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BACKGROUND: Progress in the field of gene transfer with non-viral vectors requires systems that allow efficient gene expression in the presence of biological fluids such as pulmonary surfactants, for gene transfer to the respiratory epithelium for cystic fibrosis gene therapy, or bile salts (which contain powerful anionic detergents), for gene transfer to the biliary epithelium for gene therapy of the hepatobiliary disease associated with cystic fibrosis (CF). We have performed a comparative analysis of the disintegration and DNA accessibility of fluorinated and conventional lipoplexes, and their in vitro transfection potential in the presence of a powerful biliary surfactant. METHODS: The disintegration and DNA accessibility of conventional and fluorinated cationic lipoplexes and their in vitro transfection efficiency of human lung carcinoma epithelial A549 cells were studied in the presence of various concentrations of sodium taurocholate (STC), an anionic bile salt detergent. The conventional and fluorinated lipoplexes were formulated from Transfectam" (or DOGS) and from fluorinated lipospermines, analogs of DOGS, respectively, and a luciferase reporter plasmid. The fluorinated lipids used in the present study were selected for their different degrees of fluorination in order to investigate the impact on stability and transfection. The effects of the detergent on lipoplex integrity were examined by evaluating the ability of the lipospermines to prevent, in the presence of the surfactant, ethidium bromide (BET) intercalation into the plasmid (fluorescence monitoring). RESULTS: Fluorinated cationic lipoplexes exhibited greater stability than DOGS lipoplexes with respect to STC lytic activity. Indeed, while the DOGS lipoplexes were fully disintegrated at a [STC]/[lipid] molar ratio of 1,320, all the DNA intercalation sites of the most fluorinated lipoplexes investigated became accessible to BET for a two-fold higher [STC]/[lipid] molar ratio. A higher transfection potential in the presence of the detergent was also shown for the fluorinated lipoplexes as compared with the DOGS preparation. At a 10 mM concentration of STC and at a [STC]/[lipid] molar ratio of 264, lipofection when mediated by DOGS was fully inhibited while the detergent had no inhibitory effects on the lipofection mediated by the fluorinated DF4C11-GS [spermine-5-carboxyglycine N,N-di-11-(F-butyl)-undecylamide] or DF6E11-GS [spermine-5-carboxyglycine N,N-di-[11-(F-hexyl)-undec-10-enyl]amide] lipospermines. A higher detergent concentration (up to 17.5 mM) and a higher [STC]/[lipid] ratio (up to 462) were necessary to inhibit lipofection by the fluorinated formulations. Overall, the lipoplex stability and transfection potential in the presence of the detergent was found to improve with increasing degrees of fluorination of the lipospermines. CONCLUSIONS: The present work shows improved stability of, and higher lipofection levels with, fluorinated lipoplexes in the presence of surfactants. The results confirm the very promising potential of fluorinated lipoplexes as gene transfer vectors. These compounds constitute a very attractive alternative to their more conventional homologs. The correlation found between the degree of fluorination of the lipoplexes, their stability and their lipofection levels suggests that enhanced lipophobic and hydrophobic properties protect them against disintegration and, consequently, prevents DNA from being degraded and from interacting with lipophilic and hydrophilic biocompounds responsible for lipofection inhibition.
Can the introduction of fluorine atoms affect the bioactivity of natural semiochemicals? Can fluorine contribute in the creation of specific enzyme inhibitors to interrupt or disrupt the insect communication system? The first step for the bioactivity of a molecule is interaction with the biological sensor. Hydrogen and fluorine are almost bioisosteric and the receptor site of the enzyme can still recognize and accept the fluoro analogue of its natural substrate. However, the peculiar electronegativity of the fluorine atom can affect the binding, absorption, and transport of the molecule. The differences in the molecule's electronic properties can lead to differences in the chemical interactions between the receptor and the fluorinated substrate. Fluorine introduction can modify the metabolic stability and pathway of the semiochemicals in many different ways. Fluorinated analogues can show synergism, inhibition, or hyperagonism effects on insect behaviors, that is, the activity of the nonfluorinated parent compounds can be mimicked, lost, or increased. In any case, the fluorinated molecules can interact with the bioreceptors in a new and disrupting way. The semiochemicals are olfactory substances: fluorine can affect their volatility or smell. Production of semiochemicals from exogenous substances, perception at antennal receptors, and processing of biological responses are the main steps of communication among insects. In the production step, the fluorinated molecules can interact with enzymes that catalyze the biosynthesis of the natural pheromones. In the perception step, fluorinated semiochemicals can interact with the olfactory receptor cells; this often leads to totally unpredictable behaviors. Fluorinated molecules have been developed as probes to elucidate the complex chemorecognition processes of insects. Many of these molecules have been tested to find highly effective behavior-modifying chemicals. New analogues have been synthesized to investigate the metabolic pathway of a pheromone molecule and many of them are promising disrupting agents. Despite such titanic research efforts, the results have often been random, rational trends in the induced behaviors have sometimes been impossible to find, and practical applications of the fluorinated semiochemicals are still uncertain.
OBJECTIVES: There are many unique properties associated with fluorinated polymers that make these materials attractive for use in the challenging oral environment. This study was devised to better define the influence of fluorine content and its structural distribution on properties of fluorinated resins and composites, especially with regard to their water-related and mechanical properties. METHODS: A series of fluorinated dimethacrylate monomers was prepared by reaction of aromatic diepoxides with fluoroalcohols and subsequent conversion of the resulting diols to the methacrylates. Composites based on monomer systems comprised of the fluorinated monomers with 1,10-decamethylene dimethacrylate and reinforced with silanized quartz filler were evaluated for conversion, water contact angle, water sorption and diametral tensile strength. RESULTS: By selection of reactants, fluorine was introduced as trifluoromethyl groups, extended fluoroalkyl pendant chains, or combinations of the two. Photopolymerization conversion among the experimental composites was generally equal to or greater than that of a conventional Bis-GMA/TEGDMA composite. While the water contact angles generally increased with fluorine content, no correlation was obtained between fluorine content and water sorption of the composites. The mechanical strength of the fluorinated composites showed a general decline with increasing fluorine content and consistent variations due to specific structural features. SIGNIFICANCE: A versatile route to fluorinated dimethacrylates with diverse structural and fluorine distribution patterns is presented. Composites from these monomers are very hydrophobic but have relatively low mechanical strength. The monomers described can be considered as useful additives to moderate the water sorption of conventional resins. However, the results of this study point to specific fluorinated resin structures that are expected to provide a more optimal balance between hydrophobicity and mechanical strength that will improve the long-term performance of dental composites.
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.
Fluorocarbons and fluorocarbon moieties are uniquely characterized by very strong intramolecular bonds and very weak intermolecular interactions. This results in a combination of exceptional thermal, chemical and biological inertness, low surface tension, high fluidity, excellent spreading characteristics, low solubility in water, and high gas dissolving capacities, which are the basis for innovative applications in the biomedical field. Perfluoroalkyl chains are larger and more rigid than their hydrogenated counterparts. They are considerably more hydrophobic, and are lipophobic as well. A large variety of well-defined, modular fluorinated surfactants whose polar head groups consist of polyols, sugars, sugar phosphates, amino acids, amine oxides, phosphocholine, phosphatidylcholine, etc, has recently been synthesized. Fluorinated surfactants are significantly more surface active than their hydrocarbon counterparts, both in terms of effectiveness and of efficiency. Despite this, they are less hemolytic and less detergent. Fluorosurfactants appear unable to extract membrane proteins. Fluorinated chains confer to surfactants a powerful driving force for collecting and organizing at interfaces. As compared to non-fluorinated analogs, fluorosurfactants have also a much stronger capacity to self-aggregate into discrete molecular assemblies when dispersed in water and other solvents. Even very short, single-chain fluorinated amphiphiles can form highly stable, heat-sterilizable vesicles, without the need for supplementary associative interactions. Sturdy microtubules were obtained from non-chiral, non-hydrogen bonding single-chain fluorosurfactants. Fluorinated amphiphiles can be used to engineer a variety of colloidal systems and manipulate their morphology, structure and properties. Stable fluorinated films, membranes and vesicles can also be prepared from combinations of standard surfactants with fluorocarbon/hydrocarbon diblock molecules. In bilayer membranes made from fluorinated amphiphiles the fluorinated tails segregate to form an internal teflon-like hydrophobic and lipophobic film that increases the stability of the membrane and reduces its permeability. This fluorinated film can also influence the behavior of fluorinated vesicles in a biological milieu. For example, it can affect the in vivo recognition and fate of particles, or the enzymatic hydrolysis of phospholipid components. Major applications of fluorocarbons currently in advanced clinical trials include injectable emulsions for delivering oxygen to tissues at risk of hypoxia; a neat fluorocarbon for treatment of acute respiratory failure by liquid ventilation; and gaseous fluorocarbon-stabilized microbubbles for use as contrast agents for ultrasound imaging. Fluorosurfactants also allow the preparation of a range of stable direct and reverse emulsions, microemulsions, multiple emulsions, and gels, some of which may include fluorocarbon and hydrocarbon and aqueous phases simultaneously. Highly fluorinated systems have potential for the delivery of drugs, prodrugs, vaccines, genes, markers, contrast agents and other materials.
The actual paper presents the method and results of studies concerning the content and decomposition of fluorine compounds in the component structures of eggs and in the bone system of a domestic hen, as well as its progeny under conditions of increased content of these compounds in the drinking water. The objective of the paper has been: 1) determining the effect of environmental contamination (NaF in drinking water) exerted on the presence of fluorine in eggs, 2) defining the distribution of fluorine in component structures of the egg, 3) studying the fluorine effect on selected physical parameters of eggs, 4) determination of fluorine content in tibial bones of laying hens, after receiving NaF in drinking water, and to compare the tibial bone composition in hens and their progeny with control groups, 5) analyzing the share of fluorine compounds in the construction of skeleton and beaks of chicks. The conceptions of the work were elaborated on the basis of results stemming from an accomplished experimental breeding of domestic hens in a semi-intensive system. The experiment proceeded 4 weeks. A part of eggs obtained by breeding was designed for hatching. Due to the requirements associated with analyzing the skeleton, all the experimental birds, including the chicks, were assigned for further analyses. The material, obtained in this way, (bones of hens, chicks, eggs) was subsequently subjected to detailed studies. According to the conceptions of the paper the selected physical parameters of eggs were studied, therein resistance tests, using specialized apparatuses. Fluoride was determined potentiometrically, by applying fluoride ion selective electrode, while the metallic elements by aid of atomic spectrophotometer (Tab. 1-5, Fig. 1). Finally, the following conclusions were presented, namely: 1. The egg shell in hens plays an essential role in binding fluorine compounds and constitutes one of the means of their fast elimination from the organism. 2. Egg shells may provide an easily accessible bioindicator for the exposure of birds to fluorine compound, particularly with regard to a given species. 3. Moderately increased fluorine content in the shells of eggs fails to influence their thickness and does not cause any changes in their resistance to decay. 4. In conditions of increased exposure of hens to fluorine compounds, no elevation in the accumulation of this element was disclosed in the substance, which is evidence that there is a lack of apparent influence of local contamination by emissions of fluorine compounds exerted on nutritional usefulness of eggs. 5. Comparison of fluorine content in the bones of chicks, stemming from hens being given water with NaF to drink, with control hens points to a significant rise in fluoride accumulation in progeny of hens, exposed to sodium fluoride action. That may have a negative influence on their correct development.
BACKGROUND AND OBJECTIVE: The study of biodistribution and in situ pharmacokinetics is a challenging, but sometimes very important, aspect of premarketing characterization of drugs. We aimed to develop a non-invasive fluorine magnetic resonance (MR) spectroscopic method for the absolute quantitation of a mono-fluorinated compound and of its metabolites in the heart and liver of healthy subjects for this purpose. METHOD: We used fluorine MR spectroscopy (MRS) at 4 T (Tesla) and external standardization in an open label multiple-dose study. Twenty-three healthy adult subjects were enrolled in the study. The surface coil localized fluorine MR spectrum was monitored in the heart and liver at baseline and after oral administration of multiple doses of tecastemizole. Steady-state measurements were made at set time points that depended upon dose, and washout measurements were made only on subjects in which in vivo fluorine signal was observed. RESULTS AND DISCUSSION: At 4 T, under the given experimental conditions, the method had a lower limit of quantitation (LLOQ) of about 2.6 microm and a limit of detection (LOD) of about 0.3 microm for solution state samples (linewidth approximately 15 Hz). The measurement reproducibility was 6.4% using a 50 microm phantom. The effect of MR operator and spectral analyst on the calculated calibration curve slope was small, with inter-rater correlation coefficients of 0.999 and 0.998 respectively. MR signal from fluorine-containing tecastemizole-related moieties was observed in situ only at day 8 in the liver of three of five subjects dosed at 270 mg/day. The average in situ concentration was estimated to be 58+/-22 microm, with an average test-retest reproducibility of 216%. Extrapolating the in vitro results to human measurements, with an approximate linewidth of 250 Hz, predicts in situ LOD and LLOQ values of approximately 6 and 44 microm respectively. However, the human study had a fluorine MRS LOD of approximately 20 microm. The decrease in sensitivity and the increase in variability of the in vivo, in situ measurements compared with the validation study most likely arose from coil placement and incomplete rephasing of the MR signal by the respiratory phase compensation method. CONCLUSION: The measured concentrations were the lowest ever recorded for a multi-dose exogenous mono-fluorinated compound in the human liver using a validated fluorine MR quantitation method. The proposed non-invasive MR method for studying the biodistribution and in situ pharmacokinetics of mono-fluorinated compounds in the liver and heart should have broader application to the development of non-invasive biomarkers.
The sensitivity of fluorinated organic compounds to radiation damage in the electron microscope was measured by electron energy loss spectroscopy (EELS). Five classes of molecules were investigated with fluorine atoms situated on: (1) an aliphatic chain, (2) an aromatic ring, (3) a trifluoromethyl group on an aromatic ring, (4) a trifluoromethyl group on a heterocyclic ring, and (5) a trifluoromethyl group next to a carbonyl group. The damage dose for fluorine loss was found to depend strongly on the position of the fluorine atoms and on specimen temperature. For poly-substituted fluorine on an aliphatic chain, approximately half of the fluorine was retained at doses in excess of 10(7) e/nm2. At room temperature molecules containing trifluoromethyl groups on aromatic or heterocyclic rings were much more sensitive to fluorine loss than compounds having fluorine substituted directly on the rings. This behavior is consistent with the relatively low chemical stability of the trifluoromethyl group in these structures. The rapid loss of fluorine at low electron doses (approximately 10(4) e/nm2) in the trifluoromethyl aromatic compounds was reduced several orders of magnitude by cooling the specimen to liquid-nitrogen temperatures. An understanding of how specific types of fluorinated compounds suffer damage under the electron beam will be important in their potential application as biochemical or pharmacological probes.
An improved aluminium target system for production of elemental fluorine via the 18O(p,n)18F reaction using a two-step irradiation protocol is described. In the first step highly enriched gaseous oxygen-18 is irradiated with protons to form fluorine-18 which gets deposited on the inner target surface. In the second step, after cryogenic recovery of oxygen-18 target gas, a mixture of elemental 'cold' fluorine and krypton is introduced and a short proton irradiation is done, whereby an isotopic exchange between the gaseous fluorine and the deposited radiofluorine occurs. The second step leads to the recovery of the radiofluorine as [18F]fluorine. Optimisation studies were performed regarding the yield and specific radioactivity of [18F]fluorine. Furthermore, some irradiation parameters relevant to the recovery step were investigated. It was found that a 15 to 20 min irradiation with a beam current of 20 microA is sufficient for the isotopic exchange between the fluorine-carrier and the 18F-radioactivity deposited on the inner wall of the target. The distribution of the 18F-radioactivity deposited on the inner target surface is inhomogeneous, probably due to convection effects. Extensive radioanalytical techniques were applied to characterise the reactivity of [18F]fluorine and to identify undesired nonreactive 18F-compounds, mainly [18F]tetrafluoromethane and [18F]nitrogentrifluoride. The [18F]fluorine produced in the system used has the distinction of having a negligible contamination from those inert 18F-compounds. This is a combined effect of the use of highest purity gases and a welded target construction, which avoids any contact of the gases with organic material during irradiations. The target has proved to be very reliable for production of [18F]fluorine in high yields of up to 34 GBq and specific activities of 350-600 GBq/mmol, both at 30 min after end of activation bombardment.
A versatile method for the synthesis of trifluoro fatty acids, potential metabolically blocked myocardial imaging agents, has been developed. Two trifluorohexadecanoic (palmitic) acids have been prepared [6,6,16-trifluorohexadecanoic acid (I) and 7,7,16-trifluorohexadecanoic acid (II)], each of which bears two of the fluorine atoms as a gem-difluoromethylene unit on the fatty acid chain (at C-6 or C-7) and the third at the omega (C-16) position. The metabolic stability of carbon-fluorine bonds suggests the gem-difluoro group may block the beta-oxidation pathway, while the terminal fluorine could be the site for labeling with fluorine-18. The convergent synthetic approach utilizes a 2-lithio-1,3-dithiane derived from 10-undecenal or 9-decenal, which is alkylated with the OBO (oxabicyclooctyl) ester of 5-bromopentanoic acid or 6-bromohexanoic acid, respectively. Hydroboration-oxidation and alcohol protection are followed by halofluorination to convert the 1,3-dithiane system to a gem-difluoro group. The third fluorine is introduced by fluoride ion displacement of a trifluoromethanesulfonate. This synthesis is adapted to the labeling of these trifluoro fatty acids with the short-lived radionuclide fluorine-18 (t1/2 = 110 min), with the third fluorine introduced as fluoride ion in the penultimate step. The radiochemical syntheses proceed in 3-34% radiochemical yield (decay corrected), with an overall synthesis and purification time of 90 min. Tissue distribution studies in rats were performed with I and II, as well as with 16-[18F]fluoropalmitic acid (III), [11C]palmitic acid, and [11C]octanoic acid. The heart uptake of the fluoropalmitic acids decreases with substitution, the 2-min activity level for 16-fluoropalmitic acid being 65% and that for both 6,6,16- and 7,7,17-trifluoropalmitic acids being 30% that of palmitic acid. Fluorine substitution results in some alteration in the retention of activity by the heart: 16-fluoropalmitate actually clears more rapidly than palmitate, but the two trifluoropalmitates (particularly 6,6,16-trifluoropalmitate, I) show somewhat slower clearance of activity, although the improvement of I over palmitate is only modest. There is considerable accumulation of activity in the bone after administration of the fluorine-18 labeled fatty acids, suggestive of metabolic defluorination. These results indicate that fluorine substitution alters the physicochemical properties of the fatty acid so that uptake by the myocardium is diminished. Furthermore, while the gem-difluoro substituents at C-6 and C-7 may block beta-oxidation, the chain-terminal radiofluorine substituent is subject to omega-oxidation that releases it as fluoride ion.
We have prepared nine androgens substituted with fluorine at C-16 or C-20 to evaluate their potential, as positron emission tomographic (PET) imaging agents for prostatic cancer when labeled with the positron emitting radionuclide fluorine-18 (t1/2 = 110 min). These compounds represent members from the following classes of androgens: testosterone (T), 5 alpha-dihydrotestosterone (DHT), 7 alpha-methyl-19-nortestosterone (MNT), mibolerone (Mib), and metribolone (R1881). All of these compounds were prepared by functionalization of suitable androgen precursors, and the synthetic routes were developed to allow the introduction of fluorine by a fluoride ion displacement reaction late in the synthesis, as is required for the preparation of these compounds in fluorine-18 labeled form. We have also prepared four androgens in which the C-3 carbonyl or 17 beta-hydroxyl groups are replaced by fluorine. Most of the fluorine-substituted androgens show high affinity for the androgen receptor (AR), although fluorine substitution lowers their affinity by a small factor. None of the androgens where fluorine replaces oxygen functions at C-3 or C-17 have substantial affinity for AR. Derivatives of the natural androgens (T and DHT) as well as MNT have little affinity for other steroid hormone receptors (progesterone and mineralocorticoid receptors), whereas the Mib and R1881 derivatives have somewhat greater heterologous binding. With sex steroid binding protein, a human serum binding protein, the pattern of binding affinities is nearly the reverse, with derivatives of Mib, R1881 and MNT having low affinity, and DHT and T, high affinity. From these fluorine-substituted compounds, we can select several whose preparation in fluorine-18 labeled form for further tissue distribution studies is merited.