With the rapid development of low-altitude economy and unmanned aerial vehicles (UAVs) deployment technology, aerial-ground collaborative delivery (AGCD) is emerging as a novel mode of last-mile delivery, where the ve...With the rapid development of low-altitude economy and unmanned aerial vehicles (UAVs) deployment technology, aerial-ground collaborative delivery (AGCD) is emerging as a novel mode of last-mile delivery, where the vehicle and its onboard UAVs are utilized efficiently. Vehicles not only provide delivery services to customers but also function as mobile ware-houses and launch/recovery platforms for UAVs. This paper addresses the vehicle routing problem with UAVs considering time window and UAV multi-delivery (VRPU-TW&MD). A mixed integer linear programming (MILP) model is developed to mini-mize delivery costs while incorporating constraints related to UAV energy consumption. Subsequently, a micro-evolution aug-mented large neighborhood search (MEALNS) algorithm incor-porating adaptive large neighborhood search (ALNS) and micro-evolution mechanism is proposed. Numerical experiments demonstrate the effectiveness of both the model and algorithm in solving the VRPU-TW&MD. The impact of key parameters on delivery performance is explored by sensitivity analysis.展开更多
Spores and pollen,as ubiquitous organisms found in nature,possess a remarkable core-shell structure and intricate surface morphology.These tiny particles are notable for their dimensional uniformity,sustainable utiliz...Spores and pollen,as ubiquitous organisms found in nature,possess a remarkable core-shell structure and intricate surface morphology.These tiny particles are notable for their dimensional uniformity,sustainable utilization,environmental friendliness,porosity,amphiphilicity,and strong adhesive properties.In addition,they display excellent biocompatibility and biodegradability,which significantly enhances the stability and targeting of drugs within the body.Spores and pollen can be extracted using methods such as acidic solutions,alkaline solutions,or enzyme treatments to obtain sporopollenin,which is an extremely resilient and chemically inert complex biopolymer.The sporopollenin extracted through this process removes the original bioactive substances,such as cell nuclei,enzymes,and DNA,providing greater drug loading capacity and containing no potential allergens or immunogens,thus further enhancing its drug loading capacity and improving safety in therapeutic applications.Due to these beneficial attributes,spores,pollen and sporopollenin have gained widespread use in a variety of drug delivery systems,such as targeted delivery,sustained drug delivery,toxicity mitigation,flavor masking,vaccine delivery,delivery of labile substances,and other applications.This review introduces the types of natural spores and pollen commonly used in drug delivery systems,including their main components,common effects,and uses in drug delivery systems,and so on.It subsequently summarizes novel optimization methods in their processing,such as physical treatment,surface modification,and chemical modification,which enable higher drug loading efficiency,stability,and targeting,among other benefits.Additionally,this paper reviews the research progress and applications of natural spores,pollen,and sporopollenin in drug delivery systems,while also touching on some innovative research content,such as novel nanomotor microcarriers developed based on pollen.Based on these research findings,we further elaborate on the advantages of spores,pollen,and sporopollenin in drug delivery systems.For example,they have high stability and drug loading capacity,good adhesion,excellent targeting,and are easy to modify functionally.Currently,they show promising prospects in the fields of targeted drug delivery,sustained-release drug delivery,as well as the delivery of drugs that are effective but slightly toxic,and are often used in research on the treatment of diseases such as cancer and inflammation.We have also highlighted the challenges they face in various applications and identified some issues that need to be addressed,including difficulties in largescale production,the need to improve extraction and purification processes,and the existence of a low but still noteworthy risk of allergies,in order to fully leverage their potential in drug delivery applications.According to current research,although spores,pollen,and sporopollenin face some unresolved issues in clinical drug delivery,they still have great potential overall and are expected to become a new generation of green drug delivery platforms.In the future,further research into their unique physical and chemical properties and structural characteristics will help develop more efficient and stable drug delivery systems to meet diverse treatment needs.We believe that continued exploration of natural spores,pollen,and sporopollenin will drive this emerging field to achieve continuous breakthroughs and progress,ultimately making an important contribution to the cause of human health.展开更多
As battlefield scale enlarges,cross-platform collaborative combat provides an appealing paradigm for modern warfare.Complicated constraints and vast solution space pose great challenge for reasonable and efficient mis...As battlefield scale enlarges,cross-platform collaborative combat provides an appealing paradigm for modern warfare.Complicated constraints and vast solution space pose great challenge for reasonable and efficient mission planning,where path planning and target assignment are tightly coupled.In this paper,we focus on UAV mission planning under carrier delivery mode(e.g.,by aircraft carrier,ground vehicle,or transport aircraft) and design a three-layer hierarchical solution framework.In the first layer,we simultaneously determine delivery points and target set division by clustering.To address the safety concerns of radar risk and UAV endurance,an improved density peak clustering algorithm is developed by constraint fusio n.In the second layer,mission planning within each cluster is viewed as a coope rative multiple-task assignment problem.A hybrid heuristic algorithm that integrates a voting-based heuristic solution generation strategy(VHSG) and a stochastic variable neighborhood search(SVNS),called VHSG-SVNS,is proposed for rapid solution.Based on the results of the first two layers,the third layer transforms carrier path planning into a multiple-vehicle routing problem with time window.The cost between any two nodes is calculated by the A~* algorithm,and the genetic algorithm is then implemented to determine the global route.Finally,a practical mission scenario containing 200 targets is used to validate the effectiveness of the designed framework,where three layers cooperate well with each other to generate satisfactory combat scheduling.Comparisons are made in each layer to highlight optimum-seeking capability and efficiency of the proposed algorithms.Works done in this paper provide a simple but efficient solution framework for cross-platform cooperative mission planning problems,and can be potentially extended to other applications such as post-disaster search and rescue,forest surveillance and firefighting,logistics pick and delivery,etc.展开更多
The rapid evolution of unmanned aerial vehicle(UAV)technology and autonomous capabilities has positioned UAV as promising last-mile delivery means.Vehicle and onboard UAV collaborative delivery is introduced as a nove...The rapid evolution of unmanned aerial vehicle(UAV)technology and autonomous capabilities has positioned UAV as promising last-mile delivery means.Vehicle and onboard UAV collaborative delivery is introduced as a novel delivery mode.Spatiotemporal collaboration,along with energy consumption with payload and wind conditions play important roles in delivery route planning.This paper introduces the traveling salesman problem with time window and onboard UAV(TSPTWOUAV)and emphasizes the consideration of real-world scenarios,focusing on time collaboration and energy consumption with wind and payload.To address this,a mixed integer linear programming(MILP)model is formulated to minimize the energy consumption costs of vehicle and UAV.Furthermore,an adaptive large neighborhood search(ALNS)algorithm is applied to identify high-quality solutions efficiently.The effectiveness of the proposed model and algorithm is validated through numerical tests on real geographic instances and sensitivity analysis of key parameters is conducted.展开更多
In consultative committee for space data systems（CCSDS） file delivery protocol（CFDP） recommendation of reliable transmission,there are no detail transmission procedure and delay calculation of prompted negative ac...In consultative committee for space data systems（CCSDS） file delivery protocol（CFDP） recommendation of reliable transmission,there are no detail transmission procedure and delay calculation of prompted negative acknowledge and asynchronous negative acknowledge models.CFDP is designed to provide data and storage management,story and forward,custody transfer and reliable end-to-end delivery over deep space characterized by huge latency,intermittent link,asymmetric bandwidth and big bit error rate（BER）.Four reliable transmission models are analyzed and an expected file-delivery time is calculated with different trans-mission rates,numbers and sizes of packet data units,BERs and frequencies of external events,etc.By comparison of four CFDP models,the requirement of BER for typical missions in deep space is obtained and rules of choosing CFDP models under different uplink state informations are given,which provides references for protocol models selection,utilization and modification.展开更多
Existing position-based routing algorithms, where packets are forwarded in the geographic direction of the destination, normally require that the forwarding node should know the positions of all neighbors in its trans...Existing position-based routing algorithms, where packets are forwarded in the geographic direction of the destination, normally require that the forwarding node should know the positions of all neighbors in its transmission range. This information on direct neighbors is gained by observing beacon messages that each node sends out periodically. Several beaconless greedy routing schemes have been proposed recently. However, none of the existing beaconless schemes guarantee the delivery of packets. Moreover, they incur communication overhead by sending excessive control messages or by broadcasting data packets. In this paper, we describe how existing localized position based routing schemes that guarantee delivery can be made beaconless, while preserving the same routes. In our guaranteed delivery beaconless routing scheme, the next hop is selected through the use of control RTS/CTS messages and biased timeouts. In greedy mode, the neighbor closest to destination responds first. In recovery mode, nodes closer to the source will select shorter timeouts, so that other neighbors, overhearing CTS packets, can eliminate their own CTS packets if they realize that their link to the source is not part of Gabriel graph. Nodes also cancel their packets after receiving data message sent by source to the selected neighbor. We analyze the behavior of our scheme on our simulation environment assuming ideal MAC, following GOAFR+ and GFG routing schemes. Our results demonstrate low communication overhead in addition to guaranteed delivery.展开更多
The weapon transportation support scheduling problem on aircraft carrier deck is the key to restricting the sortie rate and combat capability of carrier-based aircraft.This paper studies the problem and presents a nov...The weapon transportation support scheduling problem on aircraft carrier deck is the key to restricting the sortie rate and combat capability of carrier-based aircraft.This paper studies the problem and presents a novel solution architecture.Taking the interference of the carrier-based aircraft deck layout on the weapon transportation route and precedence constraint into consideration,a mixed integer formulation is established to minimize the total objective,which is constituted of makespan,load variance and accumulative transfer time of support unit.Solution approach is developed for the model.Firstly,based on modeling the carrier aircraft parked on deck as convex obstacles,the path library of weapon transportation is constructed through visibility graph and Warshall-Floyd methods.We then propose a bi-population immune algorithm in which a population-based forward/backward scheduling technique,local search schemes and a chaotic catastrophe operator are embedded.Besides,the randomkey solution representation and serial scheduling generation scheme are adopted to conveniently obtain a better solution.The Taguchi method is additionally employed to determine key parameters of the algorithm.Finally,on a set of generated realistic instances,we demonstrate that the proposed algorithm outperforms all compared algorithms designed for similar optimization problems and can significantly improve the efficiency,and that the established model and the bi-population immune algorithm can effectively respond to the weapon support requirements of carrier-based aircraft under different sortie missions.展开更多
A deep space multi-file delivery protocol（DSMDP） based on LT codes is proposed to reduce the influence of long delay and a high bit error rate（BER） in deep space communication. The protocol increases sending redun...A deep space multi-file delivery protocol（DSMDP） based on LT codes is proposed to reduce the influence of long delay and a high bit error rate（BER） in deep space communication. The protocol increases sending redundancy by LT codes to improve the success rate of file delivery, and adopts different protective strategies for different situations of packet loss. At the same time, the multi-file united delivery strategy is adopted to make full use of the retransmission time to reduce the end-toend transmission delay. Furthermore, the protocol determines the quantity of encoded packets according to the feedback for controlling redundancy. The simulation results show that the proposed protocol can significantly reduce the transmission delay of files, which would be effectively suitable for deep space communication environment of high BER and long delay.展开更多
Focused energy delivery(FED) is a technique that can precisely bring energy to the specific region,which arouses wide attention in precision electronic warfare(PREW).This paper first proposes a joint optimization mode...Focused energy delivery(FED) is a technique that can precisely bring energy to the specific region,which arouses wide attention in precision electronic warfare(PREW).This paper first proposes a joint optimization model with respect to the locations of the array and the transmitted signals to improve the performance of FED.As the problem is nonconvex and NP-hard,particle swarm optimization(PSO) is adopted to solve the locations of the array,while designing the transmitted signals under a feasible array is considered as a unimodular quadratic program(UQP) subproblem to calculate the fitness criterion of PSO.In the PSO-UQP framework established,two methods are presented for the UQP subproblem,which are more efficient and more accurate respectively than previous works.Furthermore,a threshold value is set in the framework to determine which method to adopt to take full advantages of the methods above.Meanwhile,we obtain the maximum localization error that FED can tolerate,which is significant for implementing FED in practice.Simulation results are provided to demonstrate the effectiveness of the joint optimization algorithm,and the correctness of the maximum localization error derived.展开更多
In this paper,a dynamic modeling method of motor driven electromechanical system is presented,and the uncertainty quantification of mechanism motion is investigated based on this method.The main contribution is to pro...In this paper,a dynamic modeling method of motor driven electromechanical system is presented,and the uncertainty quantification of mechanism motion is investigated based on this method.The main contribution is to propose a novel mechanism-motor coupling dynamic modeling method,in which the relationship between mechanism motion and motor rotation is established according to the geometric coordination of the system.The advantages of this include establishing intuitive coupling between the mechanism and motor,facilitating the discussion for the influence of both mechanical and electrical parameters on the mechanism,and enabling dynamic simulation with controller to take the randomness of the electric load into account.Dynamic simulation considering feedback control of ammunition delivery system is carried out,and the feasibility of the model is verified experimentally.Based on probability density evolution theory,we comprehensively discuss the effects of system parameters on mechanism motion from the perspective of uncertainty quantization.Our work can not only provide guidance for engineering design of ammunition delivery mechanism,but also provide theoretical support for modeling and uncertainty quantification research of mechatronics system.展开更多
OBJECTIVE Many drug candidates identified from natural products are poorly water-soluble.The surfactants used to disperse the hydrophobic anticancer drugs in water may cause a serious of acute hypersensitivity reactio...OBJECTIVE Many drug candidates identified from natural products are poorly water-soluble.The surfactants used to disperse the hydrophobic anticancer drugs in water may cause a serious of acute hypersensitivity reactions.Nanotechnology provides an alternative strategy for delivery of anticancer drugs.In the present study,different inorganic nanoparticles are utilized as hydrophobic anticancer drug carriers.METHODS Different inorganic superparamagnetic iron oxide,platinum and gold nanoparticles were synthesized.The hydrophobic anticancer drugs such as curcumin,gambogic acid and doxorubicin(DOX)base were loaded into the porous area or onto the surface of the nanoparticles.Cellular uptake and biocompatibility of nanoparticles were studied in human glioblastoma U-87 MG cells.The anticancer effect of drug loaded nanoparticles was compared with that of free drugs.Photothermal conversion of platinum and gold nanoparticles was studied by irradiation of nanoparticles with a near-infrared laser.RESULTS The synthesized nanoparticles are readily internalized by U-87 MG cells,and the internalized nanoparticles are mainly localized in endosomes/lysosomes in cells.The nanoparticle-based drug carrier provides the aqueous dispersions of the hydrophobic drugs.In endosomes/lysosomes mimicking buffers with a pH of 4.5-5.5,pH-dependent drug release was observed from drug loaded nanoparticles.The intracellular drug content and cytotoxicity are significantly higher for drug loaded nanoparticles than free drug.Photothermal treatment has a synergistic effect on drug′s anticancer activity.CONCLUSION These results suggested inorganic nanoparticles is a promising intracellular carrier for hydrophobic anticancer drugs.展开更多
The traditional Chinese medicine tripterygium glycosides(TPG)is used clinically to treat some Rheumatism,Eczema,immunosuppression and tumor,with the activities of hypnosis,antipyretic,analgesic,antiinflammatory,allerg...The traditional Chinese medicine tripterygium glycosides(TPG)is used clinically to treat some Rheumatism,Eczema,immunosuppression and tumor,with the activities of hypnosis,antipyretic,analgesic,antiinflammatory,allergy and antitumor.However TPG has low water solubility and low skin permeability,so its clinical use is limited.Transdermal delivery systems can provide a controlled drug release rate that can keep constant concentrations of drug in the plasma for up to multiple days,improved patient compliance,and the possibility ofreducing the rate and severity of side effects.In this study,a fast and sensitive technique skin-blood two sites synchronous microdialysis coupled with LC-MS was used to study the pharmacokinetic parameter of three different formulations(TPG nanoemulsion,TPG nanoemulsion based gels and TPG gel).Creating a multilayer model,use the model to simulate the three formulations dynamics in transdermal-drug delivery system.The experiment results showed that the TPG nanoemulsion,TPG nanoemulsion based gels can significantly raise the drug concentrations in skin more than that of TPG gels.The numerical simulation results indicating that TPG gel and TPG nanoemulsion are close to practical measurements,only in the concentration increase phase the numerical simulation result has some difference with the experimental results.TPG nanoemulsion based gels have significant difference with the experimental results,both in concentration increase stage and concentration decreasing stage,but its trend was same.The study shows that the skin-blood synchronous microdialysis technique provided a new method for the pharmacokinetics study of nanocarriers transdermal delivery systems.In addition,the microdialysis technique combined with mathematical modeling provides a very good platform for the further study of transdermal delivery system.展开更多
OBJECTIVE Nanotechnology provides a novel strategy for the delivery of anticancer drugs.METHODS Titanium dioxide coated gold nanostructures(Au/TiO2)was used as the drug carrier for the natural anticancer drug gambogic...OBJECTIVE Nanotechnology provides a novel strategy for the delivery of anticancer drugs.METHODS Titanium dioxide coated gold nanostructures(Au/TiO2)was used as the drug carrier for the natural anticancer drug gambogic acid in order to improve its anticancer effect.Biocompatibility and cellular uptake of Au/TiO2 was studied in human glio⁃blastoma U-87 MG cells.Cell viability was evaluated by ATP assay and calcein AM staining.LysoSensor Green DND-189 and Hoechst 33342 were used to analyze the intracellular location of Au/TiO2.The anticancer effect of gambogic acid loaded nanoparticles was compared with free drug.RESULTS Au/TiO2 was biocompatible,and they were localized at the intracellular acidic compartments of endosomes and lysosomes.The intracellular drug content delivered via Au/TiO2 was 6-fold higher than the free form,thus dramatically enhancing the anticancer effect of gambogic acid.Furthermore,mild photothermal therapy also showed synergistic effect with the drug.CONCLUSION Au/TiO2 is a promising anticancer drug carrier.展开更多
OBJECTIVE To improve the anticancer drug gambogic acid’s effect by using titanium dioxide coated gold nanorods(GNR/Ti O2)as a drug carrier.METHODS Biocompatibility and cellular uptake of GNR/Ti O2was studied in human...OBJECTIVE To improve the anticancer drug gambogic acid’s effect by using titanium dioxide coated gold nanorods(GNR/Ti O2)as a drug carrier.METHODS Biocompatibility and cellular uptake of GNR/Ti O2was studied in human glioblastoma U-87 MG cells.Cel viability was evaluated by ATP assay and calcein AM staining.Lyso SensorTMGreen DND-189 and Hoechst 33342 were used to analyze the intracellular location of GNR/Ti O2.The in vitro anticancer effect of gambogic acid loaded nanoparticles was compared with free drug.RESULTS The results showed that GNR/Ti O2is biocompatible,andthey are localized at the intracellular acidic compartments of endosomes and lysosomes.The intracellular drug content delivered via GNR/Ti O2was 6 fold higher than the free form,thus dramatically enhancing the anticancer effect of gambogic acid.Furthermore,mild photothermal therapy also showed synergistic effect with the drug.CONCLUSION Our study suggested that GNR/Ti O2is a promising anticancer drug carrier。展开更多
OBJECTIVE Nanotechnology provides a novel strategy for the delivery of anticancer drugs.In this study,titanium dioxide coated gold nanorod(GNR/TiO_2) nanostructures were used as the drug carrier for gambogic acid in o...OBJECTIVE Nanotechnology provides a novel strategy for the delivery of anticancer drugs.In this study,titanium dioxide coated gold nanorod(GNR/TiO_2) nanostructures were used as the drug carrier for gambogic acid in order to improve its anticancer effect.METHODS Biocompatibility and cellular uptake of GNR/TiO_2 nanostructures were studied in human glioblastoma U-87 MG cells.Cell viability was evaluated by ATP assay and calcein AM staining.Lyso Sensor Green DND-189 and Hoechst 33342 were used to analyze the intracellular location of GNR/TiO_2 nanostructures.The in vitro anti-cancer effect of gambogic acid loaded nanoparticles was compared with free drug.RESULTS The results showed that GNR/TiO_2 nanostructures are biocompatible,and they are localized at the intracellular acidic compartments of endosomes and lysosomes.The intracellular drug content delivered via GNR/TiO_2 nanostructures was 6 fold higher than the free form,thus dramatically enhancing the anticancer effect of gambogic acid.Furthermore,mild photothermal therapy also showed synergistic effect with the drug.CONCLUSION Our study suggested that GNR/TiO_2 nanostructures can be considered as a promising anticancer drug carrier.展开更多
The rapid development of nanotechnology enables the successful application of target drug delivery,which provides new hope for the clinical examination and treatment.In the whole process of drug delivery,we foundcoupl...The rapid development of nanotechnology enables the successful application of target drug delivery,which provides new hope for the clinical examination and treatment.In the whole process of drug delivery,we foundcouple of mechanics problems existed,including the transportation of nanocarriers,the molecular level target and the cellular uptake of nanoparticles.In recent years,we focused on the investigation of diffusion of drug delivery systems in mucus of gastrointestinal(GI)tract and tumor intestinal.We studied the stiffness effect and geometric effect of nanoparticles in cell internalization,and found that the shape,stiffness and adhesion of nanoparticle-based drug carriers affect their transportation in biological tissues.We revealed the internal mechanism with a theoretical model for the diffusion of nanoparticles in an adhesive/nonadhesive polymer network.These findings shed new light on the design of NP-based drug delivery systems targeted to mucosal and tumor sites that possess a fibrous structure/porous medium.展开更多
Pulsed electric field has been used widely as a nonviral approach to improving gene delivery in basic and translational research[1-2].The technique has been called electrotransfection(ET),electroporation,electrogene t...Pulsed electric field has been used widely as a nonviral approach to improving gene delivery in basic and translational research[1-2].The technique has been called electrotransfection(ET),electroporation,electrogene transfer,and gene electroinjection in the literature [1,3].It has a great potential to improve clinical treatment of diseases through delivery of vaccines and therapeutic genes,genome and epigenome editing,and generation of human induced pluripotent stem cells for tissue engineering[1-3].During ET,extracellular transport of plasmid DNA(pDNA)relies on electrophoresis,which is critical for applications in vivo.However,mechanisms of intracellular transport remain to be understood.The lack of understanding has hindered the translation of ET technology to the clinic.It is well known that pulsed electric field can generate transient hydrophilic pores in the plasma membrane(i.e.,electroporation)that permit membrane-impermeant molecules to enter cells.Although the pores have yet to be visualized directly under a microscope,the electric field-induced membrane permeabilization has been demonstrated through experimental measurements of electrical conductance of synthetic lipid membranes and plasma membranes,direct observation of fluorescent markers crossing the membranes facing both cathode and anode,and numerical simulations of the membrane permeabilization[1,3].Results from the simulations have predicted that the cutoff size of the pores is on the order of a few hundred nanometers,and the lifetime of the pores that are larger than 100 nm is on the order of 10 msec.Although these data provide a solid evidence of the membrane permeabilization,recent studies have demonstrated that the generation of the pores is insufficient for ET[1,4].The reasons are as follows.First,the lifetime of the pores is several orders of magnitude shorter than the time scale for pDNA uptake,which is on the order of 10 min.Second,complex formation between pDNA and plasma membrane is a necessary condition for successful gene transfer.Third,inhibition of clathrin mediated endocytosis or Rac-1 dependent micropinocytosis can reduce the amount of pDNA internalized by cells [1].Finally,we demonstrate that few pDNA molecules can be observed in the cytosol that are not associated with the intracellular vesicles[5],suggesting that pDNA uptake is mediated by endocytosis.In addition to the internalization,ET requires the pDNA in the cytoplasm to reach the nucleus.To understand mechanisms of intracellular trafficking of pDNA,we have examined time-dependent pDNA distributions in cells,quantitatively determined percentages of pDNA molecules associated with different endocytic compartments using transmission electron microscopy(TEM),and investigated different approaches to facilitate cytoplasmic transport and nuclear entry of pDNA.Our data have shown that electrotransfected pDNA is located in different vesicular ultrastructures at or near the plasma membrane at10 min post application of electric pulses[5].In the hard-to-transfect cells(e.g.,4T1),pDNA penetration from the cell surface is less active,and the total number of vesicular structures associated with pDNA is low,compared to those in the easyto-transfect cells(e.g.,COS7).Our data have also shown that macropinocytosis is the most common pathway shared by all types of cells.To investigate how improve pDNA transport in cells,we have photochemically treated cells to non-specifically induce pDNA escape from intracellular vesicles,or blocked endosome and autophagic vacuole maturation through treatment of cells with Bafilomycin Al,an inhibitor of vacuolar H+ATPase.Our data demonstrate that both treatments can lead to reduction of ET efficiency although the treatment for inducing endosomal escape can enhance poly-L-lysine mediated gene delivery.These data suggest that the vesicles play an important role in protecting the naked pDNA during intracellular trafficking.The nuclear envelope is another major barrier to ET.To facilitate the nuclear entry,we have examined three different approaches.One is to synchronize the nuclear envelope breakdown(NEBD)prior to ET;the second approach is to pre-treat cells with a nuclear pore dilating agent(i.e.,trans-1,2-cyclohexanediol);and the third one is to incorporate a nuclear targeting sequence(NTS)(i.e.,SV40)into the pDNA.Our data have shown that the synchronization of the NEBD can significantly improve the ET efficiency without compromising the cell viability.The nuclear pore dilation can improve the ET as well but the dilating agent is cytotoxic.The incorporation of NTS into pDNA can improve the gene delivery efficiency but the improvement is cell-type dependent,suggesting that the NTS has to be screened and optimized for the cells of interest.In summary,the transient pores in the plasma membrane induced by the electric pulses will enable cellular uptake of membrane-impermeant molecules up to the size of small proteins.Larger molecules(e.g.,pDNA)have to be internalized via endocytic processes triggered by the pulsed electric field.Within the cells,pDNA transport is mediated by vesicles and can be blocked by non-specific escape from vesicles or inhibition of vesicle maturation.The nuclear entry of pDNA can be enhanced,without compromising cell viability,through the use of the NTS or the synchronization of the NEBD.展开更多
基金supported by the Fundamental Research Funds for the Central Universities(2024JBZX038)the National Natural Science Foundation of China(62076023).
文摘With the rapid development of low-altitude economy and unmanned aerial vehicles (UAVs) deployment technology, aerial-ground collaborative delivery (AGCD) is emerging as a novel mode of last-mile delivery, where the vehicle and its onboard UAVs are utilized efficiently. Vehicles not only provide delivery services to customers but also function as mobile ware-houses and launch/recovery platforms for UAVs. This paper addresses the vehicle routing problem with UAVs considering time window and UAV multi-delivery (VRPU-TW&MD). A mixed integer linear programming (MILP) model is developed to mini-mize delivery costs while incorporating constraints related to UAV energy consumption. Subsequently, a micro-evolution aug-mented large neighborhood search (MEALNS) algorithm incor-porating adaptive large neighborhood search (ALNS) and micro-evolution mechanism is proposed. Numerical experiments demonstrate the effectiveness of both the model and algorithm in solving the VRPU-TW&MD. The impact of key parameters on delivery performance is explored by sensitivity analysis.
基金supported by a grant from The National Natural Science Foundation of China(32000997)。
文摘Spores and pollen,as ubiquitous organisms found in nature,possess a remarkable core-shell structure and intricate surface morphology.These tiny particles are notable for their dimensional uniformity,sustainable utilization,environmental friendliness,porosity,amphiphilicity,and strong adhesive properties.In addition,they display excellent biocompatibility and biodegradability,which significantly enhances the stability and targeting of drugs within the body.Spores and pollen can be extracted using methods such as acidic solutions,alkaline solutions,or enzyme treatments to obtain sporopollenin,which is an extremely resilient and chemically inert complex biopolymer.The sporopollenin extracted through this process removes the original bioactive substances,such as cell nuclei,enzymes,and DNA,providing greater drug loading capacity and containing no potential allergens or immunogens,thus further enhancing its drug loading capacity and improving safety in therapeutic applications.Due to these beneficial attributes,spores,pollen and sporopollenin have gained widespread use in a variety of drug delivery systems,such as targeted delivery,sustained drug delivery,toxicity mitigation,flavor masking,vaccine delivery,delivery of labile substances,and other applications.This review introduces the types of natural spores and pollen commonly used in drug delivery systems,including their main components,common effects,and uses in drug delivery systems,and so on.It subsequently summarizes novel optimization methods in their processing,such as physical treatment,surface modification,and chemical modification,which enable higher drug loading efficiency,stability,and targeting,among other benefits.Additionally,this paper reviews the research progress and applications of natural spores,pollen,and sporopollenin in drug delivery systems,while also touching on some innovative research content,such as novel nanomotor microcarriers developed based on pollen.Based on these research findings,we further elaborate on the advantages of spores,pollen,and sporopollenin in drug delivery systems.For example,they have high stability and drug loading capacity,good adhesion,excellent targeting,and are easy to modify functionally.Currently,they show promising prospects in the fields of targeted drug delivery,sustained-release drug delivery,as well as the delivery of drugs that are effective but slightly toxic,and are often used in research on the treatment of diseases such as cancer and inflammation.We have also highlighted the challenges they face in various applications and identified some issues that need to be addressed,including difficulties in largescale production,the need to improve extraction and purification processes,and the existence of a low but still noteworthy risk of allergies,in order to fully leverage their potential in drug delivery applications.According to current research,although spores,pollen,and sporopollenin face some unresolved issues in clinical drug delivery,they still have great potential overall and are expected to become a new generation of green drug delivery platforms.In the future,further research into their unique physical and chemical properties and structural characteristics will help develop more efficient and stable drug delivery systems to meet diverse treatment needs.We believe that continued exploration of natural spores,pollen,and sporopollenin will drive this emerging field to achieve continuous breakthroughs and progress,ultimately making an important contribution to the cause of human health.
文摘As battlefield scale enlarges,cross-platform collaborative combat provides an appealing paradigm for modern warfare.Complicated constraints and vast solution space pose great challenge for reasonable and efficient mission planning,where path planning and target assignment are tightly coupled.In this paper,we focus on UAV mission planning under carrier delivery mode(e.g.,by aircraft carrier,ground vehicle,or transport aircraft) and design a three-layer hierarchical solution framework.In the first layer,we simultaneously determine delivery points and target set division by clustering.To address the safety concerns of radar risk and UAV endurance,an improved density peak clustering algorithm is developed by constraint fusio n.In the second layer,mission planning within each cluster is viewed as a coope rative multiple-task assignment problem.A hybrid heuristic algorithm that integrates a voting-based heuristic solution generation strategy(VHSG) and a stochastic variable neighborhood search(SVNS),called VHSG-SVNS,is proposed for rapid solution.Based on the results of the first two layers,the third layer transforms carrier path planning into a multiple-vehicle routing problem with time window.The cost between any two nodes is calculated by the A~* algorithm,and the genetic algorithm is then implemented to determine the global route.Finally,a practical mission scenario containing 200 targets is used to validate the effectiveness of the designed framework,where three layers cooperate well with each other to generate satisfactory combat scheduling.Comparisons are made in each layer to highlight optimum-seeking capability and efficiency of the proposed algorithms.Works done in this paper provide a simple but efficient solution framework for cross-platform cooperative mission planning problems,and can be potentially extended to other applications such as post-disaster search and rescue,forest surveillance and firefighting,logistics pick and delivery,etc.
基金Fundamental Research Funds for the Central Universities(2024JBZX038)National Natural Science F oundation of China(62076023)。
文摘The rapid evolution of unmanned aerial vehicle(UAV)technology and autonomous capabilities has positioned UAV as promising last-mile delivery means.Vehicle and onboard UAV collaborative delivery is introduced as a novel delivery mode.Spatiotemporal collaboration,along with energy consumption with payload and wind conditions play important roles in delivery route planning.This paper introduces the traveling salesman problem with time window and onboard UAV(TSPTWOUAV)and emphasizes the consideration of real-world scenarios,focusing on time collaboration and energy consumption with wind and payload.To address this,a mixed integer linear programming(MILP)model is formulated to minimize the energy consumption costs of vehicle and UAV.Furthermore,an adaptive large neighborhood search(ALNS)algorithm is applied to identify high-quality solutions efficiently.The effectiveness of the proposed model and algorithm is validated through numerical tests on real geographic instances and sensitivity analysis of key parameters is conducted.
基金supported by the National Natural Science Fandation of China (6067208960772075)
文摘In consultative committee for space data systems（CCSDS） file delivery protocol（CFDP） recommendation of reliable transmission,there are no detail transmission procedure and delay calculation of prompted negative acknowledge and asynchronous negative acknowledge models.CFDP is designed to provide data and storage management,story and forward,custody transfer and reliable end-to-end delivery over deep space characterized by huge latency,intermittent link,asymmetric bandwidth and big bit error rate（BER）.Four reliable transmission models are analyzed and an expected file-delivery time is calculated with different trans-mission rates,numbers and sizes of packet data units,BERs and frequencies of external events,etc.By comparison of four CFDP models,the requirement of BER for typical missions in deep space is obtained and rules of choosing CFDP models under different uplink state informations are given,which provides references for protocol models selection,utilization and modification.
基金Supported by Natural Sciences and Engineering Research Council, Collaborative Research and Development Grant (319848) of Canada
文摘Existing position-based routing algorithms, where packets are forwarded in the geographic direction of the destination, normally require that the forwarding node should know the positions of all neighbors in its transmission range. This information on direct neighbors is gained by observing beacon messages that each node sends out periodically. Several beaconless greedy routing schemes have been proposed recently. However, none of the existing beaconless schemes guarantee the delivery of packets. Moreover, they incur communication overhead by sending excessive control messages or by broadcasting data packets. In this paper, we describe how existing localized position based routing schemes that guarantee delivery can be made beaconless, while preserving the same routes. In our guaranteed delivery beaconless routing scheme, the next hop is selected through the use of control RTS/CTS messages and biased timeouts. In greedy mode, the neighbor closest to destination responds first. In recovery mode, nodes closer to the source will select shorter timeouts, so that other neighbors, overhearing CTS packets, can eliminate their own CTS packets if they realize that their link to the source is not part of Gabriel graph. Nodes also cancel their packets after receiving data message sent by source to the selected neighbor. We analyze the behavior of our scheme on our simulation environment assuming ideal MAC, following GOAFR+ and GFG routing schemes. Our results demonstrate low communication overhead in addition to guaranteed delivery.
基金the financial support of the National Natural Science Foundation of China(No.52102453)。
文摘The weapon transportation support scheduling problem on aircraft carrier deck is the key to restricting the sortie rate and combat capability of carrier-based aircraft.This paper studies the problem and presents a novel solution architecture.Taking the interference of the carrier-based aircraft deck layout on the weapon transportation route and precedence constraint into consideration,a mixed integer formulation is established to minimize the total objective,which is constituted of makespan,load variance and accumulative transfer time of support unit.Solution approach is developed for the model.Firstly,based on modeling the carrier aircraft parked on deck as convex obstacles,the path library of weapon transportation is constructed through visibility graph and Warshall-Floyd methods.We then propose a bi-population immune algorithm in which a population-based forward/backward scheduling technique,local search schemes and a chaotic catastrophe operator are embedded.Besides,the randomkey solution representation and serial scheduling generation scheme are adopted to conveniently obtain a better solution.The Taguchi method is additionally employed to determine key parameters of the algorithm.Finally,on a set of generated realistic instances,we demonstrate that the proposed algorithm outperforms all compared algorithms designed for similar optimization problems and can significantly improve the efficiency,and that the established model and the bi-population immune algorithm can effectively respond to the weapon support requirements of carrier-based aircraft under different sortie missions.
基金supported by the National Natural Science Foundation of China(61271261)the Natural Science Foundation Project of CQ CSTC(CSTC2012jjA40048)
文摘A deep space multi-file delivery protocol（DSMDP） based on LT codes is proposed to reduce the influence of long delay and a high bit error rate（BER） in deep space communication. The protocol increases sending redundancy by LT codes to improve the success rate of file delivery, and adopts different protective strategies for different situations of packet loss. At the same time, the multi-file united delivery strategy is adopted to make full use of the retransmission time to reduce the end-toend transmission delay. Furthermore, the protocol determines the quantity of encoded packets according to the feedback for controlling redundancy. The simulation results show that the proposed protocol can significantly reduce the transmission delay of files, which would be effectively suitable for deep space communication environment of high BER and long delay.
基金Anhui Provincial Natural Science Foundation(Project for Youth:1908085QF252)Research Program of National University of Defense Technology(ZK19-10)。
文摘Focused energy delivery(FED) is a technique that can precisely bring energy to the specific region,which arouses wide attention in precision electronic warfare(PREW).This paper first proposes a joint optimization model with respect to the locations of the array and the transmitted signals to improve the performance of FED.As the problem is nonconvex and NP-hard,particle swarm optimization(PSO) is adopted to solve the locations of the array,while designing the transmitted signals under a feasible array is considered as a unimodular quadratic program(UQP) subproblem to calculate the fitness criterion of PSO.In the PSO-UQP framework established,two methods are presented for the UQP subproblem,which are more efficient and more accurate respectively than previous works.Furthermore,a threshold value is set in the framework to determine which method to adopt to take full advantages of the methods above.Meanwhile,we obtain the maximum localization error that FED can tolerate,which is significant for implementing FED in practice.Simulation results are provided to demonstrate the effectiveness of the joint optimization algorithm,and the correctness of the maximum localization error derived.
基金supported by the National Natural Science Foundation of China(Grant Nos.11472137 and U2141246)。
文摘In this paper,a dynamic modeling method of motor driven electromechanical system is presented,and the uncertainty quantification of mechanism motion is investigated based on this method.The main contribution is to propose a novel mechanism-motor coupling dynamic modeling method,in which the relationship between mechanism motion and motor rotation is established according to the geometric coordination of the system.The advantages of this include establishing intuitive coupling between the mechanism and motor,facilitating the discussion for the influence of both mechanical and electrical parameters on the mechanism,and enabling dynamic simulation with controller to take the randomness of the electric load into account.Dynamic simulation considering feedback control of ammunition delivery system is carried out,and the feasibility of the model is verified experimentally.Based on probability density evolution theory,we comprehensively discuss the effects of system parameters on mechanism motion from the perspective of uncertainty quantization.Our work can not only provide guidance for engineering design of ammunition delivery mechanism,but also provide theoretical support for modeling and uncertainty quantification research of mechatronics system.
基金The project supported by Macao Science and Technology Development Fund(014/2014/A1)
文摘OBJECTIVE Many drug candidates identified from natural products are poorly water-soluble.The surfactants used to disperse the hydrophobic anticancer drugs in water may cause a serious of acute hypersensitivity reactions.Nanotechnology provides an alternative strategy for delivery of anticancer drugs.In the present study,different inorganic nanoparticles are utilized as hydrophobic anticancer drug carriers.METHODS Different inorganic superparamagnetic iron oxide,platinum and gold nanoparticles were synthesized.The hydrophobic anticancer drugs such as curcumin,gambogic acid and doxorubicin(DOX)base were loaded into the porous area or onto the surface of the nanoparticles.Cellular uptake and biocompatibility of nanoparticles were studied in human glioblastoma U-87 MG cells.The anticancer effect of drug loaded nanoparticles was compared with that of free drugs.Photothermal conversion of platinum and gold nanoparticles was studied by irradiation of nanoparticles with a near-infrared laser.RESULTS The synthesized nanoparticles are readily internalized by U-87 MG cells,and the internalized nanoparticles are mainly localized in endosomes/lysosomes in cells.The nanoparticle-based drug carrier provides the aqueous dispersions of the hydrophobic drugs.In endosomes/lysosomes mimicking buffers with a pH of 4.5-5.5,pH-dependent drug release was observed from drug loaded nanoparticles.The intracellular drug content and cytotoxicity are significantly higher for drug loaded nanoparticles than free drug.Photothermal treatment has a synergistic effect on drug′s anticancer activity.CONCLUSION These results suggested inorganic nanoparticles is a promising intracellular carrier for hydrophobic anticancer drugs.
基金The project supported by National Natural Science Foundation of China(81573613,81373896)the Major Program for the Fundamental Research of Shanghai Committee of Science and Technology(14JC1491300)Open Fund of State Key Laboratory of Natural Medicines(SKLNMKF201612)
文摘The traditional Chinese medicine tripterygium glycosides(TPG)is used clinically to treat some Rheumatism,Eczema,immunosuppression and tumor,with the activities of hypnosis,antipyretic,analgesic,antiinflammatory,allergy and antitumor.However TPG has low water solubility and low skin permeability,so its clinical use is limited.Transdermal delivery systems can provide a controlled drug release rate that can keep constant concentrations of drug in the plasma for up to multiple days,improved patient compliance,and the possibility ofreducing the rate and severity of side effects.In this study,a fast and sensitive technique skin-blood two sites synchronous microdialysis coupled with LC-MS was used to study the pharmacokinetic parameter of three different formulations(TPG nanoemulsion,TPG nanoemulsion based gels and TPG gel).Creating a multilayer model,use the model to simulate the three formulations dynamics in transdermal-drug delivery system.The experiment results showed that the TPG nanoemulsion,TPG nanoemulsion based gels can significantly raise the drug concentrations in skin more than that of TPG gels.The numerical simulation results indicating that TPG gel and TPG nanoemulsion are close to practical measurements,only in the concentration increase phase the numerical simulation result has some difference with the experimental results.TPG nanoemulsion based gels have significant difference with the experimental results,both in concentration increase stage and concentration decreasing stage,but its trend was same.The study shows that the skin-blood synchronous microdialysis technique provided a new method for the pharmacokinetics study of nanocarriers transdermal delivery systems.In addition,the microdialysis technique combined with mathematical modeling provides a very good platform for the further study of transdermal delivery system.
基金Macao Science and Technology Development Fund(FDCT)(014/2014/A1)
文摘OBJECTIVE Nanotechnology provides a novel strategy for the delivery of anticancer drugs.METHODS Titanium dioxide coated gold nanostructures(Au/TiO2)was used as the drug carrier for the natural anticancer drug gambogic acid in order to improve its anticancer effect.Biocompatibility and cellular uptake of Au/TiO2 was studied in human glio⁃blastoma U-87 MG cells.Cell viability was evaluated by ATP assay and calcein AM staining.LysoSensor Green DND-189 and Hoechst 33342 were used to analyze the intracellular location of Au/TiO2.The anticancer effect of gambogic acid loaded nanoparticles was compared with free drug.RESULTS Au/TiO2 was biocompatible,and they were localized at the intracellular acidic compartments of endosomes and lysosomes.The intracellular drug content delivered via Au/TiO2 was 6-fold higher than the free form,thus dramatically enhancing the anticancer effect of gambogic acid.Furthermore,mild photothermal therapy also showed synergistic effect with the drug.CONCLUSION Au/TiO2 is a promising anticancer drug carrier.
基金The project supported by Macao Science and Technology Development Fund(014/2014/A1)
文摘OBJECTIVE To improve the anticancer drug gambogic acid’s effect by using titanium dioxide coated gold nanorods(GNR/Ti O2)as a drug carrier.METHODS Biocompatibility and cellular uptake of GNR/Ti O2was studied in human glioblastoma U-87 MG cells.Cel viability was evaluated by ATP assay and calcein AM staining.Lyso SensorTMGreen DND-189 and Hoechst 33342 were used to analyze the intracellular location of GNR/Ti O2.The in vitro anticancer effect of gambogic acid loaded nanoparticles was compared with free drug.RESULTS The results showed that GNR/Ti O2is biocompatible,andthey are localized at the intracellular acidic compartments of endosomes and lysosomes.The intracellular drug content delivered via GNR/Ti O2was 6 fold higher than the free form,thus dramatically enhancing the anticancer effect of gambogic acid.Furthermore,mild photothermal therapy also showed synergistic effect with the drug.CONCLUSION Our study suggested that GNR/Ti O2is a promising anticancer drug carrier。
基金supported by Macao Science and Technology Development Fund(FDCT)(014/2014/A1)
文摘OBJECTIVE Nanotechnology provides a novel strategy for the delivery of anticancer drugs.In this study,titanium dioxide coated gold nanorod(GNR/TiO_2) nanostructures were used as the drug carrier for gambogic acid in order to improve its anticancer effect.METHODS Biocompatibility and cellular uptake of GNR/TiO_2 nanostructures were studied in human glioblastoma U-87 MG cells.Cell viability was evaluated by ATP assay and calcein AM staining.Lyso Sensor Green DND-189 and Hoechst 33342 were used to analyze the intracellular location of GNR/TiO_2 nanostructures.The in vitro anti-cancer effect of gambogic acid loaded nanoparticles was compared with free drug.RESULTS The results showed that GNR/TiO_2 nanostructures are biocompatible,and they are localized at the intracellular acidic compartments of endosomes and lysosomes.The intracellular drug content delivered via GNR/TiO_2 nanostructures was 6 fold higher than the free form,thus dramatically enhancing the anticancer effect of gambogic acid.Furthermore,mild photothermal therapy also showed synergistic effect with the drug.CONCLUSION Our study suggested that GNR/TiO_2 nanostructures can be considered as a promising anticancer drug carrier.
文摘The rapid development of nanotechnology enables the successful application of target drug delivery,which provides new hope for the clinical examination and treatment.In the whole process of drug delivery,we foundcouple of mechanics problems existed,including the transportation of nanocarriers,the molecular level target and the cellular uptake of nanoparticles.In recent years,we focused on the investigation of diffusion of drug delivery systems in mucus of gastrointestinal(GI)tract and tumor intestinal.We studied the stiffness effect and geometric effect of nanoparticles in cell internalization,and found that the shape,stiffness and adhesion of nanoparticle-based drug carriers affect their transportation in biological tissues.We revealed the internal mechanism with a theoretical model for the diffusion of nanoparticles in an adhesive/nonadhesive polymer network.These findings shed new light on the design of NP-based drug delivery systems targeted to mucosal and tumor sites that possess a fibrous structure/porous medium.
基金supported by grants from National Institutes of Health ( GM098520 and GM130830)National Science Foundation ( CBET-1264186)
文摘Pulsed electric field has been used widely as a nonviral approach to improving gene delivery in basic and translational research[1-2].The technique has been called electrotransfection(ET),electroporation,electrogene transfer,and gene electroinjection in the literature [1,3].It has a great potential to improve clinical treatment of diseases through delivery of vaccines and therapeutic genes,genome and epigenome editing,and generation of human induced pluripotent stem cells for tissue engineering[1-3].During ET,extracellular transport of plasmid DNA(pDNA)relies on electrophoresis,which is critical for applications in vivo.However,mechanisms of intracellular transport remain to be understood.The lack of understanding has hindered the translation of ET technology to the clinic.It is well known that pulsed electric field can generate transient hydrophilic pores in the plasma membrane(i.e.,electroporation)that permit membrane-impermeant molecules to enter cells.Although the pores have yet to be visualized directly under a microscope,the electric field-induced membrane permeabilization has been demonstrated through experimental measurements of electrical conductance of synthetic lipid membranes and plasma membranes,direct observation of fluorescent markers crossing the membranes facing both cathode and anode,and numerical simulations of the membrane permeabilization[1,3].Results from the simulations have predicted that the cutoff size of the pores is on the order of a few hundred nanometers,and the lifetime of the pores that are larger than 100 nm is on the order of 10 msec.Although these data provide a solid evidence of the membrane permeabilization,recent studies have demonstrated that the generation of the pores is insufficient for ET[1,4].The reasons are as follows.First,the lifetime of the pores is several orders of magnitude shorter than the time scale for pDNA uptake,which is on the order of 10 min.Second,complex formation between pDNA and plasma membrane is a necessary condition for successful gene transfer.Third,inhibition of clathrin mediated endocytosis or Rac-1 dependent micropinocytosis can reduce the amount of pDNA internalized by cells [1].Finally,we demonstrate that few pDNA molecules can be observed in the cytosol that are not associated with the intracellular vesicles[5],suggesting that pDNA uptake is mediated by endocytosis.In addition to the internalization,ET requires the pDNA in the cytoplasm to reach the nucleus.To understand mechanisms of intracellular trafficking of pDNA,we have examined time-dependent pDNA distributions in cells,quantitatively determined percentages of pDNA molecules associated with different endocytic compartments using transmission electron microscopy(TEM),and investigated different approaches to facilitate cytoplasmic transport and nuclear entry of pDNA.Our data have shown that electrotransfected pDNA is located in different vesicular ultrastructures at or near the plasma membrane at10 min post application of electric pulses[5].In the hard-to-transfect cells(e.g.,4T1),pDNA penetration from the cell surface is less active,and the total number of vesicular structures associated with pDNA is low,compared to those in the easyto-transfect cells(e.g.,COS7).Our data have also shown that macropinocytosis is the most common pathway shared by all types of cells.To investigate how improve pDNA transport in cells,we have photochemically treated cells to non-specifically induce pDNA escape from intracellular vesicles,or blocked endosome and autophagic vacuole maturation through treatment of cells with Bafilomycin Al,an inhibitor of vacuolar H+ATPase.Our data demonstrate that both treatments can lead to reduction of ET efficiency although the treatment for inducing endosomal escape can enhance poly-L-lysine mediated gene delivery.These data suggest that the vesicles play an important role in protecting the naked pDNA during intracellular trafficking.The nuclear envelope is another major barrier to ET.To facilitate the nuclear entry,we have examined three different approaches.One is to synchronize the nuclear envelope breakdown(NEBD)prior to ET;the second approach is to pre-treat cells with a nuclear pore dilating agent(i.e.,trans-1,2-cyclohexanediol);and the third one is to incorporate a nuclear targeting sequence(NTS)(i.e.,SV40)into the pDNA.Our data have shown that the synchronization of the NEBD can significantly improve the ET efficiency without compromising the cell viability.The nuclear pore dilation can improve the ET as well but the dilating agent is cytotoxic.The incorporation of NTS into pDNA can improve the gene delivery efficiency but the improvement is cell-type dependent,suggesting that the NTS has to be screened and optimized for the cells of interest.In summary,the transient pores in the plasma membrane induced by the electric pulses will enable cellular uptake of membrane-impermeant molecules up to the size of small proteins.Larger molecules(e.g.,pDNA)have to be internalized via endocytic processes triggered by the pulsed electric field.Within the cells,pDNA transport is mediated by vesicles and can be blocked by non-specific escape from vesicles or inhibition of vesicle maturation.The nuclear entry of pDNA can be enhanced,without compromising cell viability,through the use of the NTS or the synchronization of the NEBD.
