Geodesic surfactant structures.
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Cholesterol↗
Biomedical subjects
A T Florence
Publications and source records attributed to A T Florence.
Distribution, metabolism and tumoricidal activity of doxorubicin administered in sorbitan monostearate (Span 60) niosomes in the mouse.
PURPOSE: Encapsulation of doxorubicin in niosomes was sought as a route to tumour targeting and improved tumoricidal through the alteration of doxorubicin pharmacokinetics and metabolism. METHODS: Doxorubicin niosomes (10 mg kg-1 doxorubicin) prepared from sorbitan monostearate (Span 60), cholesterol and choleth-24 (a 24 oxyethylene cholesteryl ether) in the molar ratio 45:45:10 were administered intravenously to female NMRI mice bearing the MAC 15A subcutaneously implanted tumour. Plasma doxorubicin was fractionated by gel filtration and quantified by HPLC with fluorometric detection as niosome-associated doxorubicin and released doxorubicin. Tumoricidal activity of the formulation was assessed by the intravenous injection of 5 mg kg-1 and 10 mg kg-1 doxorubicin niosomes to male NMRI mice bearing a 6 day old MAC 15A tumour. RESULTS: At least 90% of the plasma doxorubicin was associated with the niosome fraction 4 h after dosing, and 50% was still associated after 24 h. The clearance of doxorubicin released from the niosomes was about 10 fold greater than the clearance of niosomal doxorubicin (176.5 mL h-1 and 16.2 mL h-1, respectively). The area under the plasma level-time curve increased 6 fold when doxorubicin was administered in niosomes, compared to doxorubicin solution (66.0 micrograms.h mL-1 and 10.3 micrograms. h mL-1, respectively). The area under the tumour level time curve was increased by over 50% by the administration of doxorubicin in niosomes when compared to the drug administered in solution (58.6 micrograms.h mL-1 and 34.3 micrograms.h mL-1, respectively). There was no statistically significant difference between levels of the drug in the heart when niosomal doxorubicin or doxorubicin solution were administered. Doxorubicin metabolites, namely doxorubicinol and the aglycones doxorubicinone, doxorubicinolone and 7-deoxydoxorubicinone, were found associated with the niosomes in the plasma, possibly due to their adsorption to the vesicle surface once formed outside the niosome. Overall metabolite levels in the liver were increased when doxorubicin niosomes were administered compared to the drug in solution. A 5 mg kg-1 injection of doxorubicin niosomes produced a terminal mean tumour weight that was similar to that obtained from animals administered 10 mg kg-1 doxorubicin solution. CONCLUSIONS: Modest tumour targeting was achieved by the delivery of doxorubicin in sorbitan monostearate niosomes, increasing the tumour to heart AUC0-24 ratio from 0.27 to 0.36 and a doubling of tumoricidal activity. The overall level of doxorubicin metabolites was also increased.
Animals↗
A non-ionic surfactant vesicle-in-water-in-oil (v/w/o) system: potential uses in drug and vaccine delivery.
An aqueous dispersion of niosomes (non-ionic surfactant vesicles) emulsified in an external oil phase forms the vesicle-in-water-in-oil (v/w/o) system described in this paper. The properties of the surfactant used to form the vesicles, the surfactant or surfactant mixture used to stabilize the emulsion and the nature of the oil phase can be changed to provide systems of different capacities for drug or antigen and different release characteristics. The same nonionic surfactant is used as the principle amphipile to form the niosomes and to stabilize the w/o emulsion, thus promoting stability by decreasing transfer of surfactant between the stabilizing monolayers and the vesicle bilayers. The in vitro release of carboxyfluoroscein and 5-fluorouracil encapsulated within the niosomes of the v/w/o system has been investigated, the nature of the oil phase and surfactant-oil interactions being important in determining the rate of solute release. Initial studies of the system in vivo, as an adjuvant for tetanus toxoid, using cottonseed oil as the external oil phase, showed enhanced immunological activity over the free antigen or vesicles.
Adjuvants, Immunologic↗
Factors affecting the oral uptake and translocation of polystyrene nanoparticles: histological and analytical evidence.
Quantitative and qualitative evidence from our laboratories on the absorption and translocation of polystyrene latex nanoparticles both by histological (qualitative) and analytical measurement of levels of polystyrene (quantitative) is briefly reviewed in this paper. We have previously compared the uptake of nonionized polystyrene latex ranging in size from 50nm to 3 microns, and made some comparisons of uptake between carboxylated microspheres and nonionic systems, showing the lower uptake of the former through the lymphoid tissue of the gastrointestinal tract. Size is a key parameter, uptake increasing with decreasing particle diameter. Early evidence suggested that uptake is by way of the Peyer's patches and other elements of the gut associated lymphoid tissue (GALT). Adsorption of hydrophilic block-copolymers onto polystyrene markedly reduces the uptake by intestinal GALT. Modification of the surface with specific ligands such as by covalent attachment of tomato lectin molecules has indicated widespread uptake by non-GALT tissues, following their binding to and internalisation by enterocytes. The ability to decrease and increase uptake is clear evidence of a phenomenon which has the potential for further control to allow it to be exploited fully for drug or vaccine delivery. The evidence to date with nanoparticles as carriers systems for labile drugs such as proteins by the oral route remains to be substantiated.
Animals↗
Drug distribution and a pulmonary adverse effect of intraperitoneally administered doxorubicin niosomes in the mouse.
Niosomes (non-ionic surfactant vesicles) prepared from C16G2 (a hexadecyl-diglycerol ether), and loaded with doxorubicin, were administered intraperitoneally to male AKR mice at dose levels of 0, 2.5, 5.0, and 10.0 mg kg-1. Free drug was given at 10.0 mg kg-1 by the intraperitoneal route. At a dose level of 10.0 mg kg-1, peak doxorubicin levels in the central compartment were attained faster with the free drug than with the niosome formulation. However, the peak plasma levels were similar for the free drug and the niosome preparation at the 10 mg kg-1 dose level. With doxorubicin administered as the niosome preparation by the intraperitoneal route at 2.5, 5.0, and 10.0 mg kg-1, mean peak plasma concentrations of the drug showed a tendency to be dose-related although the differences were not significant. Over the 24 h period of the experiment, with doxorubicin at 10 mg kg-1, the niosome formulation delivered significantly more drug to the plasma compartment than the free drug (p < 0.05). When doxorubicin was given in niosomes at 2.5, 5.0 and 10.0 mg kg-1 by the intraperitoneal route, the resulting levels of doxorubicin in cardiac tissue were not dose related and the differences not significant and, although the mean peak cardiac-tissue concentration was higher in animals receiving the free drug at 10.0 mg kg-1 intraperitoneally than in mice given intraperitoneal doxorubicin niosomes at this dose level, the differences were again not significant. There were clinical signs of toxicity in mice given doxorubicin-containing niosomes intraperitoneally at 5.0 and 10.0 mg kg-1, and at post-mortem an accumulation of fluid in the pleural cavity was evident. These changes were not seen in mice dosed intraperitoneally with free drug at 10 mg kg-1, or in animals given doxorubicin niosomes intraperitoneally at 2.5 mg kg-1. In mice dosed intraperitoneally with doxorubicin niosomes at 12.0 mg kg-1 and at a dose volume of 0.2-0.4 mL, histological examination of the lungs demonstrated a congestion of the alveolar capillaries, and an increased number of acute inflammatory cells in the alveolar walls. There was no histological evidence of lung toxicity in mice dosed with doxorubicin niosomes at 12.0 mg kg-1 when the formulation was administered with the higher dose volume of 1.8-2.0 mL. Importantly there was no histological evidence of lung toxicity in mice dosed with empty niosomes intraperitoneally or with doxorubicin niosomes given intravenously at 12.0 mg kg-1.
Analysis of Variance↗
Recent advances in drug targeting.
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Animals↗
Liposomes in drug delivery. Clinical, diagnostic and ophthalmic potential.
Liposomes (phospholipid-based vesicles) have been investigated since 1970 as a system for the delivery or targeting of drugs to specific sites in the body. Because of their structural versatility in terms of size, composition, surface charge, bilayer fluidity and ability to incorporate almost any drug regardless of solubility, or to carry on their surface cell-specific ligands, liposomes have the potential to be tailored in a variety of ways to ensure the production of formulations that are optimal for clinical use. This includes controlled retention of entrapped drugs in the presence of biological fluids, controlled vesicle residence in the blood circulation or other compartments in the body, and enhanced vesicle uptake by target cells. Accumulated in vivo evidence, particularly in areas such as cancer chemotherapy, antimicrobial therapy, vaccines, diagnostic imaging and the treatment of ophthalmic disorders has indicated clearly that some liposome-entrapped drugs and vaccines exhibit superior pharmacological properties to those observed with conventional formulations. Such work has encouraged the application of liposomes in the treatment of diseases in humans. A large number of trials in patients with cancer or infections suggest that certain liposomal drug formulations are likely to prove clinically useful.
Adjuvants, Immunologic↗
Targeting peptides and proteins: NATO ASI.
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Animals↗
Lipoproteins and microemulsions as carriers of therapeutic and chemical agents.
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Drug Carriers↗
Liposomes and cancer therapy.
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Antineoplastic Agents↗
Nanoparticle uptake by the rat gastrointestinal mucosa: quantitation and particle size dependency.
Polystyrene microspheres in the size range 50 nm to 3 microns were fed by gavage to female Sprague Dawley rats daily for 10 days at a dose of 1.25 mg/kg-1. Previous histological evidence of the uptake of these particles and their absorption across the gastrointestinal tract and passage via the mesentery lymph supply and lymph nodes to the liver and spleen was confirmed by analysis of tissues for the presence of polystyrene by gel permeation chromatography. Measurement of radioactivity of tissues following administration of 100 nm and 1 micron I125-labelled polystyrene latex particles for 8 days was corroborative although less secure because of the potential lability of the labelled particles. The extent of absorption of 50 nm particles under the conditions of these experiments was 34% and of the 100 nm particles 26% (as measured by determination of polystyrene content), of which total, about 7% (50 nm) and 4% (100 nm), was in the liver, spleen, blood and bone marrow. Particles larger than 100 nm did not reach the bone marrow, and those larger than 300 nm were absent from blood. No particles were detected in heart or lung tissue.
Administration, Oral↗
Effects of hydrotropic agents on the solubility, precipitation, and protein binding of etoposide.
Etoposide, a commonly used anticancer agent, has an aqueous solubility of 0.2 mg/mL. It is formulated for intravenous use as a more concentrated solution (Vepesid; 20 mg/mL) with polysorbate 80 and with cosolvents. In this work, hydrotropic agents such as sodium benzoate, sodium o-hydroxybenzoate (sodium salicylate), sodium 2,5-dihydroxybenzoate (sodium gentisate), and the sodium salts of 2,4-dihydroxy- and 2,6-dihydroxybenzoic acid and of 2,4,6-trihydroxybenzoic acid have been used as alternative solubilizers of etoposide. The weakest and strongest interactants with etoposide were, respectively, sodium benzoate and sodium 2,4,6-trihydroxybenzoate. The effect of mono- and dihydroxybenzoates on etoposide solubility was intermediate. Although sodium 2,4,6-trihydroxybenzoate is the most efficient solubilizer, its use is limited by its own low aqueous solubility. The effect of sodium salicylate and other formulation ingredients on the in vitro protein binding and precipitation of etoposide upon dilution with normal saline and human plasma has been studied. Etoposide binds to the extent of 94% to human serum albumin (HSA) and human plasma, but only 24% to bovine serum albumin (BSA) in vitro. Sodium salicylate significantly decreased the binding of the drug to both HSA and human plasma, whereas the components of Vepesid did not. Dilution of Vepesid (1:2 and 1:3) with plasma in vitro resulted in immediate precipitation, while the corresponding dilutions of etoposide aqueous solution (20 mg/mL in 2 M sodium salicylate) produced no precipitate for the first hour.
Chemistry, Pharmaceutical↗
Etoposide (VP-16) uptake by tumour spheroids and activity in the presence of Brij 30, formulation additives and sodium salicylate.
A number of additives typically used in the formulation of poorly soluble drugs can be shown to influence drug transport across various physiological barriers. Multicellular spheroids from a human neuroblastoma cell line (NB1-G) were used to investigate the effect of etoposide in solution, as its commercial formulation, Vepesid, in the presence of a nonionic surfactant, Brij 30, and a hydrotropic agent, sodium salicylate. Enhanced growth delay, apparently related to increased drug uptake, was observed both with the Vepesid and the sodium salicylate formulations. Brij 30, however, showed no enhancement of growth delay or drug uptake at a concentration at which it was not in itself cytotoxic. Significant morphological changes in the spheroid were observed at higher concentrations of additives, particularly with Brij 30, emphasizing the fact that many formulation additives cannot be used with impunity in tissue culture systems. The enhanced uptake of drug into tumour cells and potential synergy between additive and drug is worthy of further investigation.
Adjuvants, Pharmaceutic↗
The uptake and translocation of latex nanospheres and microspheres after oral administration to rats.
Non-ionic and carboxylated fluorescent polystyrene microspheres (100, 500 nm, 1 and 3 microns in diameter), were fed by gavage (2.5% w/v; 1.25 mg kg-1) daily for 10 days to female Sprague Dawley rats. Peyer's patches, villi, liver, lymph nodes and spleen of animals fed the non-ionic microspheres from 100 nm to 1 micron showed unequivocal evidence of uptake and translocation of the particles. Heart, kidney and lung showed no evidence of the presence of microspheres. Carboxylated microspheres were taken up to a lesser degree than the non-ionised particles. Experiments with 125I radiolabelled 100 nm and 1 micron particles showed a higher uptake of the smaller particles, which were concentrated in GI tissue and liver. Particles were not distributed randomly in the tissues, but were concentrated at the serosal side of the Peyer's patches and could be seen traversing the mesentery lymph vessels towards the lymph nodes. The results demonstrate a need to re-examine the possibilities of particulate oral delivery, as well as the potential toxicity of ingested particulates.
Administration, Oral↗
Incorporation of dyes into low density lipoprotein in the presence of non-ionic surfactants.
The interaction of low density lipoprotein (LDL) with two model dyes in the presence or absence of non-ionic surfactants has been studied. The water soluble dye, thymol blue, only weakly interacts with LDL to cause slight increases in particle size and the interaction can be reversed on column chromatography and dialysis. The oil-soluble dye sudan III reacts strongly with LDL to produce marked changes in particle size the complex formed being stable to dialysis and gel exclusion chromatography. These interactions are not affected by the presence of surfactants. The results indicate that even small quantities of lipophilic materials will easily partition into the particle, with or without the aid of surfactants and can have a marked effect on the measured size of the particle.
Azo Compounds↗
Physiochemical characterization of methotrexate-bovine serum albumin conjugates.
Physiochemical parameters have been determined for a series of methotrexate-bovine serum albumin conjugates produced using a water-soluble carbodiimide. Drug coupling produces a heterogeneous product consisting of mixtures of albumin and albumin polymers with varying quantities of covalently bound drug. Due to this heterogeneity, the measurement of absolute physiochemical values was not possible but two factors producing change were evident. The water soluble carbodiimide is responsible for major changes by producing polymers that dominate the properties of the conjugates. The changes induced by the covalently attached drug are less dramatic but still appreciable. The results emphasize that both the attached drug and the method of coupling are significant factors in altering the physiochemical properties of proteinaceous drug carriers.
Animals↗
The effect of hydrotropic agents on the heat coagulation of bovine serum albumin.
The effect of two hydrotrophic solubilizers on the heat coagulation of bovine serum albumin (BSA) has been investigated. Photon correlation spectroscopy indicated possible unfolding of BSA molecules in solutions of sodium benzoate and sodium salicylate at 25 degrees C. The effect of these hydrotropes on the heat coagulation of BSA was concentration-dependent. Relatively low concentrations stabilized the protein structure as indicated by the increase in the transition temperature(Tm) and induced gelation at temperatures and BSA concentrations lower than those required in the absence of hydrotropes. Higher concentrations of the hydrotropes considerably reduced Tm and inhibited gelation of BSA, the effect of sodium salicylate being more pronounced, as was the lower aggregation rate of BSA. The behaviour of these hydrotropes as protein denaturants differs from that of neutral electrolytes but is similar to that of concentrated solutions of urea.
Benzoates↗
Biodegradation rate of embolized protein microspheres in lung, liver and kidney of rats.
The targeting and sustained release characteristics of cytotoxic drug-loaded protein microspheres may prove useful in the therapeutic chemoembolization of solid tumours. Because biodegradation rate of embolized particles will influence rate of incorporated drug release and duration of exposure, this parameter was studied for microspheres (10-30 microns mean diam.) prepared from the proteins albumin and casein, that we have previously used as carriers for doxorubicin. As a measure of microsphere loss in-vivo the radionuclide 125I was chosen because it can be covalently bound to proteins and also homogeneously distributed throughout the matrix. Radiolabelled microspheres were administered to rats both intravenously (lung as target organ, 1.4-2.2 mg/100 g) and via the hepatic artery (liver as target organ, 0.4-0.8 mg/100 g). In both cases it was observed that the casein system biodegraded more slowly than the albumin in-vivo. Thus, time taken for loss of 50% of embolized microspheres from lung was: albumin 2.0 days; casein 3.5 days and from liver:albumin 3.6 days; casein 6.8 days. Microsphere "debris" did not markedly accumulate in other organs. In-vitro experiments showed that microspheres were stable in serum and that albumin microspheres were not innately more sensitive to enzymic digestion than casein. The results may be useful in estimating duration of exposure of target organs to drug-loaded microsphere systems prepared from these proteins.
Animals↗