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Biomedical subjects

R L Magin

Publications and source records attributed to R L Magin.

At least 55 records · Page 3Linked to original sources
PubMed1989

Feasibility of blood flow measurement by externally controlled dye delivery.

We are developing a new method of delivering substances locally and repeatedly in the retinal vasculature under external control. This delivery system is based on encapsulating the substance in heat-sensitive lipsomes, which are injected intravenously and lysed by a heat pulse delivered by a laser. The feasibility of using this system with dyes and creating a sharp dye front was tested in vitro and in vivo. The results indicate that the background fluorescence of intact liposomes is minimal but in contrast a dramatic increase in fluorescence is achieved where the dye is released. In vivo tests indicated that only the selected vascular branch fluoresced. Moreover, a sharp dye front could be obtained repeatedly and preserved over significant distances. The presence of a sharp dye front allowed measurements, in vitro, of blood velocity which correlated well (r = 0.985, P less than 0.001) with the average blood velocity values calculated from the known flow rate.

Animals↗
PubMed1988

Modulation of water proton relaxation rates by liposomes containing paramagnetic materials.

Liposomes containing paramagnetic chemicals have significant potential for enhancing the effectiveness and selectivity of contrast agents in magnetic resonance imaging. We have studied the interactions of water, liposomes, and contrast agents using NMR and ESR. We find that the permeability of liposomes to water is of major importance in determining the effects of these systems on water proton relaxation. Key factors include (1) liposome composition, which determines the phospholipid membrane phase behavior as a function of temperature; (2) liposome structure (unilamellar or multilamellar); (3) location of the contrast agent in the liposome (aqueous space or lipid membrane); and (4) binding of contrast agents by liposomes. By appropriate selection of these factors it is possible to obtain effective proton relaxation enhancement in a manner suitable for particular experimental or clinical needs for contrast in MRI. For maximum relaxivity using lipophilic nitroxides, the optimum system appears to be 5-doxyl stearate in multilamellar vesicles with a membrane composition that gives a phase transition temperature slightly above body temperature.

Contrast Media↗
PubMed1988

Delivery of nitroxide spin label to cultured cells by liposomes.

The positively charged nitroxide spin label, 2,2,6,6-tetramethyl-piperidine-N-oxyl-4-trimethylammonium (Cat1), was encapsulated in two types of liposomes, phosphatidylserine/phosphatidylcholine (PS/PC) and phosphatidylserine/distearoylphosphatidylcholine/dipalmitoylphosphatidyl choline (PS/DSPC/DPPC). The liposomes were incubated with mouse thymus-bone marrow (TB) cells to study the uptake and metabolism of nitroxides entrapped in liposomes. The effects of temperature, metabolic inhibitors, and fixation of cells were investigated. The results indicate that different mechanisms are involved in the uptake of these two types of liposomes. PS/PC liposomes interact predominantely with the plasma membrane of TB cells and release Cat1 continuously, whereas the majority of PS/DSPC/DPPC liposomes are taken into the cells intact via endocytosis. These findings suggest that it may be possible to deliver nitroxides selectively, either to the membrane of cells or to their interior by manipulating the lipid composition of the liposomes. This study also found that the rate of reduction of Cat1 delivered using liposomes was increased under hypoxic conditions. Thus, the use of liposomes for in vivo delivery of nitroxides has the potential to provide NMR contrast that reflects different metabolic conditions.

Animals↗
PubMed1988

Externally triggered release of dye and drugs from liposomes into the eye. An in vitro and in vivo study.

Temperature-sensitive liposomes were made with carboxyfluorescein (CF) (100 mM) entrapped in the aqueous compartment. This liposome dye system was used in vitro to evaluate the feasibility of using microwaves as a triggering mechanism for the release of drugs in the anterior chamber of the eye. The in vitro study demonstrated that CF can be released from liposomes in response to a localized temperature rise induced by microwave irradiation. In an in vivo study in rabbits, CF and the antineoplastic agent, cytosine arabinoside, were administered intravenously and selectively released by increasing the temperature of the ciliary body with microwaves. In the eyes receiving liposome-encapsulated dye, the average concentration of CF in the anterior chamber of the heated eyes was 8.0 times higher than in the contralateral unheated control eyes. In the eyes receiving liposome-encapsulated drug, the average concentration of cytosine arabinoside in the aqueous of the heated eyes was 4.1 times higher than the concentration in the contralateral unheated control eyes. The importance of this finding lies in the potential for a new method of targeting the delivery of dyes and drugs to specific sites in the eye.

Animals↗
PubMed1988

A potential method for local drug and dye delivery in the ocular vasculature.

We propose a new drug and dye delivery system that would allow repeated release of substances in the ocular vasculature by an externally controlled mechanism. The substances are encapsulated in heat-sensitive liposomes, which are lysed by locally applying a heat pulse produced by an argon laser. The system was tested by investigating the release of carboxyfluorescein encapsulated in the liposomes. The liposome suspension was incubated at 37 degrees or 38.5 degrees C and irradiated at different powers and pulse durations. The amount of dye released was monitored by fluorophotometry and compared with the concentration obtained when the liposomes were lysed at their transition temperature of 41 degrees C. The results showed that 85% of the encapsulated substance can be released. Moreover, a dramatic contrast was observed between the fluorescence before and after the lysis. Presently the energy density is higher than but close to the maximal permissible exposure for humans. The release mechanism with the short laser pulse appeared to be similar to that present when liposomes were heated slowly.

Coloring Agents↗
PubMed1987

Effects of divalent cations on the ultrasonic absorption coefficient of negatively charged liposomes (LUV) near their phase transition temperature.

The ultrasonic absorption coefficient per wavelength (alpha lambda), as a function of temperature and frequency, was determined for large unilamellar vesicles (LUV) in the vicinity of their phospholipid phase transition temperature, using a double crystal acoustic interferometer. (The vesicles were composed of a 4:1 (w/w) mixture of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG). It has been found that alpha lambda reaches a maximum (alpha lambda)max at the phase transition temperature (tm) of the phospholipids in the bilayer, at an ultrasonic relaxation frequency of 2.1 MHz. Divalent cations (Ca2+ and Mg2+), added to LUV suspensions, shifted (alpha lambda)max to higher temperatures, dependent upon the concentration of divalent cation. It was also found that the shape of the alpha lambda versus t curve was significantly changed, representing changes in the Van't Hoff enthalpy of the transition, and therefore, the cooperative unit of the transition. This suggests that divalent cations interact individually with the negatively charged phospholipid headgroups of DPPG and with DPPC headgroups, thus decreasing the cooperative unit of the transition. The observed upward shift in tm suggests an interaction that increases the activation energy and, therefore, the temperature of the phase transition. However, alpha lambda as a function of frequency did not change with the addition of divalent cations and, thus, the relaxation time of the event responsible for the absorption of ultrasound is not changed by the addition of divalent cations.

Calcium↗
PubMed1986

Liposome delivery of NMR contrast agents for improved tissue imaging.

Large unilamellar liposomes containing the paramagnetic contrast agent manganese chloride were shown to selectively enhance the intensity of the proton NMR signal from the livers of experimental mice. The kinetics of the observed effect indicate that the liposomes are rapidly removed from the circulation and deposited in high concentration within the liver. This process is known to involve the phagocytic activity of macrophages. These results show that liposomes could provide a useful and efficient vehicle for delivering NMR contrast agents to organs like the liver, spleen, and bone marrow. It may also be possible to use liposomes to selectively deliver contrast agents to tissue regions of developing pathology that are rich in macrophage activity.

Animals↗
PubMed1986

Effect of vesicle size on the clearance, distribution, and tumor uptake of temperature-sensitive liposomes.

The blood clearance, tissue distribution, and tumor uptake of temperature-sensitive liposomes containing the anticancer drug cytosine [3H]-1-beta-D-arabino-furanoside (Ara-C) or [3H]-methotrexate (MTX) were measured. Large unilamellar liposomes composed of a mixture of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol (4:1 by weight) were formed by reverse-phase evaporation and sequentially extruded through polycarbonate membranes with pore sizes of 0.4, 0.2, 0.1, 0.08, and 0.05 micron. The liposomes were injected intravenously via the tail vein into B6D2F1 mice containing solid tumors (M5076 ovarian carcinoma) implanted in both hind feet. Drug release, organ distribution, and tumor uptake were studied during and following local hyperthermia treatments (42 degrees C, 60 minutes). Local hyperthermia increased the relative amount of liposome encapsulated drug delivered to a heated solid tumor compared with the unheated control. The clearance studies showed that liposome blood clearance was inversely proportional to liposome size. However, tumor uptake was not significantly affected by reducing liposome size. In addition, for the range of liposome sizes studied, the majority of the liposome encapsulated drug was found in the liver, spleen, and kidney; not in the heated tumor.

Animals↗
PubMed1986

Magnetic field-induced drug permeability in liposome vesicles.

Liposome vesicles maintained in a uniform static magnetic field release a chemotherapeutic drug (ARA-C, MW = 243) at temperatures approaching the phase-transition region where these liposomes are not normally leaky. Drug release is rapid, and a maximum difference between treated and unexposed liposomes of 30% of the total maximal release of ARA-C was observed within 1 min in a magnetic field. Dose-effect studies conducted between 0.01 and 7.5 T (1 T = 10(4) G) reveal that this permeability effect has a sigmoidal dependence on magnetic flux density. The ED50 is 15 mT, with a 95% confidence interval of 6.50-34.9 mT. Magnetic field exposures were conducted using a superconducting magnet with the liposomes maintained at +/- 0.08 degrees C. For comparison, samarium-cobalt permanent magnets induced a comparable drug release at 0.4 T. These results indicate that a static magnetic field of 10 mT or greater can increase passive transport in phospholipid membrane bilayers maintained at or near their membrane phase-transition temperature. Lipid clustering which occurs at prephase-transition temperatures may predispose phospholipid domains to diamagnetic orientation in a magnetic field and thereby facilitate drug release.

Cytarabine↗
PubMed1985

Ultrasonic absorption and permeability for liposomes near phase transition.

The specific ultrasonic absorption coefficient per wavelength as a function of temperature in the vicinity of the phase transition of liposomes, composed of a 4:1 mixture of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG), of different sizes was determined using an acoustic interferometer. Small unilamellar vesicles (SUV) and multilamellar vesicles (MLV) yielded results similar to those in the literature, viz., an absorption maximum at the transition temperature. Seven intermediate sizes including several size distributions of large unilamellar vesicles (LUV) were studied, yielding information on size dependencies of the temperatures at which the peaks occur, the widths at half peak amplitude, and the peak amplitudes. All liposome sizes except the SUV exhibited approximately the same transition temperature as did the largest MLV. The widths of the peaks were inversely related to liposome size, with a strong dependence for the smallest vesicles and an approach to independence for the largest vesicles. The amplitudes of the peaks exhibited a general increase with size with two exceptions, viz., the SUV and the vesicles with average diameters of 90-100 nm. It was also found that the membrane permeability increased near the transition temperature. The temperature dependencies of ultrasonic absorption and membrane permeability are compared.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1985

Microwave-stimulated drug release from liposomes.

Microwaves (2450 MHz) are shown to stimulate the release of an aqueous chemotherapeutic drug from phospholipid vesicles. This effect occurs at temperatures below the membrane phase transition temperature of 41 degrees C where these liposomes are normally not leaky. In buffered saline, microwave exposure (60 mW/g) triggers the onset of drug release at 33 degrees C, whereas in plasma a near maximal release is observed as low as 27 degrees C. Significantly, this drug release is enhanced by oxygen and is attenuated by antioxidants. These results demonstrate that phospholipids in artificial membranes devoid of protein are influenced by nonionizing electromagnetic radiation, and that this interaction can be modulated by two physiologically important factors, plasma and oxygen. Such a permeability effect may provide a means for investigating microwave interactions with ordered membrane bilayers.

Antioxidants↗
PubMed1984

Ultrasonic evidence for structural relaxation in large unilamellar liposomes.

The ultrasonic absorption of large unilamellar vesicles (average diameter 0.2 micron) was determined in the frequency range 0.5-5 MHz. The liposomes were composed of a 4:1 mixture by weight of dipalmitoyl phosphatidylcholine and dipalmitoyl phosphatidylglycerol. They were studied with and without cholesterol or gramicidin incorporated into the bilayer. A large increase in absorption occurs at the solid to liquid-crystalline phase transition temperature (42 degrees C) of the pure lipid vesicles. This increase in absorption is interpreted as a structural relaxation of the 'melting' fatty acid chains occurring with an average relaxation time of 76 ns. The liposomes were also found to be extremely permeable near the transition temperature. Essentially complete release of cytosine arabinoside, a small water-soluble molecule, occurred at 42 degrees C. Addition of cholesterol or gramicidin to the bilayer of the liposomes broadened the ultrasonic absorption and reduced the efflux of cytosine arabinoside at the phase transition. No increase in absorption was observed at the transition temperature in the presence of 50 mol% of cholesterol. Gramicidin, in addition to broadening the transition, slows the isomerization of bonds in the hydrocarbon chains of the lipids. A concentration of 5 mol% gramicidin increased the average relaxation time to 211 ns.

Cytarabine↗
PubMed1984

Temperature-dependent permeability of large unilamellar liposomes.

The temperature-dependent drug leakage from liposomes composed of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol (4:1, by weight) was studied. Experiments were performed in Hepes buffer and 50% fetal calf serum. Large unilamellar liposomes were formed by the reverse phase evaporation process and extruded through a series of polycarbonate membranes with pore sizes of 0.4, 0.2, 0.1 and 0.08 micron. The release of the water soluble radioisotopes cytosine 1-beta-D-[3H]arabinofuranoside and [3H]inulin from the aqueous compartment of these liposomes was measured as a function of time and temperature. Both radioisotopes were released at temperatures near 42 degrees C, the solid-to-liquid-crystalline phase transition temperature of these lipids. The percent drug release decreased as the size of the liposomes was reduced. This effect was more pronounced in Hepes buffer than serum. The release of both radioisotopes was greatest at 40 degrees C in Hepes buffer and at 43 degrees C in 50% fetal calf serum. In addition, the rate of drug release was much faster in serum than in buffer. These results suggest that different drug release processes are occurring in buffer and in serum.

Carbon Radioisotopes↗
PubMed1984

Electromagnetic dosimetry in a Crawford cell: 225 to 500 MHz.

A Crawford cell exposure chamber (main section 30 cm square) was used for electromagnetic dosimetry in the 225 to 500 MHz frequency range. Electric field patterns were measured within the cell. No higher-order modes were observed at any of the frequencies studied below 500 MHz, but significant field perturbations were seen at 2450 MHz. Energy absorption in a prolate spheroidal hamster phantom and in saline-filled spheres of various sizes was measured. The normalized whole-body specific absorption rate (SAR) in watts/kg per mW/cm2 increased from 0.11 (at 225 MHz) to 0.42 (at 450 MHz) for the hamster phantom in E polarization, from 0.06 (at 325 MHz) to 0.20 (at 500 MHz) for K polarization, and from 0.03 (at 325 MHz) to 0.12 (at 500 MHz) for H polarization. Although these values exceed predictions from the long-wavelength far-field approximation for power absorption, the measured SARs were corroborated directly using calorimetry. In addition, calorimetric data obtained using saline-filled spheres suggests that absorbed power in a Crawford cell converges to the far-field plane wave theoretical values only for objects occupying less than 20% of the vertical dimension from the septum to the outer wall.

Electromagnetic Fields↗
PubMed1984

Temperature-dependent drug release from large unilamellar liposomes.

The drug-release properties of large unilamellar liposomes were measured at temperatures near the lipid's phase-transition temperature. The liposomes were formed from a mixture of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol (4:1 by weight) by the reverse-phase evaporation process. These liposomes captured 25-35% of the radiolabeled anticancer drug cytosine [3H]-1-beta-arabinofuranoside in their aqueous compartment. They were stable in serum below the lipid's phase-transition temperature of 41 degrees C. Complete drug release occurred within seconds after the liposomes reached a temperature of 43 degrees C in serum. Addition of cholesterol or phosphatidylglycerol to the liposomal membrane reduced the drug-release temperature and broadened the range of drug release. These results show that suspensions of large unilamellar liposomes can be made to encapsulate a therapeutically useful quantity of drug that is rapidly and completely released at 43 degrees C in serum.

Blood↗
PubMed1983

Rapid measurement of drug release from temperature-sensitive liposomes by electron paramagnetic resonance and radioisotope techniques.

We have developed two new methods for quantifying drug release from temperature-sensitive liposomes. Large unilamellar vesicles were made by the reverse phase evaporation process. They contained a water-soluble electron paramagnetic resonance probe, trimethyl-4-amino-2,2,6,6-tetramethyl piperidine N-oxyl and the radioisotope cytosine-[3H]1-beta-D-arabinofuranoside in their aqueous compartment. Release of the electron paramagnetic resonance probe was measured by placing the liposomes in a solution of a spin label quenching agent, potassium ferricyanide, and monitoring the reduction in signal strength. The measurement of radioisotope released involved rapid ultracentrifugation of the liposomes after which the supernatant was tested for the presence of radioactivity. Both methods were found to be rapid and convenient ways of measuring drug release from temperature-sensitive liposomes and both methods gave comparable results. The radioisotope assay provides a direct measurement of drug leakage, whereas the electron spin resonance assay provides a continuous marker for liposome stability as a function of temperature.

Cytarabine↗