous potential for microwave applications such as wireless communication,electromagnetic imaging,and smart antennas.

Resetting amino acid metabolism of cancer cells by ATB^(0,+)-targeted nanoparticles for enhanced anticancer therapy

Reprogramed cellular metabolism is one of the most significant hallmarks of cancer.All cancer cells exhibit increased demand for specific amino acids,and become dependent on either an exogenous supply or upregulated de novo synthesis.The resultant enhanced availability of amino acids supports the reprogramed metabolic pathways and fuels the malignant growth and metastasis of cancers by providing energy and critical metabolic intermediates,facilitating anabolism,and activating signaling networks related to cell proliferation and growth.Therefore,pharmacologic blockade of amino acid entry into cancer cells is likely to have a detrimental effect on cancer cell growth.Here we developed a nanoplatform(LJ@Trp-NPs)to therapeutically target two transporters,SLC6A14(ATB^(0,+))and SLC7A5(LAT1),that are known to be essential for the sustenance of amino acid metabolism in most cancers.The LJ@Trp-NPs uses tryptophan to guide SLC6A14-targeted delivery of JPH203,a high-affinity inhibitor of SLC7A5.In the process,SLC6A14 is also down-regulated.We tested the ability of this strategy to synergize with the anticancer efficacy of lapatinib,an inhibitor of EGFR/HER1/HER2-assocated kinase.These studies show that blockade of amino acid entry amplifies the anticancer effect of lapatinib via interference with mTOR signaling,promotion of apoptosis,and suppression of cell proliferation and metastasis.This represents the first study to evaluate the impact of amino acid starvation on the anticancer efficacy of widely used kinase inhibitor.