Prediction of the biological effect of magnetically regulated drugs

Kinetic aspects of magnetically targeted drug transport are discussed. The influence of the magnetic drug carrier properties, the transported drug and the target organ parameters on the biological effect of the drug was investigated. A mathematical model reflecting mass transfer processes in the circulatory system was used for estimating the influence of these factors on the therapeutic effect of the drug delivered to the target. The nature of the effect of the drug release parameters, inactivation rate of the released drug in the blood and intensity of the carrier capture out of the target organ on the drug therapeutic action was revealed. Mathematical modeling of magnetically targeted drug kinetics was shown to provide prognostication of the drug effect and increasing of the experiment informative capacity.     

A freight network planning model in oligopolistic shipping markets

The paper presents a multi-level hierarchical approach which models the oligopolistic behavior of carriers in maritime freight transportation networks. With the merger of the carriers’ industry and some dominant carriers in today’s shipping markets, carrier competition frequently exhibits an oligopolistic nature. This study considers the following three types of carriers; ocean carriers, land carriers, and port terminal operators. The oligopolistic ocean carriers, land carriers, and port terminal operators compete with each other in their pricing and routing decisions. The carriers determine service charges and delivery routes at different parts of the multi-modal freight network, creating hierarchical relationships. When using a game theoretic approach, ocean carriers become the leaders in an oligopoly shipping market. When dealing with individual carrier problems, the Nash equilibrium reveals the optimal decision where each carrier obtains the greatest profit. A three-level model is formulated to capture the interactions among different types of carriers. The validity and capability of the model gets demonstrated through an empirical example.     

Magnetic nanoparticles for targeted vascular delivery

Magnetic targeting has shown promise to improve the efficacy and safety of different classes of therapeutic agents by enabling their active guidance to the site of disease and minimizing dissemination to nontarget tissues. However, its translation into clinic has proven difficult because of inherent limitations of traditional approaches inapplicable for deep tissue targeting in human subjects and a need for developing well-characterized and fully biocompatible magnetic carrier formulations. A novel magnetic targeting scheme based on the magnetizing effect of deep-penetrating uniform fields is presented as an example of a strategy providing a potentially clinically viable solution for preventing injury-triggered reobstruction of stented blood vessels (in-stent restenosis). The design of optimized magnetic carrier formulations and experimental results showing the feasibility of uniform field-controlled targeting for site-specific vascular delivery of small-molecule pharmaceuticals, biotherapeutics, and cells are discussed in the context of antirestenotic therapy. The versatility of this approach applicable to different classes of therapeutic agents exerting their antirestenotic effects through distinct mechanisms prompts exploring the utility of uniform field-mediated magnetic stent targeting for combination therapies with enhanced efficiencies and improved safety profiles. Additional improvements in terms of site specificity and protracted carrier retention at the site of injury may be expected from the development and use of magnetic carriers exhibiting affinity for arterial wall-specific antigens.     

The mechanism of interaction between high-affinity probes and the uridine transport system of mammalian cells.

The carrier of uridine transport in hamster cells in culture is highly susceptible to the inhibitory effect of probes like S-benzylated derivatives of mercaptopurine nucleosides. The interaction between the probes and the carrier is competitive and reversible and it takes place at a site different from the substrate binding site. The Ki for the most potent derivative p-nitrobenzyl-6-mercaptoinosine is 0.15 n Molar at 20 degrees C. The effect of the probes is interpreted in terms of conformational change induced on the carrier upon binding of the probe. The carrier assumes distinct conformations depending on whether it is probe-free (form A) or probe bound (form B). Kinetic as well as chemical evidence supports the predictions of the allosteric carrier model. A single component of kinetics is observed either in the absence of inhibitor (Km form A) or at high concentrations of inhibitor (Km form B). A two component kinetics is observed at intermediate concentrations of inhibitor (some carriers in form B and others in form A). The two forms have distinct Km values for uridine: form A50 muMolar and form B 250 muMolar. Two forms have also different susceptibilities to the action of organomercurials: form A is insensitive whereas form B is highly inhibited by the chemical modified of SH groups. The existence of putative allosteric sites in carriers is discussed in terms of modifier sites capable of modulating transport activities as a result of specific membrane-ligand interactions.     

微球载体固定化纤维素酶的反应动力学模型研究

建立了固定化纤维素酶的反应动力学模型,该模型以米氏方程为基础并考虑了产物竞争性抑制的影响。在此模型的基础上进行模拟,系统研究了产物竞争性抑制、内扩散限制、溶液中的宏观底物浓度、载体大小等因素对球形载体内部的底物、产物浓度分布和效率因子的影响。产物竞争性抑制的存在将增加载体颗粒内的底物浓度,对效率因子的影响较小。底物内扩散系数或者反应体系中底物浓度增大时,载体颗粒内的底物浓度和效率因子都将增大。载体粒径增大,载体颗粒内的底物浓度和效率因子均减小。     

Liposomes disposition in vivo V. Liposome stability in plasma and implications for drug carrier function

The kinetics of [¹⁴C]sucrose release from multilamellar liposomes of fixed diameter (approx. 0.23 μm) incubated in human plasma (serum and blood) were quantified. Composition was various ratios of phosphatidylcholine, phosphatidic acid and cholesterol with α-tocopherol included as antioxidant. Considerable intra-individual variability was noted for liposome stability in blood and its derived fluids, yet reproducible results were obtained for pooled samples. The destabilizing effects of plasma decreased with increasing lipid concentrations. Results of fitting a kinetic model to the data showed that four of five model parameters were linearly related to liposome cholesterol content. Liposomes depleted plasma of its destabilizing factors, and when pre-incubated with plasma were partially stabilized to the effects of a subsequent plasma addition. Plasma caused a rapid rise in liposome membrane permeability which then declined non-linearly, presumably because of a rearrangement of membrane lipids and adsorbed proteins to form their most stable configuration. the therapeutic availability of drugs administered encapsulated in liposomes, which can be governed by the kinetics of their in vivo extracellular release, may be directly proportional to - and predictable from - the time-course and extent of release in plasma. The kinetic model was used in conjuction with simple pharmacokinetic assumptions to show that the effectiveness of a liposome drug carrier cannot be predicted based simply on its plasma stability; more stable liposomes may not be more effective drug carriers. Interestingly, plasma-induced solute release from liposomes serendipitously mimics an important facet of ideal carrier behavior.     

Generalized plasma skimming model for cells and drug carriers in the microvasculature

In microvascular transport, where both blood and drug carriers are involved, plasma skimming has a key role on changing hematocrit level and drug carrier concentration in capillary beds after continuous vessel bifurcation in the microvasculature. While there have been numerous studies on modeling the plasma skimming of blood, previous works lacked in consideration of its interaction with drug carriers. In this paper, a generalized plasma skimming model is suggested to predict the redistributions of both the cells and drug carriers at each bifurcation. In order to examine its applicability, this new model was applied on a single bifurcation system to predict the redistribution of red blood cells and drug carriers. Furthermore, this model was tested at microvascular network level under different plasma skimming conditions for predicting the concentration of drug carriers. Based on these results, the applicability of this generalized plasma skimming model is fully discussed and future works along with the model’s limitations are summarized.     

Viscoelastic characterization and modeling of gelation kinetics of injectable in situ cross-linkable poly(lactide-co-ethylene oxide-co-fumarate) hydrogels

Cell transplantation by injection of biodegradable hydrogels is a recently developed strategy for the treatment of degenerated tissues. A cell carrier should be cytocompatible, have suitable working time and rheological properties for injection, and harden in situ to attain dimensional stability and the desired mechanical strength. Hydrophilic macromer/cross-linker polymerizing systems, due to the relatively high molecular weight of the macromer and its inability to cross the cell membrane, are very attractive as injectable cell carriers. The objective of this research was to determine the effects of cross-linker, initiator, and accelerator concentrations on the gelation kinetics and ultimate modulus of a biodegradable, in situ cross-linkable poly(lactide-co-ethylene oxide-co-fumarate) (PLEOF) macromer. The in situ polymerizing mixture consisted of PLEOF macromer, methylene bisacrylamide cross-linker, and a neutral redox initiation system of ammonium persulfate initiator and tetramethylethylenediamine accelerator. Measurement of the time evolution of the viscoelastic properties of the network during the sol-gel transition showed the important influence of each component on the gel time and stiffness of the hydrogels. A kinetic model was developed to predict the modulus as a function of composition. Model predictions were consistent with most of the experimental findings. The values of the storage and loss moduli at the gel point were found to be approximately equal for samples with equal PLEOF concentrations, resulting in a simple method to predict the gelation time based on the Winter--Chambon criterion, with the use of the proposed kinetic model. The results of this study can be coupled with component cytocompatibility measurements to predict the effect of composition on the viability of the cells encapsulated in the hydrogel matrix.     

Controlled Release of Doxorubicin from Magnetoliposomes Assisted by Low-Frequency Magnetic Field

The article presents magnetoliposomes as potential carriers of doxorubicin. The magnetic properties of nanoparticles embedded in liposomes enable the targeting of drug-loaded carriers to cancer cells and subsequent release of their payload using an external alternating magnetic field as a trigger. The cytotoxicity of empty and doxorubicin-loaded magnetoliposomes in the absence and after exposure to magnetic field was evaluated in cancerous and normal breast cells. The characteristic shows the carrier with size distribution <130 nm, slightly negative zeta potential and polydispersity index <0.2. Doxorubicin was encapsulated in magnetoliposomes with an efficiency of 31 % and released in the presence of an alternating magnetic field at 50 %. Magnetoliposomes with drug provided high cytotoxic effect on tumor cells and low cytotoxic effect on normal cells. The research conducted in this article may indicate the potential application of the studied magnetoliposomes in release of drugs under the influence of magnetic field in cancer cells.     

Kinetics of the immobilization of trypsin on activated silichrome

Trypsin is studied for kinetics of its immobilization on the surface of a porous spheric inorganic carrier with the grafted aldehyde groups in the surface layer. This process is found to be controlled by the enzyme diffusion. It is shown possible to use a body of mathematics known for kinetics of physical adsorption on the porous adsorbents to describe kinetics of protein chemosorption on the analogous carriers. A simple method is suggested for plotting a kinetic curve of the enzyme immobilization on the matrix with any sizes of particles from the experimentally obtained kinetic curve of its binding on the carrier with a definite diameter of particles.     

In vivo accumulation of self-assembling dye Congo red in an area marked by specific immune complexes: possible relevance to chemotherapy

Supramolecular micellar structures have been proposed as carriers in aim-oriented drug transportation to a target marked by specific immune complexes. In this study, the self-assembling dye Congo red was used as a model supramolecular carrier and its accumulation in the target was studied in vivo. The target was created in vivo as the local specific inflammation provoked by subcutaneous injection of antigen to the ear of a previously immunized rabbit. The color caused by accumulation of Congo red after its intravenous injection was registered by pictures of the ear with suitably filtered visible light shining through it to distinguish Congo red against the background color of hemoglobin. The results confirmed the expected accumulation and retention of Congo red in the inflammation area marked by deposits of specific immune complexes. The role of albumin and its possible interference with transportation of drugs through the blood by supramolecular carriers was also subjected to preliminary examination. The results revealed that albumin collaborates rather than interferes with drug transportation; this is another factor making the use of supramolecular carriers for aim-oriented chemotherapy highly promising.     

A theoretical approach to the analysis of axonal transport.

A theoretical model of intra-axonal transport is proposed that presupposes a carrier system moving down the axon in a distal direction. Protein and particle transport is achieved by their reversible association with the distally moving carriers. Mathematical equations representing the concentrations of moving carriers and proteins and/or particles within the axon at any position and time are proposed. Analysis of the equations demonstrates that a traveling wave solution for the particle concentration (an experimental fact) is possible provided the chemical interaction between particles and carriers exhibits positive cooperativity. The phase velocity of the wave solution is interpreted as the observed velocity of the intra-axonal transport, known to be independent of position of observation. In addition, the theory predicts a spectrum of transport velocities for different proteins, in agreement with observations. The velocity of a given protein is dependent on its affinity to the carrier.     

Development of the Method of Magnetic Neutron Capture Therapy of Cancer

The method of magnetic neutron capture therapy (MNTC) of cancer can be described as a combination of two methods: the targeted delivery of drugs using magnetic carriers and the proper neutron capture therapy which consists in tumor irradiation with thermal neutrons following the delivery of ¹⁰B compounds to the tumor site. Two-component ultradispersed particles containing Fe and C were tested as magnetic adsorbents of boron phenylalanine and borax. The quantities of absorbed borax proved sufficient for high concentration of boron atoms at the tumor site. The kinetics of boron release to saline substantiates the application of Fe-B (10%) ultradispersed particles for efficient MNTC. Both particle types have high magnetization and magnetic homogeneity, can form stable magnetic suspensions, and have low toxicity.__________Translated from Izvestiya Akademii Nauk, Seriya Biologicheskaya, No. 4, 2005, pp. 448–452.Original Russian Text Copyright © 2005 by Kuznetsov, Podoinitsyn, Filippov, Komissarova.     

High proportion of mutant osteoblasts is compatible with normal skeletal function in mosaic carriers of osteogenesis imperfecta

Individuals with mosaicism for the autosomal dominant bone dysplasia osteogenesis imperfecta (OI) are generally identified by having more than one affected child. The mosaic carriers have both normal and mutant cell populations in somatic and germline tissues but are unaffected or minimally affected by the type I collagen mutation that manifests clinically in their heterozygous offspring. We determined the proportion of mutant osteoblasts in skeletal tissue of two mosaic carriers who each have a COL1A1 mutation in a high proportion of dermal fibroblasts. Both carriers had normal height and bone histology; the first carrier had normal lumbar spine measurements (L1-L4), as determined by dual-energy x-ray absorptiometry (Z = +1.17). In cultured cells from the first carrier, studied by labeled PCR and single-cell PCR over successive passages, the collagen mutation was present in 85% of fibroblasts and 50% and 75% of osteoblasts from her right iliac crest and left patella, respectively, with minimal selection. The second carrier was studied by PCR amplification of DNA from autopsy paraffin blocks. The proportion of heterozygous cells was 40% in calvarium, 65% in tracheal ring, and 70% in aorta. Thus, in OI, substantially normal skeletal growth, density, and histology are compatible with a 40%-75% burden of osteoblasts heterozygous for a COL1A1 mutation. These data are encouraging for mesenchymal stem-cell transplantation, since mosaic carriers are a naturally occurring model for cell therapy.     

Human Mitochondrial Transmembrane Metabolite Carriers: Tissue Distribution and Its Implication for Mitochondrial Disorders

Mitochondrial transmembrane carrier deficiencies are a recently discovered group of disorders, belonging to the so-called mitochondriocytopathies. We examined the human tissue distribution of carriers which are involved in the process of oxidative phosphorylation (adenine nucleotide translocator, phosphate carrier, and voltage-dependent anion channel) and some mitochondrial substrate carriers (2-oxoglutarate carrier, carnitine-acylcarnitine carrier, and citrate carrier). The tissue distribution on mRNA level of mitochondrial transport proteins appears to be roughly in correlation with the dependence of these tissues on mitochondrial energy production capacity. In general the main mRNA expression of carriers involved in mitochondrial energy metabolism occurs in skeletal muscle and heart. Expression in liver and pancreas differs between carriers. Expression in brain, placenta, lung, and kidney is lower than in the other tissues. Western and Northern blotting experiments show a comparable HVDAC1 protein and mRNA distribution for the tested tissues. Patient's studies showed that cultured skin fibroblasts may not be a reliable alternative for skeletal muscle in screening for human mitochondrial carrier defects.     

Investigation of the Spatiotemporal Responses of Nanoparticles in Tumor Tissues with a Small-Scale Mathematical Model

The transport and accumulation of anticancer nanodrugs in tumor tissues are affected by many factors including particle properties, vascular density and leakiness, and interstitial diffusivity. It is important to understand the effects of these factors on the detailed drug distribution in the entire tumor for an effective treatment. In this study, we developed a small-scale mathematical model to systematically study the spatiotemporal responses and accumulative exposures of macromolecular carriers in localized tumor tissues. We chose various dextrans as model carriers and studied the effects of vascular density, permeability, diffusivity, and half-life of dextrans on their spatiotemporal concentration responses and accumulative exposure distribution to tumor cells. The relevant biological parameters were obtained from experimental results previously reported by the Dreher group. The area under concentration-time response curve (AUC) quantified the extent of tissue exposure to a drug and therefore was considered more reliable in assessing the extent of the overall drug exposure than individual concentrations. The results showed that 1) a small macromolecule can penetrate deep into the tumor interstitium and produce a uniform but low spatial distribution of AUC; 2) large macromolecules produce high AUC in the perivascular region, but low AUC in the distal region away from vessels; 3) medium-sized macromolecules produce a relatively uniform and high AUC in the tumor interstitium between two vessels; 4) enhancement of permeability can elevate the level of AUC, but have little effect on its uniformity while enhancement of diffusivity is able to raise the level of AUC and improve its uniformity; 5) a longer half-life can produce a deeper penetration and a higher level of AUC distribution. The numerical results indicate that a long half-life carrier in plasma and a high interstitial diffusivity are the key factors to produce a high and relatively uniform spatial AUC distribution in the interstitium.     

An Evaluation of Irreversible Inhibition of Synaptosomal High-Affinity Choline Transport by Choline Mustard Aziridinium Ion

Abstract: Choline mustard aziridinium is a potent, irreversible and selective blocker of sodium-dependent, high-affinity transport of choline into rat forebrain synaptosomes; it was found to be 30 times less potent against low-affinity transport of choline. The IC₅₀ value for high-affinity transport was 0.94 μM, compared to 29 μM for low-affinity uptake. The inhibitory action of choline mustard aziridinium ion on high-affinity transport of choline was graded with respect to time; a 12-fold increase in potency was obtained by increasing the inhibitor preincubation times from 1 to 30 min. Low concentrations of choline mustard aziridinium ion could produce significant blockade of choline carriers providing the exposure time was prolonged. The characteristics of the blockade of synaptosomal high-affinity choline transport by choline mustard aziridinium ion also changed depending upon preincubation time. The kinetics of inhibition of high-affinity choline transport by choline mustard aziridinium ion showed apparent competitive inhibition initially, followed by noncompetitive characteristics at longer preincubations with inhibitor. The rate of irreversible inhibition of carriers by this nitrogen mustard analogue would appear to be rapid; the rate constant was determined to be 5 × 10^?2 s^?1for micromolar concentrations of inhibitor. This action may preclude the transport of the mustard analogue into the nerve terminal, although initially some reversible binding with the carrier may result in the translocation of some choline mustard aziridinium ion into the presynaptic ending. The progressive alkylation of high-affinity carriers by the analogue could indicate the presence of excess carrier sites in the presynaptic membrane, or subpopulations of carriers in an inactive state in equilibrium with active carriers. A model is described for the inhibitory action of choline mustard aziridinium ion on synaptosomal high-affinity choline carriers.     

Secretory cargo regulates the turnover of COPII subunits at single ER exit sites

The COPII coat complex mediates the formation of transport carriers at specialized sites of the endoplasmic reticulum (ERES). It consists of the Sar1p GTPase and the Sec23/24p and the Sec13/31p subcomplexes . Both stimulate the GTPase activity of Sar1p , which itself triggers coat disassembly. This built-in GAP activity makes the COPII complex in principle unstable and raises the question of how sufficient stability required for cargo capture and carrier formation is achieved. To address this, we analyzed COPII turnover at single ERES in living cells. The half times for Sar1p, Sec23p, and Sec24p turnover are 1.1, 3.7, and 3.9 s, respectively. Decreasing the amount of transport-competent cargo in the endoplasmic reticulum accelerates turnover of the Sec23/24p and slows down that of Sar1p. A mathematical model of COPII membrane turnover that reproduces the experimental in vivo FRAP kinetics and is consistent with existing in vitro data predicts that Sec23/24p remains membrane associated even after GTP hydrolysis by Sar1p for a duration that is strongly increased by the presence of cargo. We conclude that secretory cargo retains the COPII complex on membranes, after Sar1p release has occurred, and prevents premature disassembly of COPII during cargo sorting and transport carrier formation.