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Biomedical subjects

J G Riess

Publications and source records attributed to J G Riess.

At least 19 recordsLinked to original sources
PubMed1996

Vesicles made of glycophospholipids with homogeneous (two fluorocarbon or two hydrocarbon) or heterogeneous (one fluorocarbon and one hydrocarbon) hydrophobic double chains.

The vesicle-forming ability of the new anionic double chain glycophospholipids 1-4, with either two hydrocarbon or two perfluorocarbon chains, or a mixed double chain (one fluorinated, one hydrogenated), was investigated. When dispersed in water, 1a-c,e, 2b,c and 4b,c readily gave heat-sterilizable vesicles, 30-70 nm in diameter. The galactose and mannose-based fluorinated vesicles were also highly stable on aging. The 6-substituted glucose derivatives 3 formed tubules that reversibly interconverted into vesicles, depending on temperature. The leakage rate in buffer of carboxyfluorescein or calcein from vesicles made from 1a-c,e 2b,c and 4b,c depended on the sugar (t1/2 galactose > mannose > glucose). It decreased significantly with increasing fluorination and length of the hydrophobic tails. The mixed perfluorocarbon/hydrocarbon-tailed amphiphiles were found to be miscible with both the two fluorocarbon chains and the two hydrocarbon chains derivatives. Such admixing tended, however, to increase the small unilamellar vesicles' permeability. In buffered serum, all the vesicles investigated were highly permeable, but incorporation of cholesterol or DSPC in vesicles made of 1e significantly reduced their permeability in serum. The new vesicle and membrane components have i.v. maximum tolerated doses as high as 500 mg/kg body weight in mice; hemolytic activity sharply decreases with increasing degree of fluorination.

Animals↗
PubMed1995

Hydrolysis of DMPC or DPPC by pancreatic phospholipase A2 is slowed down when (perfluoroalkyl) alkanes are incorporated into the liposomal membrane.

The effect of the incorporation of linear (perfluoroalkyl)alkanes (CmF2m + 1CnH2n + 1, FmHn) into liposomes made of DMPC or DPPC on the activity of porcine pancreatic phospholipase A2 was investigated. A large decrease in enzyme activity and modifications of the kinetic profile, especially at and above the phospholipid's phase transition temperature, were observed; both depend on the relative lengths of the phospholipid's fatty acid chains and of the Hn segment of the FmHn molecule. With DMPC Hn must have a minimum of 10 carbon atoms to be effective, as in F6H10, F8H10 and F4H12; F8H8 had no significant hydrolysis-rate-reducing effect. With DPPC Hn must have a minimum of 12 carbon atoms, as in F4H12, while F8H8, F6H10 and F8H10 were ineffective. The absence of effect when C10H22 or C16H34 was incorporated establishes that the fluorinated segment, although its length (from C4 to C8) is not crucial, is required to hinder hydrolysis by PLA2, indicating that this segment plays an important role in structuring the liposomal membrane.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Fluorinated phosphatidylcholine-based liposomes: H+/Na+ permeability, active doxorubicin encapsulation and stability, in human serum.

The active encapsulation of doxorubicin (DOX) into fluorinated liposomes, the stability of these liposomes with respect to encapsulated DOX release in buffer and in human serum, and their H+/Na+ membrane permeability have been investigated and compared to those of their conventional hydrogenated analogues. These fluorinated liposomes are made from highly fluorinated phosphatidylcholines and contain a fluorinated core within their membrane. We found that the presence of this fluorinated core is not a barrier for the active encapsulation of DOX. Efficient (> 90%) and stable loading could be achieved using a transmembrane ammonium sulfate or even, in the absence of Na+, a transmembrane pH gradient. The higher H+/Na+ permeability found for the fluorinated membranes, as compared to conventional ones, is responsible for the lower stability observed for the DOX-loaded fluorinated liposomes when incubated in a physiological buffer (PBS) or in human serum. It is also noticeable that the retention of DOX is increased in human serum and for the liposomes whose membranes are in a gel or in a semi-fluid semi-gel state at 37 degrees C.

Doxorubicin↗
PubMed1994

Vesicles and other supramolecular systems from biocompatible synthetic glycolipids with hydrocarbon and/or fluorocarbon chains.

A series of double-tailed hydrocarbon and/or fluorocarbon glycolipids derived from galactose and glucose have been prepared. These compounds were obtained upon opening a lactono- and maltonolactone moiety by the amino group of either a glycine, glycylglycine or lysine residue. The carboxyl terminus of the glycyl and glycylglycine conjugates was further reacted with the appropriate double-tailed amine. In the case of lysine, the lactonamide conjugate was functionalized with a hydrocarbon and/or fluorocarbon fatty amine and acid, respectively. The ability of such glycolipids to disperse in water, the morphology of self-assemblies formed and the stability of the supramolecular structure obtained were shown to depend on the presence or absence and on the nature of the aminoacid spacer. Most of the compounds described were shown by conventional techniques (TEM, Cryo-TEM, LLS, etc.) to produce stable vesicular systems.

Animals↗
PubMed1994

Permeability and stability in buffer and in human serum of fluorinated phospholipid-based liposomes.

The stability (with respect to encapsulated carboxyfluorescein release) of fluorinated liposomes and their membrane permeability have been investigated in buffer and in human serum as compared to conventional hydrogenated analogues. These fluorinated liposomes are made from highly fluorinated phosphatidylcholines and contain a fluorinated core within their membrane. In buffer and in their fluid state, the fluorinated liposomes retain much more efficiently their entrapped content and display lower membrane permeability coefficients than any of their hydrogenated counterparts. This indicates that the fluorinated core acts as a very efficient barrier to permeation. In terms of molecular structure/permeability relationships, the thicker the fluorinated lipophobic core, the more efficient the barrier to permeation. In their gel state, the fluorinated core has, however, almost no effect on permeation. Interestingly, some of the 'fluid' fluorinated liposomes were even less permeable than 'gel' or 'gel-like' ones, including egg phosphatidylcholines/cholesterol liposomes. Human serum destabilizes the 'fluid' fluorinated liposomes but to a lesser extent than the 'fluid' hydrogenated ones, indicating that the fluorinated lipophobic core inside the liposomal membrane protects the vesicles, possibly by reducing their interactions with serum components. 'Gel' or 'gel-like' fluorinated liposomes are significantly more stable in serum than in buffer. They are also more stable than conventional 'gel' or 'gel-like' liposomes.

Blood↗
PubMed1994

Polymorphic phase behavior of perfluoroalkylated phosphatidylcholines.

The polymorphic phase behavior of the F-alkyl modified phosphatidylcholines FnCmPC with Fn = CnF2n + 1 and Cm = -(CH2)m- and the physicochemical properties of their aqueous dispersions have been investigated. We show that the supramolecular assemblies formed by F4C4PC, F6C4PC, F8C4PC and F4C10PC dispersed in water consist of liposomes. F6C10PC forms, as does F8C10PC, a ribbon-like phase (two-dimensional centered rectangular lattice) at 25 degrees C, but on heating, it forms a lamellar phase. Upon cooling, the lamellar gel phase is metastable and converts slowly back into the ribbon-like phase. Analyses of the dispersions before and after heat sterilization and upon storage at 25 degrees C reveal an exceptional stability of the FnCmPC-based liposomes which contrasts strongly with that of DPPC vesicles. This enhanced stability most likely arises from the increased hydrophobic character resulting from the presence of the perfluoroalkyl tails. The gel to fluid phase transition temperature of the FnCmPCs is found to be related to the total length of the hydrophobic chain and more markedly to the length of the perfluoroalkyl tail. This phase transition is first induced by the melting of the fluorocarbon chain. Each portion of the Fn tail and of the hydrocarbon spacer experiences intrinsic changes of molecular motion with temperature. The partitioning of a lipophilic/hydrophilic paramagnetic probe between the aqueous and lipidic phases present in the FnCmPC dispersions shows that an increase in fluorophilic character results in a lower solubility of the probe in the membrane, thus reflecting a dramatic decrease of the membrane's lipophilicity.

Calorimetry, Differential Scanning↗
PubMed1994

Biodistribution of mixed fluorocarbon-hydrocarbon dowel molecules used as stabilizers of fluorocarbon emulsions: a quantitative study by fluorine nuclear magnetic resonance (NMR).

19F NMR spectroscopy was used to determine quantitatively the organ distribution and organ retention time in rats of the mixed fluorocarbon-hydrocarbon dowel molecule C6F13CH = CHC10H21 (F6H10E), which stabilizes highly concentrated injectable fluorocarbon emulsions destined for in vivo oxygen transport and delivery. The only fluorine resonances detected in the 19F NMR spectra of the organs analyzed were those of the F6H10E dowel itself, indicating that metabolites, if present, have very low concentrations (< 10(-4) M, limit of our assay). The F6H10E content in the liver peaked 1 day after administration (7 days for the spleen). At a dose of 3.6 g/kg body weight, the half-life of F6H10E in the liver was 25 +/- 5 days.

Animals↗
PubMed1994

Current status of injectable oxygen carriers.

In this review the current status of what commonly are termed "blood substitutes" is discussed. The term blood substitute is a misnomer because the formulations under development at this time transport respiratory gases but do not perform the metabolic, regulatory, and protective functions of blood. Either hemoglobin or a perfluorochemical form the base to transport oxygen; the advantages and disadvantages of each base are discussed. The availability of a blood substitute in the U.S. will require approval by the Food and Drug Administration (FDA) and, by law, both its efficacy and safety must be demonstrated prior to approval. Showing efficacy of any blood substitute is complicated by the oxygen reserve and the compensatory mechanisms to acute blood loss in man. The challenge is to prove that the administration of these formulations offer clinical advantages compared with replacement of volume alone. Several efficacy models, the most attractive among them being perioperative hemodilution, should provide data that would bring these formulations into clinical practice. When hemoglobin is not within the favorable environment of the red cell, whether the hemoglobin is derived from expression vectors developed through recombinant biotechnology or from lysed human red cells, it acquires a left-shifted oxygen disassociation curve. Further, because the tetramer disassociates when injected intravenously and the resulting dimers are cleared rapidly from the circulation by the kidneys, intravascular dwell time is brief. Hemoglobins have been modified chemically and linked intramolecularly, intermolecularly, and to macromolecules to correct these problems. While these manipulations have normalized the p50 and extended the dwell time significantly, some toxicity problems remain unresolved. The binding of nitric oxide to hemoglobin preparations and the presumably resultant systemic and pulmonary hypertension observed in animals may be the most difficult to overcome, although the implications of these reactions in man is poorly understood. Perfluorochemicals (PFC) provide a fundamentally different and simpler approach to oxygen transport than hemoglobin formulations. Typically, the PFCs used are liquids composed of 8 to 10 carbon atoms that dissolve oxygen and obey Henry's law. Thus, the recipient's inspired oxygen and cardiac output assume importance. Because they are insoluble in water, PFCs are administered as emulsions, that is, as small droplets about 0.1 to 0.2 microns in diameter. In this respect, they are very similar to the lipid emulsions widely used for parenteral nutrition. Egg yolk phospholipid and poloxamers are most commonly used as emulsifiers. PFCs are not metabolized and are excreted unchanged by the lungs, following temporary storage by the monocyte-macrophage system (MMS).(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Substitutes↗
PubMed1994

Fluorinated vesicles.

Stable fluorinated vesicles--i.e. vesicles with a hydrophobic and lipophobic fluorinated film within their bilayer membranes--have been obtained from a variety of neutral, zwitterionic or anionic fluorinated amphiphiles, including single chain phosphocholine derivatives, double-chain phospholipids, glycolipids and glycophospholipids, as well as from combinations of standard phospholipids with amphiphilic mixed fluorocarbon/hydrocarbon compounds. The strong hydrophobic interactions developed by perfluoroalkyl chains result in increased membrane stability, as strikingly illustrated by the fact that even short single-chain fluorinated amphiphiles can form stable, heat-sterilizable vesicles without the need for any additive. They also result in increased versatility in the aggregation behavior of fluorinated surfactants, as shown by the formation, depending on molecular structure and experimental conditions, of a range of supramolecular assemblies other than vesicles, including disks, helical tubules and fibers, for example from fluorinated glycolipids. The more impermeable, adjustable fluorinated core within the liposomal membrane confers to liposomes added drug and probe encapsulation stability as compared to their hydrogenated analogs, whether in buffer or in serum. Fluorinated vesicles made from perfluoroalkylated phospholipids were also found to have 3 to 6 times longer circulation half-lives in mice than similarly sized conventional DSPC/cholesterol liposomes. Finally, the incorporation of mixed fluorocarbon/hydrocarbon alkanes or alkenes into standard liposomes may provide an alternative, straightforward and cost efficient approach to fluorinated vesicles.

Animals↗
PubMed1994

The design and development of improved fluorocarbon-based products for use in medicine and biology.

Fluorocarbons and other highly fluorinated materials offer considerable potential in diagnosis and therapeutics due to their unique physical properties, chemical inertness, capacity to transport oxygen and drugs, and ability to function as contrast agents. Applications such as hemodilution and organ preservation, cancer diagnosis and chemotherapy, x-ray imaging of the lymph nodes and magnetic resonance imaging of the GI tract, cardioplegia and reperfusion, the treatment of myocardial ischemia and respiratory distress syndrome, as well as drug delivery, all obviously require different product characteristics, calling for an array of products which may range from different neat fluorocarbons to diversely formulated emulsions, or fluorinated vesicles. Substantial progress has been made in terms of emulsion efficacy and stability. Stable, ready-to-use, concentrated, though fluid, injectable emulsions have now been developed. Small doses of such emulsions were demonstrated to be highly efficient in tissue oxygenation. Commercial-scale manufacturing including heat sterilization of these emulsions have been achieved. Some of the side-effects, which generally relate to the normal response of the organism to injected particles, have been reduced, and their mechanism determined. Further efforts will undoubtedly be devoted to understanding and adjusting emulsion properties for optimal efficacy in each identified application and to maximizing benefit vs side-effect ratio. Our ability to modulate in vivo recognition, intravascular persistence and subsequent biodistribution of fluorocarbon droplets, vesicles and other particulate matter in the organism is still in its infancy. Proper control of these characteristics would further extend the potential of such products for medical uses. It is essential that no effort be spared to increase our general understanding of their physicochemical properties and in vivo "physiology".

Contrast Media↗
PubMed1994

Fluorocarbon emulsions--the stability issue.

Long-term room temperature stability of ready-to-use concentrated fluorocarbon emulsions is necessary in order to fully exploit the therapeutic potential of fluorocarbons. Consequently, considerable efforts have been directed at investigating the physical nature of such emulsions, the mechanisms which lead to their degradation and the means of counteracting these. The particles which constitute typical fluorocarbon/egg yolk phospholipid emulsions have been identified to be surfactant-coated fluorocarbon droplets and lipid vesicles. Better understanding has been gained on the formation, structure and evolution of these particles during processing and storage. This has led to optimized formulations and processing, better control of emulsion characteristics and significantly improved stability. Molecular diffusion (Ostwald ripening or transcondensation) has been shown to be the maun mechanism of degradation when particles are less than 1 micron in diameter, even for the highly concentrated (volume fraction of fluorocarbon up to 50%) second generation fluorocarbon emulsions. Significant emulsion stabilization has been accomplished by adding fluorochemicals which are both less volatile and less water soluble, and nevertheless have an organ dwell time acceptable for intravascular use. The rate of molecular diffusion can also be reduced by decreasing the fluorocarbon/water interfacial tension; this was effectively achieved with appropriate, well-defined fluorinated surfactants. A further, novel means of stabilizing fluorocarbon-in-water emulsions makes use of mixed fluorocarbon-hydrocarbon amphiphiles which act as molecular dowels to reinforce the adhesion between the fluorocarbon phase and the lipophilic zone of the surfactant film. Both long-term room temperature stability, and particle-size control over a large range of diameter, have been achieved by applying this principle. All in all it can be said that the challenge of producing injectable fluorocarbon emulsions with long-term room temperature particle size stability has been met.

Blood Substitutes↗
PubMed1994

Improved control over particle sizes and stability of concentrated fluorocarbon emulsions by using mixed fluorocarbon/hydrocarbon molecular dowels.

The use of a surfactant system consisting in equimolar amounts of egg yolk phospholipids and of a mixed fluorocarbon/hydrocarbon amphiphile (C8H17CH = CHC8F17) allows the preparation of concentrated (90% w/v, i.e. 47% v/v) emulsions of perfluorooctyl bromide (perflubron), with average particle sizes ranging from 0.12 to 16 microns post-sterilization, depending on the surfactant/fluorocarbon ratio. Emulsion droplet diameters varied linearly as a function of the emulsifier's concentration, thus allowing easy pre-determination of the emulsion's average particle size. Excellent stability was observed for the dowel-containing emulsions for at least 6 months at 40 degrees C over the whole domain of particle sizes investigated.

Drug Stability↗
PubMed1994

Biodistribution and excretion of a mixed fluorocarbon-hydrocarbon "dowel" emulsion as determined by 19F NMR.

To investigate the biodistribution, possible metabolism and excretion of mixed fluorocarbon-hydrocarbon "dowel" molecules used as stabilizers of fluorocarbon emulsions, we have prepared a 25% w/v emulsion of such a molecule, and quantitatively evaluated, by means of 19F NMR, its behavior in the blood and reticuloendothelial system (RES) of rats. C6F13CH = CHC10H21 (F6H10E) was emulsified using egg yolk phospholipids (EYP). The emulsion (F6H10E/EYP: 25/6% w/v) was injected intravenously into 33 Sprague Dawley female rats at a 3.6 g/kg body weight dose of F6H10E. The animals were sacrificed at regular intervals of time. 24 hours after the injection, 70% of the injected dose was located in the liver, 17% in the spleen, 4% in the lungs, 2% in the kidneys and 2% in the blood. The half-time retention of the dowel molecule in the liver was estimated to be 25 +/- 5 days. None of the 33 treated animals died prior to the planned sacrifice date. The dowel molecule F6H10E proved to be well tolerated, and excreted reasonably fast, without metabolism. This appears to warrant the use of such molecules as stabilizers in injectable fluorocarbon emulsions destined to serve as oxygen carriers, contrast agents or drug delivery systems.

Animals↗
PubMed1994

Mixed fluorocarbon/hydrocarbon molecular dowels help protect concentrated fluorocarbon emulsions with large size droplets against coalescence.

Mixed fluorocarbon/hydrocarbon amphiphiles, the so-called molecular dowels, have previously been reported to strongly stabilize concentrated (90% w/v, i.e. 47% w/v) submicronic size perfluorooctyl bromide emulsions emulsified by egg yolk phospholipids. The dowel molecules, used in equimolar amounts with phospholipids, enable the preparation of emulsions with large-sized particles which are impossible to obtain with phospholipids alone. We report here that molecular dowels (C6F13C10H21, F6H10) also hinder droplet coalescence induced by mechanical stress in sterilized emulsions with average particle sizes ranging from ca 1 to 16 microns. In contrast, the addition of equimolar amounts of perfluorodecyl bromide was found to have little influence on these emulsions' resistance to mechanical stress. This is consistent with the view that mixed fluorocarbon/hydrocarbon dowels are held in the interfacial film and reinforce its cohesion with the fluorocarbon phase.

Drug Stability↗
PubMed1994

Amphiphilic sugar phosphates with single or double perfluoroalkylated hydrophobic chains for use in oxygen and drug delivery systems.

New anionic amphiphiles with a phosphate ester junction between the fluorophilic-lipophilic tail and the sugar-based hydrophilic head were synthesized and evaluated. The single hydrophobic chain surfactants 1 a, b and 2a allowed the preparation of stable and fine highly concentrated emulsions of perfluorodecalin or perfluoroocytl bromide, either when used alone or in conjunction with egg yolk phospholipids (EYP). Surfactants 3d, 5d, 6d and 6e, with two hydrophobic chains, one fluorinated the other not, gave liposomal structures, and displayed encapsulation properties for carboxyfluorescein. The phosphodiesters tested cause no significant inhibition of the growth and viability of Namalva cell cultures (0.1-1 g/L range). Single chain phosphodiesters manifest no detectable hemolytic activity (at 100 g/L for 1a) whereas double chain compounds do moderately (ca 20% hemolysis at 20 g/L). The maximum tolerated dose compatible with the survival of all of a series of 10 intravenously injected mice is in 130 mg/kg body weight range.

Alkylation↗
PubMed1994

Fluorinated phospholipid-based vesicles as potential drug carriers: encapsulation/sustaining of drugs and stability in human serum.

The release of entrapped 5(6)-carboxyfluorescein from fluorinated vesicles in a buffer or in human serum is considerably less than that from hydrogenated liposomes. The presence of a fluorinated core inside the liposomal membrane definitely reduces its permeability. In some cases, the stability of liposomes made from fluorinated phospholipids alone is better than that of egg phosphatidylcholine cholesterol 1/1 vesicles, which are among the least permeable and most stable hydrogenated liposomes.

Blood Physiological Phenomena↗