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Solutions of compound 1 exhibit dramatic, characteristic color changes in response to sugar analytes. Structurally related saccharides including glucose phosphates and amino and carboxylic acid sugars can be readily distinguished by visual inspection. These findings should promote the design of unique color sensory materials based on readily available, functional macrocyclic hosts.
A Phase I/II clinical trial of boron neutron capture therapy (BNCT) for glioblastoma multiforme is underway using the amino acid analog p-boronophenylalanine (BPA) and the epithermal neutron beam at the Brook-haven Medical Research Reactor. Biodistribution studies were carried out in 18 patients at the time of craniotomy using an i.v. infusion of BPA, solubilized as a fructose complex (BPA-F). There were no toxic effects related to the BPA-F administration at doses of 130, 170, 210, or 250 mg BPA/kg body weight. The tumor/ blood, brain/blood and scalp/blood boron concentration ratios were approximately 3.5:1, 1:1 and 1.5:1, respectively. Ten patients have received BNCT following 2-hr infusions of 250 mg BPA/kg body weight. The average boron concentration in the blood during the irradiation was 13.0 +/- 1.5 micrograms 10B/g. The prescribed maximum dose to normal brain (1 cm3 volume) was 10.5 photon-equivalent Gy (Gy-Eq). Estimated maximum and minimum doses (mean +/- sd, n = 10) to the tumor volume were 52.6 +/- 4.9 Gy-Eq (range: 64.4-47.6) and 25.2 +/- 4.2 Gy-Eq (range: 32.3-20.0), respectively). The estimated minimum dose to the target volume (tumor +2 cm margin) was 12.3 +/- 2.7 Gy-Eq (range: 16.2-7.8). There were no adverse effects on normal brain. The scalp showed mild erythema, followed by epilation in the 8 cm diameter field. Four patients developed recurrent tumor, apparently in the lower dose (deeper) regions of the target volume, at post-BNCT intervals of 7,5,3.5 and 3 months, respectively. The remaining patients have had less than 4 months of post-BNCT follow-up. BNCT, at this starting dose level, appears safe. Plans are underway to begin the dose escalation phase of this protocol.
Boronophenylalanine (BPA) has been used for boron neutron capture therapy (BNCT) of brain tumors in both experimental animals and humans. The purpose of the present study was to determine if the efficacy of BNCT could be enhanced by means of intracarotid (i.c.) injection of BPA with or without blood-brain barrier disruption (BBB-D) and neutron irradiation using a rat brain tumor model. For biodistribution studies, F98 glioma cells were implanted stereotactically into the brains of Fischer rats, and 12 days later BBB-D was carried out by i.c. infusion of 25% mannitol (1.373 mOsmol/ml), followed immediately by i.c. administration of 300, 500 or 800 mg of BPA/kg body weight (b.w.). At the 500 mg dose a fourfold increase in tumor boron concentration (94.5 micrograms/g) was seen at 2.5 hours after BBB-D. compared to 20.8 micrograms/g in i.v. injected animals. The best composite tumor to normal tissue ratios were observed at 2.5 hours after BBB-D, at which time the tumor: blood (T: Bl) ratio was 10.9, and the tumor: brain (T:Br) ratio was 7.5, compared to 3.2 and 5.0 respectively for i.v. injected rats. In contrast, animals that had received i.c. BPA without BBB-D had T : Bl and T:Br ratios of 8.5 and 5.9, respectively, and the tumor boron concentration was 42.7 micrograms/g. For therapy experiments, initiated 14 days after intracerebral implantation of F98 glioma cells, 500 mg/kg b.w. of BPA were administered i.v. or i.c. with or without BBB-D, and the animals were irradiated 2.5 hours later at the Brook-haven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head. The mean survival time for untreated control rats was 24 +/- 3 days, 30 +/- 2 days for irradiate controls, 37 +/- 3 days for those receiving i.v. BPA, 52 +/- 15 days for rats receiving i.c. BPA without BBB-D, and 95 +/- 95 days for BBB-D followed by i.c. BPA and BNCT. The latter group had a 246% increase in life span (ILS) compared to untreated controls and a 124% ILS compared to that of i.v. injected animals. These survival data are the best ever obtained with the F98 glioma model and suggest that i.c. administration of BPA with or without BBB-D may be useful as a means to increase the efficacy of BNCT.
Clinical trials of boron neutron capture therapy (BNCT) for glioblastoma multiforme are currently in progress using p-boronophenylalanine (BPA) as the 10B delivery agent. Enhancement of tumor boron uptake and/or the tumor-to-blood (T:B) boron concentration ratio would have the potential of significantly improving the therapeutic gain of BNCT. The effects of total dose, infusion time, and route of administration of BPA on tumor and blood boron concentrations were studied in rats bearing the 9L gliosarcoma. Increasing the total dose of BPA from 250 to 1000 mg/kg, administered intravenously over a 2-h infusion period, resulted in an increase in tumor boron concentration from approximately 30 to approximately 70 microg 10B/g, with a constant T:B boron concentration ratio of about 3.7:1. Similarly, extension of the infusion time from 2 to 6 h, at a constant dose-rate of 125 mg BPA/kg/h, resulted in an increase in tumor boron concentration from approximately 30 to approximately 80 microg 10B/g, while, again, maintaining a constant T:B ratio of about 3.7:1. In contrast, intracarotid infusion of BPA for 1 h at a dose rate of 125 mg BPA/kg resulted in an increase in the tumor boron concentration from approximately 26 to approximately 38 microg 10B/g with a corresponding increase in the T:B ratio from 3.5:1 to 5.0:1. The effects of these results on the therapeutic gain potentially achievable with BNCT are discussed.
Twelve normal dogs underwent brain irradiation in a mixed-radiation, mainly epithermal neutron field at the Brookhaven Medical Research Reactor following intravenous infusion of 950 mg of 10B-enriched BPA/kg as its fructose complex. The 5 x 10 cm irradiation aperture was centered over the left hemisphere. For a subgroup of dogs reported previously, we now present more detailed analyses including dose-volume relationships, longer follow-ups, MRIs, and histopathological observations. Peak doses (delivered to 1 cm3 of brain at the depth of maximum thermal neutron flux) ranged from 7.6 Gy (photon-equivalent dose: 11.8 Gy-Eq) to 11.6 Gy (17.5 Gy-Eq). The average dose to the brain ranged from 3.0 Gy (4.5 Gy-Eq) to 8.1 Gy (11.9 Gy-Eq) and to the left hemisphere, 6.6 Gy (10.1 Gy-Eq) to 10.0 Gy (15.0 Gy-Eq). Maximum tolerated 'threshold' doses were 6.7 Gy (9.8 Gy-Eq) to the whole brain and 8.2 Gy (12.3 Gy-Eq) to one hemisphere. The threshold peak brain dose was 9.5 Gy (14.3 Gy-Eq). At doses below threshold, some dogs developed subclinical MRI changes. Above threshold, all dogs developed dose-dependent MRI changes, neurological deficits, and focal brain necrosis.
1. Osmotic opening of the blood-brain barrier by intracarotid infusion of a hypertonic arabinose or mannitol solution is mediated by vasodilatation and shrinkage of cerebrovascular endothelial cells, with widening of the interendothelial tight junctions to an estimated radius of 200 A. The effect may be facilitated by calcium-mediated contraction of the endothelial cytoskeleton. 2. The marked increase in apparent blood-brain barrier permeability to intravascular substances (10-fold for small molecules) following the osmotic procedure is due to both increased diffusion and bulk fluid flow across the tight junctions. The permeability effect is largely reversed within 10 min. 3. In experimental animals, the osmotic method has been used to grant wide access to the brain of water-soluble drugs, peptides, antibodies, boron compounds for neutron capture therapy, and viral vectors for gene therapy. The method also has been used together with anticancer drugs to treat patients with metastatic or primary brain tumors, with some success and minimal morbidity.
New clinical protocols are being developed that will entail the administration of considerably higher doses of the boron delivery agent boronophenylalanine (BPA) than those in current clinical use. Fractionation (2 or 4 fractions) of BPA mediated boron neutron capture therapy (BNCT) is also under consideration at some clinical centres. Given the considerably higher infusion volumes that will be entailed in the delivery of BPA in the new high dosage protocols, there will be a requirement to extend the gap between fractions to 2 or more days. In order to assess the effects of a 2 fraction protocol on the therapeutic efficacy of BPA mediated BNCT, a series of split dose irradiations (two equal fractions) were undertaken using the rat intracranially implanted 9L gliosarcoma model. A single dose exposure to BPA mediated BNCT of 3.0 Gy resulted in long term survival levels of 50%. Survival levels increased to 71% and 77% with a 3 and 5 day gap between dose fractions (two equal fractions), respectively, using the same total dose. A further increase in the time interval between dose fractions to 7 days resulted in a reduction in survival to 36%. However, there was no significant difference between the single dose and the 3, 5 and 7 day survival data (P > 0.1) The difference between the 5 and 7 day split dose survival data was of border-line significance (P = 0.05). It is anticipated that mucositis, could become a potential problem in future BNCT clinical protocols involving higher doses, larger field sizes or multiple fields. The potential sparing of the oral mucosa, due to repopulation during the interval between the two fractions, was investigated using a series of split dose BPA mediated BNC irradiations. The ventral surface of the rat tongue was utilised as a model for oral mucosa. The ED50 (50% incidence) values for the ulceration end point were 3.0+/-0.1, 3.2+/-0.1, 3.0+/-0.1 and 3.6+/-0.1 Gy, for 3, 5, 7 and 9 day splits between doses, respectively. It is evident from this data that there were no significant changes in the ED50 (p < 0.001) until the 9 day dose split, when the ED50 value was 20% higher than the ED50 value after a 7 day split. It was concluded that the two fraction BNCT protocol, with dose splits of up to 5 days, did not diminish the therapeutic response of the rat 9L gliosarcoma, when compared with a single dose BNCT protocol. Tolerance of the oral mucosa to BNC irradiation was not increased until there was a 9 day gap between fractions. However, the beneficial effects of dose sparing at this time interval between doses, would probably be counteracted by a reduction in the therapeutic effectiveness of the BNCT modality, due to repopulation of tumour clonogens between doses.
Effective management of diabetes relies on the frequent monitoring of blood glucose concentrations. The current approach of blood sampling and glucose concentration determination in vitro) presents many problems. Therefore, there is a drive for the development of non-invasive and continuous monitoring of glucose concentrations. The use of implanted glucose fluorescent sensors represents a promising approach. Due to its strong interaction with diol moieties, the boronic acid group often plays a critical role in the design of such glucose sensors. This paper reviews the progress in this area during the last ten years.
Boronic acid based anthracene dyes were designed, synthesized, and immobilized to solid phase, creating a continuous glucose sensor. Glucose sensitivities of dyes can decrease drastically after immobilization, therefore how to immobilize a dye to solid phase without changing the dye property is a key issue in developing the sensor. The glucose sensitivity of the simplest 1st generation sensor, which is based on an immobilized mono-phenylboronate/single-arm type, came short of the sensitivity requirement for practical use, because of the very moderate fluorescence intensity change over the physiological glucose range. However, the 2nd generation, an immobilized bis-phenylboronate/double-arm type sensor, which contained two boronate groups in the dye moiety in expectation of a large intensity change, brought about considerable improvement on its glucose sensitivity. We tried to introduce functional groups onto an anthracene ring in order to improve the dies' fluorescence properties. Acetyl or carboxyl substitution on anthracene contributed to shift the fluorescence wavelength into the more visible range (red-shift) and a divergence of wavelength between an excitation peak and an emission peak. This improvement is advantageous to the design of an optical detection system. Furthermore, single arm immobilization to this carboxyl group, thus linking directly to the fluorophore led to a 3rd generation sensor, an immobilized bis-phenylboronate/single-arm type, that was twice as sensitive as that of the 2nd generation sensor, presumably due to increased mobility of the dye moiety. The results of our study advance closer toward a clinically useful continuous fluorescent glucose sensor.
In an ongoing program to synthesize a glucose sensing polymer that could be used for real time glucose monitoring in vivo, we have been exploring the use of boronic acid functional viologens as glucose responsive quenchers for fluorescent dyes. The present study focuses on the effect of ionic interactions between pyranine or its various sulfonamide derivatives and the viologen quenchers. Dyes bearing anionic groups were quenched more efficiently when compared to dyes with nonionic substituents. The anionic dyes in conjunction with the cationic quenchers exhibited a broader range of glucose response both in solution and when immobilized in a hydrogel. The interaction of glucose with the sensing components was similar whether they are soluble or immobilized.
Modular photoinduced electron transfer (PET) sensors bearing two phenylboronic acid groups, one or two fluorophores: pyrene(a), phenanthrene(b), anthracene(c), 1-naphthalene(d), 2-naphthalene(e) and alkylene linkers, from trimethylene(3) to octamethylene(8), have been evaluated. Systems with a single pyrene fluorophore 34a, 35a and 36a bind the strongest with D-glucose (36a also binds well with D-melibiose). Whilst 37a and 38a bind the strongest with D-galactose. Changing the fluorophore, also, influences the binding, 36a, 36b and 36c are D-glucose selective, whilst 36d and 36e are D-galactose selective. Systems with two fluorophores 36a-a and 36a-b show an overall decrease in binding efficiency. Energy transfer in 36a-b results in enhanced sensitivity and selectivity towards D-glucose.
In order to develop a protocol to treat brain metastatic melanoma using our 10B-p-boronophenylalanine (BPA) boron neutron capture therapy (BNCT), we initiated the following studies (i), Comparative analyses of boron biodistribution between melanoma proliferating in the brain and skin among melanotic and amelanotic types, and (ii) Therapeutic evaluation of BPA-BNCT for brain melanoma models of both types, using survival times. Our present data have revealed that boron concentration in melanoma proliferating in the brain, the major prerequisite for successful BNCT, showed a positive correlation to melanin synthesizing activity in the same way as melanoma proliferating in skin. Further, the boron concentration ratio of melanoma to normal surrounding tissue for brain melanoma models was considerably higher than that for subcutaneous (s.c.) ones because of the existence of the blood-brain barrier (BBB). Additionally, from analyses of median and mean survival times following BNCT using low, middle, and high neutron doses, the therapeutic effect of BNCT for the amelanotic A1059 melanoma appeared at first glance to be higher than that for the highly BPA attracting and highly relative biological effect equivalent dose obtaining B15b melanoma. As the survival time was dependent on both regression and regrowth curves, and because the brain melanoma model in small animals made it difficult to evaluate these curves separately, we further examined the in vivo growth curve of both types of melanomas following implantation in s.c. tissue. The melanotic B15b melanoma was indeed found to possess much higher growth rate as compared with that of the amelanotic A1059 melanoma. The significance of boron biodistribution studies and BNCT survival curve analyses in forming an effective clinical protocol for individual human cases of melanoma brain metastasis is discussed.
The cellular distribution of 4-borono-2-[18F]fluoro-L-phenylalanine ([18F]FBPA, an analog of p-boronophenylaline), a potential agent for boron neutron capture therapy (BNCT), and [6-3H]thymidine ([3H]Thd, a DNA precursor) in murine two B16 melanoma sublines and FM3A mammary carcinoma was studied in vivo using double-tracer microautoradiography. Tumour volume, tumour age, cell density in the tissues and the proportion of S phase cells in the cell cycle were the same in the three tumour models. Volume doubling time, which represents tumour growth rate, was fastest in B16F10, followed by B16F1 (P < 0.05), the slowest being in FM3A (P < 0.001). The rate of DNA synthesis in S phase cells corresponded to the volume doubling time. The greatest amount of [18F]FBPA was observed in S phase melanocytes and the lowest amount was found in non-S phase non-melanocytes. The [18F]FBPA accumulation was primarily related to the activity of DNA synthesis and, secondarily, to the degree of pigmentation in melanocytes. The therapeutic efficacy of BNCT with p-boronophenylalanine may be greater in melanoma that exhibits greater DNA synthesis activity and higher melanin content.
1. We investigated the effect of bisphenol A (BPA), which binds estrogen receptors, on immune responses including production of antigen-specific antibodies, proliferative responses of lymphoid cells, and Th1 and Th2 responses. 2. For this investigation, mice were p.o. given varying doses including 3, 30, 300, and 3000 micro g kg(-1) of BPA immediately after immunization with hen egg lysozyme (HEL) (day 0) and then daily by day 20. On day 21, anti-HEL IgG antibodies in sera and proliferative responses of spleen cells to the antigen were measured. Anti-HEL IgG2a antibodies and IFN-gamma secreted from splenic lymphocytes were also measured as indicators of Th1 immune responses, while anti-HEL IgG1 antibodies and IL-4, as those of Th2 responses. 3. The results showed that treatment with 3000 micro g kg(-1) of BPA was followed by a significant increase in anti-HEL IgG as well as the antigen-specific cell proliferation. Anti-HEL IgG2a production and IFN-gamma secretion were significantly enhanced in mice treated with 300 and 30 micro g kg(-1) of BPA, respectively, while anti-HEL IgG1 production and IL-4 secretion were augmented in animals given 3000 and 300 micro g kg(-1) of the chemical, respectively. 4. Augmentation of these immune responses was also observed in mice exposed to 0.3-30 micro g kg(-1) of estradiol, although Th1 responses appeared to be more sensitive to the sex hormone than Th2 responses. 5. These results suggest that BPA may play a role in augmenting immune responses, especially Th1 responses.
The syntheses of the dodeca(carboranyl)-substituted closomers, dodeca[7-(2-methyl-1,2-dicarba-closo-dodecaboran-1-yl)heptanoate]-closo- dodecaborate(2-) and dodeca[7-(8-methyl-7,8-dicarba-nido-dodecaboran-7-yl)- heptanoate]-closo-dodecaborate(14-) are reported. These boron-rich, unimolecular nanospheres possess great potential for future use as drug-delivery platforms for boron neutron capture therapy (BNCT).
Among the polyhedral [closo-BnHn]2- ion series (n = 5-12 inclusive) the aromatic [closo-B10H10]2- ion is both readily available and quite reactive. Among its many reactions which retain its cage structure one finds the oxidative dimerization reaction in which two [closo-B10H12]2- ions each formally lose a hydride ion and undergo dimerization of the resulting [closo-B10H9]- ions to produce the [trans-B20H18]2- ion. The two-component [closo-B10H9]- ions of the latter are linked together by a pair of unique B-B-B bonds which provide unprecedented reactivity to the structure. Among these reactions are the two-electron reduction to a set of three interconvertible [B20H18]4- ions having intercage B-B bonds and the related reductive substitution reaction in which [trans-B20H18]2- undergoes attack by nucleophile, L, to produce [B20H18L]2-. The latter species is formally a substituted [B20H19]3- (L = H) ion formed by B-B bond protonation of one of the isomeric [B20H18]4- ions. These and a variety of novel reactions are described here along with interrelated reaction mechanisms considered for the first time.
A boron-rich, water-soluble porphyrin conjugate was synthesized by coupling of two carboranyl alcohols with 2-chlorophenoxyphosphorus dichloride, followed by conjugation to an amine-functionalized tetraphenyl-porphyrin via an amide linkage.
Homocoupling of naphthyl triflates 27, 16, 17 to the respective binaphthyls 28, 31 and 35 has been achieved in a one-pot procedure using bis(pinacolato)diboron and PdCl2(dppf). Use of potassium acetate as the base provides access to the initial naphthylboronate intermediates whereas the stronger base potassium phosphate is required in order to promote subsequent coupling of the naphthylboronate with a second equivalent of the naphthyl triflate. Attempts to convert binaphthyl 35 into bis-acetylnaphthalene 14, a key intermediate for the synthesis of the dimeric pyranonaphthoquinone antibiotic crisamicin A 2, via double Fries rearrangement of bis-acetate 37 derived from binaphthyl 35, were unsuccessful. Attempts to introduce the acetyl groups at C-7 and C-7' on bis-acetylnaphthalene 14 via Fries rearrangement of the monomeric precursors 21 and 15, before effecting homocoupling to a biaryl were unsuccessful. Introduction of an acetyl group via initial bromination ortho to the hydroxyl group in naphthol 18, which bears an electron rich benzyl ether at C-7, was plagued by the formation of phenolic coupling product 42 and naphthoquinone 43. Bromination of naphthol 45, bearing a less electron rich triflate group at C-7, also afforded binaphthol 47 resulting from phenolic coupling as well as naphthoquinone 48 when using N-bromosuccinimide at low temperature.