Cargo Delivery Systems Research Articles

Biocompatible stimuli‐responsive nanogels for controlled antitumor drug delivery

ABSTRACTHerein, the synthesis and potential application as cargo delivery systems of thermo‐responsive poly(N‐vinylcaprolactam) (PVCL)‐based, pH‐responsive poly(2‐(diethylamino)ethyl) methacrylate (PDEAEMA)‐based, and thermo‐, and pH‐responsive PDEAEMA/PVCL‐based core–shell nanogels are reported. All the nanogels have been synthesized using different dextran‐methacrylates (Dex‐MAs) as macro‐cross‐linkers. Doxorubicin hydrochloride (DOXO), an anticancer drug, has been effectively loaded into nanogels via hydrogen‐bonding interactions between OH groups of DOXO and OH groups of Dex‐MA chains. Drug‐release profiles at various pHs, and the cytocompatibility of the DOXO‐loaded nanogels have been assessed in vitro using cervical cancer HeLa and breast cancer MDA‐MB‐231 cell lines. In all the cases, the DOXO release is controlled by Fickian diffusion and case‐II transport, being the diffusional process dominant. In addition, DOXO‐loaded nanogels are efficiently internalized by HeLa and MDA‐MB‐231 cells and DOXO is progressively released in time. Therefore, nanogels synthesized could be suitable and potentially useful as nanocarriers for antitumor drug delivery. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 1694–1705

Multi-objective hub network design under uncertainty considering congestion: An M/M/c/K queue system

Hub location problems have applications in a variety of fields including cargo delivery systems and telecommunication network design. Hub location problems deal with locating a set of hub nodes and allocating non-hub nodes to the located hubs. This paper presents a new bi-objective model for a multi-modal hub location problem under uncertainty considering congestion in the hubs. The objective functions attempt to minimize the total transportation cost as well as minimize the maximum transportation time between each pair of Origin-Destination (O-D) nodes in the network. To cope with the computational complexity of the problem, a well-known meta-heuristic algorithm, namely differential evolution (DE), is developed to obtain near-optimal Pareto solutions. Furthermore, several computational experiments and sensitivity analyses are provided to demonstrate the efficiency and applicability of the presented model and solution algorithm. Finally, the conclusion is presented.

A bi-objective hub maximal covering location problem considering time-dependent reliability and the second type of coverage

The hub location problem seeks to find the best location for hubs and the assignment of non-hub nodes to hubs. The hub location problem appears in a variety of applications including airline systems, cargo delivery systems, and telecommunication network design. In this paper, a bi-objective hub maximal covering location problem is presented considering time-dependent reliabilities. The two objective functions are: (i) maximizing the weighted network reliability and (ii) maximizing the total flow in a hub network, where the type of coverage used for locating is the second type. Additionally, the transportation cost between each pair of nodes is assumed to be an uncertain parameter. Chance constrained programming is employed to formulate the bi-objective problem. The model is transformed into a single-objective model using the goal attainment method – a technique in multi-objective decision making procedures. As the problem belongs to the class of NP-hard problems, a genetic algorithm is developed to solve it. Since there is no benchmark available in the literature, a simulated annealing algorithm is developed as well in order to validate the results obtained. The response surface methodology is utilized to tune the parameters of both algorithms in order to find better solutions. Some numerical examples are presented to investigate the efficiency of the proposed algorithms. Finally, the results obtained using the two algorithms are compared by the technique for order preference by similarity to the ideal solution.

Catalytic mesoporous Janus nanomotors for active cargo delivery.

We report on the synergy between catalytic propulsion and mesoporous silica nanoparticles (MSNPs) for the design of Janus nanomotors as active cargo delivery systems with sizes <100 nm (40, 65, and 90 nm). The Janus asymmetry of the nanomotors is given by electron beam (e-beam) deposition of a very thin platinum (2 nm) layer on MSNPs. The chemically powered Janus nanomotors present active diffusion at low H2O2 fuel concentration (i.e., <3 wt %). Their apparent diffusion coefficient is enhanced up to 100% compared to their Brownian motion. Due to their mesoporous architecture and small dimensions, they can load cargo molecules in large quantity and serve as active nanocarriers for directed cargo delivery on a chip.

A stochastic approach for a novel p-hub location-allocation problem with opening and reopening modes

A hub location problem appears in a variety of applications involving airline systems, cargo delivery systems and telecommunication network design. The plants known as hubs serve client nodes involving hub and spoke nodes. To act optimally plants work through time horizon. Thus, opening, reopening and active modes as well as their operational cost are accounted for. We have a single objective function that minimises the total expected cost. Additionally, to come close more and more to reality, we consider a stochastic environment, in which a scenario-based type is considered and dedicated a specific probability. The experimental results illustrate the impact of the stochastic environment compared to the deterministic one. A stochastic mathematical model yields a less amount of the objective function value compared with the deterministic one. Finally, a wide sensitivity analysis is performed to recognise the impact of the main parameters on the final solutions.

Single‐Particle Tracking and Modulation of Cell Entry Pathways of a Tetrahedral DNA Nanostructure in Live Cells

AbstractDNA is typically impermeable to the plasma membrane due to its polyanionic nature. Interestingly, several different DNA nanostructures can be readily taken up by cells in the absence of transfection agents, which suggests new opportunities for constructing intelligent cargo delivery systems from these biocompatible, nonviral DNA nanocarriers. However, the underlying mechanism of entry of the DNA nanostructures into the cells remains unknown. Herein, we investigated the endocytotic internalization and subsequent transport of tetrahedral DNA nanostructures (TDNs) by mammalian cells through single‐particle tracking. We found that the TDNs were rapidly internalized by a caveolin‐dependent pathway. After endocytosis, the TDNs were transported to the lysosomes in a highly ordered, microtubule‐dependent manner. Although the TDNs retained their structural integrity within cells over long time periods, their localization in the lysosomes precludes their use as effective delivery agents. To modulate the cellular fate of the TDNs, we functionalized them with nuclear localization signals that directed their escape from the lysosomes and entry into the cellular nuclei. This study improves our understanding of the entry into cells and transport pathways of DNA nanostructures, and the results can be used as a basis for designing DNA‐nanostructure‐based drug delivery nanocarriers for targeted therapy.

Single-particle tracking and modulation of cell entry pathways of a tetrahedral DNA nanostructure in live cells.

DNA is typically impermeable to the plasma membrane due to its polyanionic nature. Interestingly, several different DNA nanostructures can be readily taken up by cells in the absence of transfection agents, which suggests new opportunities for constructing intelligent cargo delivery systems from these biocompatible, nonviral DNA nanocarriers. However, the underlying mechanism of entry of the DNA nanostructures into the cells remains unknown. Herein, we investigated the endocytotic internalization and subsequent transport of tetrahedral DNA nanostructures (TDNs) by mammalian cells through single-particle tracking. We found that the TDNs were rapidly internalized by a caveolin-dependent pathway. After endocytosis, the TDNs were transported to the lysosomes in a highly ordered, microtubule-dependent manner. Although the TDNs retained their structural integrity within cells over long time periods, their localization in the lysosomes precludes their use as effective delivery agents. To modulate the cellular fate of the TDNs, we functionalized them with nuclear localization signals that directed their escape from the lysosomes and entry into the cellular nuclei. This study improves our understanding of the entry into cells and transport pathways of DNA nanostructures, and the results can be used as a basis for designing DNA-nanostructure-based drug delivery nanocarriers for targeted therapy.

Hemolytic Activity of Membrane-Active Peptides Correlates with the Thermodynamics of Binding to 1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphocholine Bilayers

Understanding the mechanisms of antimicrobial, cytolytic and cell-penetrating peptides is important for the design of new peptides to be used as cargo-delivery systems or antimicrobials. But these peptides should not be hemolytic. Recently, we designed a series of such membrane-active peptides and tested several hypotheses about their mechanisms on model membranes. To that end, the Gibbs free energy of binding to 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) vesicles was determined experimentally. Because the main lipid components of the outermost monolayer of erythrocyte membranes are zwitterionic, like POPC, we hypothesized that the Gibbs free energy of binding of these peptides to POPC would also be a good indicator of their hemolytic activity. Now, the hemolytic activity of those synthetic peptides was examined by measuring the lysis of sheep erythrocyte suspensions after peptide addition. Indeed, the Gibbs free energy of binding was in good correlation with the hemolytic activity, which was represented by the concentration of peptide in solution that produced 50% hemolysis. Furthermore, with two exceptions, those peptides that caused graded dye release from POPC vesicles were also hemolytic, while most of those that caused all-or-none release were not.

NBR1-Mediated Selective Autophagy Targets Insoluble Ubiquitinated Protein Aggregates in Plant Stress Responses

Plant autophagy plays an important role in delaying senescence, nutrient recycling, and stress responses. Functional analysis of plant autophagy has almost exclusively focused on the proteins required for the core process of autophagosome assembly, but little is known about the proteins involved in other important processes of autophagy, including autophagy cargo recognition and sequestration. In this study, we report functional genetic analysis of Arabidopsis NBR1, a homolog of mammalian autophagy cargo adaptors P62 and NBR1. We isolated two nbr1 knockout mutants and discovered that they displayed some but not all of the phenotypes of autophagy-deficient atg5 and atg7 mutants. Like ATG5 and ATG7, NBR1 is important for plant tolerance to heat, oxidative, salt, and drought stresses. The role of NBR1 in plant tolerance to these abiotic stresses is dependent on its interaction with ATG8. Unlike ATG5 and ATG7, however, NBR1 is dispensable in age- and darkness-induced senescence and in resistance to a necrotrophic pathogen. A selective role of NBR1 in plant responses to specific abiotic stresses suggest that plant autophagy in diverse biological processes operates through multiple cargo recognition and delivery systems. The compromised heat tolerance of atg5, atg7, and nbr1 mutants was associated with increased accumulation of insoluble, detergent-resistant proteins that were highly ubiquitinated under heat stress. NBR1, which contains an ubiquitin-binding domain, also accumulated to high levels with an increasing enrichment in the insoluble protein fraction in the autophagy-deficient mutants under heat stress. These results suggest that NBR1-mediated autophagy targets ubiquitinated protein aggregates most likely derived from denatured or otherwise damaged nonnative proteins generated under stress conditions.

Forming a Set of Alternate Variants of Transport and Technological Container Cargo Delivery Systems

Представлені теоретичні основи формування повної множини альтернативних варіантів транспортно-технологічних систем доставки вантажів. Наведені приклади використання пропонованої методології для формування множин альтернативних варіантів доставки вантажів у контейнерах. Показана необхідність використання пропонованого підходу при вирішенні задачі вибору оптимального варіанту доставки вантажів.

Hub covering location problems with different coverage types

The hub location problem is used for many applications, including cargo delivery systems, airline systems, telecommunication network design and so on. Each area has its own characteristics in hub location. In this paper, we study the hub covering problem with different coverage type over complete hub networks. Furthermore, hub set and maximal covering are expressed with single and multiple allocation strategies. First, a quadratic formulation is proposed for single allocation hub set covering problem. Then a linearization idea is considered for it and applied for multiple allocation hub set, single and multiple allocation hub maximal covering problems. The aim of these models is to find the location of hubs and allocate non-hub nodes to the located hub nodes subject to the travel time (cost or distance) between two nodes in origin-destination doesn’t exceed a given bound. The formulations with this coverage constraint have not been remarked in the literature. Two heuristic procedures are proposed to handle these models in an agreeable solution quality and computational time. The computational experience of Turkish dataset was presented for better illustration of proposed model. And a special application on Iranian hub airports location is discussed.

An M/M/c queue model for hub covering location problem

The hub location problem appears in a variety of applications including airline systems, cargo delivery systems, and telecommunication network design. Hub location problems deal with finding the location of hub facilities and the allocation of demand nodes to these located hub facilities. We consider a hub-and-spoke network problem with crowdedness or congestion in the system. The transportation time and the rate of arrived trucks to each hub are random variables. In addition, a hub cannot service all trucks simultaneously and it has some restrictions like capacity constraint and the service time limitations. Hubs, which are the most crowded parts of network, are modeled as M/M/c queuing systems. In the application of the proposed model for a cargo transportation system, the number of trucks follows Poisson probability distribution in the queuing system. In this paper at first a nonlinear mathematical programming is presented to find an optimal solution for the considered problem. A probabilistic constraint is included to ensure that the probability of b trucks in a queue is less than a threshold value θ for each hub. Then, we transfer the introduced nonlinear constraints of the mathematical programming model to the linear constraints. Due to the computational complexity of the resulted model, we propose an improved meta-heuristic based on Imperialist Competitive Algorithm and Genetic Algorithm to find near optimal solution of the problem. The performance of the solutions found by the proposed improved meta-heuristic is compared with those of pure GA and those of the mathematical programming model.

A multi-objective imperialist competitive algorithm for a capacitated hub covering location problem

Article history: Received 20 October 2010 Received in revised form 20 December 2010 Accepted 28 December 2010 Available online 28 December 2010 The hub location problem appears in a variety of applications, including airline systems, cargo delivery systems and telecommunication network design. Hub location problems deal with finding the location of hub facilities and the allocation of demand nodes to these located hub facilities. In this paper, a new model for the capacitated single allocation hub covering location problem is presented. Instead of using capacity constraints to limit the amount of flow received by the hubs, the second objective function is introduced to minimize service times in the hubs. The service time in the hubs includes the waiting time of received flows in a queue and the time to get services. Due to the NP-hardness of the problem, a new weight-based multi-objective imperialist competitive algorithm (MOICA) is designed to find near-optimal solutions. To validate the performance of the proposed algorithm, the solutions obtained by the MOICA are compared by the exact solutions of the mathematical programming model. © 2011 Growing Science Ltd. All rights reserved

МетодикА формуваннЯ альтернативниХ транспортно-теХнологічниХ систеМ доставкИ ВантажіВ

The choice model of optimum transport-technological cargo delivery system is presented. The forming mechanism of alternative cargo delivery systems aggregate is described

In vitro assembly of cubic RNA-based scaffolds designed in silico.

The organization of biological materials into versatile three-dimensional assemblies could be used to build multifunctional therapeutic scaffolds for use in nanomedicine. Here we report a strategy to design three-dimensional nanoscale scaffolds that can be self-assembled from RNA with precise control over their shape, size and composition. These cubic nanoscaffolds are only ~13 nm in diameter and are composed of short oligonucleotides making them amenable to chemical synthesis, point modifications and further functionalization. Nanocube assembly is verified by gel assays, dynamic light scattering and cryogenic electron microscopy. Formation of functional RNA nanocubes is also demonstrated by incorporation of a light-up fluorescent RNA aptamer that is optimally active only upon full RNA assembly. Moreover, we show the RNA nano-scaffolds can self-assemble in isothermal conditions (37°C) during in vitro transcription, which opens a route towards the construction of sensors, programmable packaging and cargo delivery systems for biomedical applications.

The latest arrival hub location problem for cargo delivery systems with stopovers

In this paper, we concentrate on the service structure of ground-transportation based cargo delivery companies. The transient times that arise from nonsimultaneous arrivals at hubs (typically spent for unloading, loading, and sorting operations) can constitute a significant portion of the total delivery time for cargo delivery systems. The latest arrival hub location problem is a new minimax model that focuses on the minimization of the arrival time of the last item to arrive, taking into account journey times as well as the transient times at hubs. We first focus on a typical cargo delivery firm operating in Turkey and observe that stopovers are essential components of a ground-based cargo delivery system. The existing formulations of the hub location problem in the literature do not allow stopovers since they assume direct connections between demand centers and hubs. In this paper, we propose a generic mathematical model, which allows stopovers for the latest arrival hub location problem. We improve the model using valid inequalities and lifting. We present computational results using data from the US and Turkey.

A hub covering model for cargo delivery systems

AbstractThe hub location problem appears in a variety of applications including airline systems, cargo delivery systems, and telecommunication network design. When we analyze the application areas separately, we observe that each area has its own characteristics. In this research we focus on cargo delivery systems. Our interviews with various cargo delivery firms operating in Turkey enabled us to determine the constraints, requirements, and criteria of the hub location problem specific to the cargo delivery sector. We present integer programming formulations and large‐scale implementations of the models within Turkey. The results are compared with the current structure of a cargo delivery firm operating in Turkey. © 2006 Wiley Periodicals, Inc. NETWORKS, Vol. 49(1), 28–39 2007

The Latest Arrival Hub Location Problem

The traditionally studied hub location problems in the literature pay attention to flight times but not to transient times spent at hubs for unloading, loading, and sorting operations. The transient times may constitute a significant portion of the total delivery time for cargo delivery systems. We focus on the minimization of the arrival time of the last arrived item in cargo delivery systems and develop a model that correctly computes the arrival times by taking into account both the flight times and the transient times. Nonlinear and linear integer formulations are given and computational results are provided. The effects of delays on the system performance are analyzed.