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PubMed2002

Determination of alpha-emitting Pu isotopes in environmental samples.

This paper presents an improved radiochemical procedure for the determination of alpha-emitting Pu isotopes in environmental samples (soils, sediments, vegetation) by alpha-particle spectrometry. Quantitative Pu recovery yields were obtained (average 60%), 0.1 mBq being the average minimum detectable activity by the complete technique. Special efforts were made to ensure the removal of traces of different natural alpha-emitting radionuclides, which can interfere with the correct determination of 239+240Pu and 238Pu concentrations. The radiochemical procedure was validated by application to reference material and by participation in intercomparison exercises. This radiochemical procedure was applied to the different layers of a high-resolution sediment core taken from a lake in Sweden. The 239+240Pu and 238Pu/239+240Pu profiles obtained in the high-resolution sediment core correctly reproduced the expected evolution of these quantities as observed historically in the atmosphere, validating the procedure for this purpose and showing the power of these radionuclides for dating purposes.

Journal Article↗

PubMed1994

Potential vascular damage from radiation in the space environment.

Cultured endothelial cells of blood vessels have a Do of 2 Gy for X-rays. A dose of 0.5 Gy of X-rays has an acute effect on vessel diameter. The vessels may show other acute effects such as change in permeability including a change in the blood brain barrier. Changes occurring from late effects of chronic exposure in vascular architecture include telangiectasia and decrease in vascular density. Changes in the perivascular connective tissue particularly collagen may play a role in these changes. After charged particle exposure of 15 and 30 Gy, radiation changes in the blood brain barrier and vascular changes are noted in the nervous system. These long term changes are recorded by PET, MRI, and CT imaging. Chronic exposure to alpha particles causes vascular damage in compact bone resulting in bone infarcts. Using tandem scanning confocal microscopy in-situ imaging of the capillaries and collagen of the papillary dermis provides a non-invasive method of serial recording of changes in irradiated microvasculature.

Animals↗

PubMed1995

Bispecific antibodies as targeting agents for boron neutron capture therapy of brain tumors.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10, a stable isotope, is irradiated with low energy (< or = 0.025 eV) or thermal neutrons to yield alpha particles and recoiling lithium-7 nuclei. A major requirement for the success of BNCT is the selective delivery of a sufficient number of boron atoms (approximately 10(9)) to individual cancer cells to sustain a lethal 10B (n, alpha) 7Li capture reaction. A panel of BsAb reactive with polyhedral borane anions (PBA) and a tumor-associated chondroitin sulfate proteoglycan has been produced. All of these BsAb showed strong reactivity with a panel of human glioblastoma and melanoma cell lines, as demonstrated by indirect membrane immunofluorescence. Two of them (H6 and B8) also reacted with cells that had been exposed to PBA (Na2B10H10 and Na2B12H11SH) and a boronated starburst dendrimer, which contained approximately 250-400 B atoms per molecule. The affinity constant (Ka) of BsAb-B8 was 2.57 x 10(8) M-1 on M21 human melanoma cell and 3.49 x 10(8) M-1 on A172 glioblastoma cells, which were almost identical to those of the parental monoclonal antibody (mAb) 9.2.27 on the same cell lines (2.62 x 10(8) M-1). Since our BsAb recognize both human glioblastoma and melanoma-associated antigens, as well as PBA, they potentially could be used to target 10B to these tumors for BNCT.

Animals↗

PubMed2006

The anti-CD25 monoclonal antibody 7G7/B6, armed with the alpha-emitter 211At, provides effective radioimmunotherapy for a murine model of leukemia.

Radioimmunotherapy of cancer with radiolabeled antibodies has shown promise. alpha-Particles are very attractive for cancer therapy, especially for isolated malignant cells, as is observed in leukemia, because of their high linear energy transfer and short effective path length. We evaluated an anti-CD25 [interleukin-2 receptor alpha (IL-2R alpha)] monoclonal antibody, 7G7/B6, armed with (211)At as a potential radioimmunotherapeutic agent for CD25-expressing leukemias and lymphomas. Therapeutic studies were done in severe combined immunodeficient/nonobese diabetic mice bearing the karpas299 leukemia and in nude mice bearing the SUDHL-1 lymphoma. The results from a pharmacokinetic study showed that the clearance of (211)At-7G7/B6 from the circulation was virtually identical to (125)I-7G7/B6. The biodistributions of (211)At-7G7/B6 and (125)I-7G7/B6 were also similar with the exception of a higher stomach uptake of radioactivity with (211)At-7G7/B6. Therapy using 15 microCi of (211)At-7G7/B6 prolonged survival of the karpas299 leukemia-bearing mice significantly when compared with untreated mice and mice treated with (211)At-11F11, a radiolabeled nonspecific control antibody (P < 0.01). All of the mice in the control and (211)At-11F11 groups died by day 46 whereas >70% of the mice in the (211)At-7G7/B6 group still survived at that time. In summary, (211)At-7G7/B6 could serve as an effective therapeutic agent for patients with CD25-expressing leukemias.

Animals↗

PubMed2006

On the relationship between dose-, energy- and LET-response of thermoluminescent detectors.

Measurements of the response of thermoluminescent (TL) detectors after gamma ray doses high enough to observe signal saturation provide input to microdosimetric models which relate this gamma-ray response with the energy response after low doses of photons (gamma rays and low-energy X rays) and after high-LET irradiation. To measure their gamma ray response up to saturation, LiF:Mg,Ti (MTS-7 and MTT), LiF:Mg,Cu,P (MCP-7), CaSO4:Dy (KCD) and Al2O3:C detectors were irradiated with 60Co gamma rays over the range 1-5000 Gy. The X-ray photon energy response and TL efficiency (relative to gamma rays) after doses of beta rays and alpha particles, were also measured, for CaSO4:Dy and for Al2O3:C. Microdosimetric and track structure modelling was then applied to the experimental data. In a manner similar to LiF:Mg,Cu,P, the experimentally observed under response of alpha-Al2O3:C to X rays <100 keV, compared with cross-section calculations, is explained as a microdosimetric effect caused by the saturation of response of this detector without prior supralinearity (saturation of traps along the tracks). The enhanced X-ray photon energy response of CaSO4:Dy is related to the supralinearity observed in this material after high gamma ray doses, similarly to that in LiF:Mg,Ti. The discussed model approaches support the general rule relating dose-, energy- and ionisation density-responses in TL detectors: if their gamma ray response is sublinear prior to saturation, the measured photon energy response is lower, and if it is supralinear, it may be higher than that expected from the calculation of the interaction cross sections alone. Since similar rules have been found to apply to other solid-state detector systems, microdosimetry may offer a valuable contribution to solid-state dosimetry even prior to mechanistic explanations of physical phenomena in different TL detectors.

Computer Simulation↗

PubMed2002

Summary of stationary and personal air sampling measurements made during a plutonium glovebox decommissioning project.

Workplace air sampling was performed during the decommissioning of a previously active plutonium glovebox facility located at Argonne National Laboratory. Personal air samplers (PAS) were used to measure breathing zone activity concentrations of workers engaged in size-reducing contaminated gloveboxes. Stationary air samplers (SAS) were used to measure the work area activity concentrations and test their application in providing representative sampling of breathing zone activity concentrations. The relative response of these samplers (PAS:SAS) was tracked during the course of the decommissioning work, with results yielding favorable agreement to within a factor of +/-5. A cascade impactor was used to determine the particle size distribution of workplace aerosols. The average activity median aerodynamic diameter (AMAD) was estimated to be 3.0 microm, with a corresponding geometric standard deviation of 2.4. A gas-flow proportional counter was utilized to measure the gross alpha activity collected on both the SAS glass fiber and the PAS cellulose fiber filters. A subset of this filter group was subsequently analyzed using an alpha spectrometer post radiochemical processing and isotopic separation. The quantity of alpha activity measured on the SAS filters was generally within +/-30% of the alpha spectrometry measurements. However, measurements made of the activity present on the PAS cellulose fiber filters were consistently underestimated using a gas-flow proportional counter, suggesting a small correction factor of 15-20% to account for the absorption of alpha particle emissions.

Air Pollutants, Occupational↗

PubMed2006

Probing lethal damage expression in cytochalasin B-induced polykaryons by radiation quality.

The polykaryon-forming unit (PFU) cell survival assay is based on the postirradiation flow cytometric analysis of the DNA content accumulated in high-ploidy cells (polykaryons) induced by the cytokinesis inhibitor cytochalasin B and can provide a meaningful measure of cell radiosensitivity. In this assay, cell survival is defined as the ability to form a polykaryon of a given ploidy after irradiation. The slope of the polykaryon dose response has been shown to be highly correlated with the initial slope of the clonogenic survival curves after gamma irradiation, which implies a common subset of lethal lesions. We reported previously on an apoptotic mode of cell death in the polykaryon system and on the heritability of small variations in polykaryon radioresponse. We now show that exposure of PFUs to a given dose of alpha particles results in a greater reduction in the proportion of cells able to reach at least 16C when compared to the same dose of low-LET radiation. This reduction is less than that observed in the low-dose (alpha term) region of the clonogenic curve. On the basis of published LET-dependent spectra of radiation-induced DNA damage, we suggest that this behavior reflects a differential expression of lethal damage that can be probed by varying the LET of the radiation and that base damages contributing additional complexity to clustered DNA lesions may be more deleterious in PFUs than in clonogens.

Animals↗

PubMed2003

Genomic instability and bystander effects induced by high-LET radiation.

An understanding of the radiobiological effects of high-linear energy transfer (LET) radiation is essential for radiation protection and human risk assessment. Ever since the discovery of X-rays was made by Röntgen more than a century ago, it has always been accepted that the deleterious effects of ionizing radiation, such as mutation and carcinogenesis, are due mainly to direct damage to DNA. With the availability of a precision single-particle microbeam, it is possible to demonstrate, unequivocally, the presence of a bystander effect with many biological end points. These studies provide clear evidence that irradiated cells can induce a bystander mutagenic response in neighboring cells not directly traversed by alpha-particles, and that cell-cell communication processes play a critical role in mediating the bystander phenomenon. Following exposure to high-LET radiation, immortalized human bronchial (BEP2D) and breast (MCF-10F) cells have been shown to undergo malignant transformation through a series of successive steps, before becoming tumorigenic in nude mice. There is a progressive increase in genomic instability, determined either by gene amplification or allelic imbalance, with the highest incidence observed among established tumor cell lines, relative to transformed, nontumorigenic and control cell lines.

Animals↗

PubMed1990

Iodine-125-NRLU-10 kinetic studies and bismuth-212-NRLU-10 toxicity in LS174T multicell spheroids.

Alpha emitter-labeled antibodies (Abs) are of considerable interest in cancer therapy. Alpha particles are densely ionizing and therefore have a high radiobiologic effectiveness, and the cell killing produced is influenced very little by dose rate or hypoxic conditions. LS174T human colon adenocarcinoma spheroids were used in this study to evaluate the efficacy of alpha emitter-labeled Abs in a three-dimensional model. NRLU-10, an IgG2b Ab to a pancarcinoma antigen, and its Fab fragment were used. Initial kinetic studies using 125I-NRLU-10 revealed that a large number of binding sites/cell and high Ab affinity led to slow Ab penetration. This effect could be overcome by increasing the Ab concentration ten-fold for Fab but not for intact Ab. Bismuth-212-NRLU-10 therapy was very effective in killing single cells (over 3 log reduction in surviving fraction) but was ineffective in spheroids (less than 1 log reduction). This was likely due to inadequate penetration into the spheroids before the 212Bi decayed. The use of higher Ab concentrations, tumors with fewer antigenic sites/cell for the Ab being used, lower affinity Abs, alpha emitters with longer half-lives, and pretargeting with bifunctional Ab are all potential ways of increasing the efficacy of alpha emitter-labeled Abs for cancer therapy.

Adenocarcinoma↗

PubMed1990

DNA radiolysis by fast neutrons.

The effects of fast neutron irradiation on DNA were studied using DNA of the pBR322 plasmid (4362 base pairs), and the results compared to those obtained with 60Co gamma rays. Irradiation of the plasmid DNA in solution with a neutrons beam (p34+Be) of the CERI (CNRS Orléans) cyclotron (with a flat energy spectrum from 34 MeV to low energies) results in half the yield of single-strand breaks (ssb), and 1.5 times higher yield of double-strand breaks (dsb) for neutrons as compared to gamma-rays. Possible specificity of the neutron-induced breaks was examined: the scavenging of OH. radicals by 0.1 mol dm-3 ethanol inhibits all neutron-induced ssb, but only 85 per cent of the dsb. For gamma-irradiation, both ssb and dsb are completely inhibited in these conditions. These results suggest at least three different origins for neutron-induced dsb. The occurrence of around 30 per cent of dsb can be explained by a radical transfer mechanism (proposed by Siddiqi and Bothe (1987) for gamma-irradiation). Around 55 per cent of dsb may be due to the non-random distribution of radicals in high-density tracks of the secondary particles of neutrons, which results in a simultaneous attack of the two strands by OH. radicals. These first two processes are both OH.-mediated and thus are sensitive to ethanol. The direct effect of fast neutrons and their secondaries (recoil protons, alpha-particles and recoil nuclei) can account for the remaining 15 per cent of dsb, not inhibited by 0.1 mol dm-3 ethanol.

Cobalt Radioisotopes↗

PubMed1992

Boron neutron capture therapy for cancer. Realities and prospects.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10 (10B), is irradiated with low-energy thermal neutrons (nth) to yield (4He) alpha-particles and 7Li nuclei (10B+nth-->[11B]-->4He+7Li+2.31 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of 10B and nth to individual cancer cells to sustain a lethal 10B(n, alpha) 7Li reaction. The current review covered the radiobiologic considerations on which BNCT is based, including a brief discussion of microdosimetry and normal tissue tolerance. The development of tumor-localizing boron compounds was discussed, including the sulfhydryl-containing polyhedral borane, sodium borocaptate (Na2B12H11SH), and boronophenylalanine (BPA), both of which are currently being used clinically in Japan as capture agents for malignant brain tumors and melanomas, respectively. Compounds currently under evaluation, such as boronated porphyrins, nucleosides, liposomes, and monoclonal antibodies (MoAbs), were also considered. Nuclear reactors have been used as the exclusive source of neutrons for BNCT. The use of low-energy (0.025 eV) thermal neutrons and higher-energy (1-10,000 eV) epithermal beams, beam optimization, and possible alternative neutron sources (accelerators) were also discussed. Clinical studies performed in the United States during the 1950s and 1960s for the treatment of malignant brain tumors were reviewed. Current studies in Japan and future studies in Europe and the United States concerning the treatment of glioblastomas and melanomas by BNCT were discussed, as were critical issues that must be addressed if BNCT is ever to be a useful therapeutic modality.

Boron Neutron Capture Therapy↗

PubMed2003

Assessment of proton microbeam analysis of 11B for quantitative microdistribution analysis of boronated neutron capture agents in biological tissues.

The (11)B(p,alpha)(8)Be* nuclear reaction was assessed for its ability to quantitatively map the in vivo subcellular distribution of boron within gliosarcomas treated with a boronated neutron capture therapy agent. Intracranial 9L gliosarcomas were produced in Fischer 344 rats. Fourteen days later, the majority of the rats were treated with f-boronophenylalanine and killed humanely 30 or 180 min after intravenous injection. Freeze-dried tumor cryosections were imaged using the (11)B(p,alpha)(8)Be* nuclear reaction and proton microbeams obtained from the nuclear microprobe at Lawrence Livermore National Laboratory. The (11)B distributions within cells could be imaged quantitatively with spatial resolutions down to 1.5 microm, minimum detection limits of 0.8 mg/kg, and acquisition times of several hours. These capabilities offer advantages over alpha-particle track autoradiography, electron energy loss spectroscopy, and secondary ion mass spectrometry (SIMS) for quantification of (11)B in tissues. However, the spatial resolution, multi-isotope capability, and analysis times achieved with SIMS are superior to those achieved with (11)B(p,alpha)(8)Be* analysis. When accuracy in quantification is crucial, the (11)B(p,alpha)(8)Be* reaction is well suited for assessing the microdistribution of (11)B. Otherwise, SIMS may well be better suited to image the microdistribution of boron associated with neutron capture therapy agents in biological tissues.

Animals↗

PubMed2006

Particle therapy and treatment of cancer.

The desire of radiation oncologists and medical physicists to maximise the radiation dose to the tumour while minimising that to healthy tissues has led to attempts to improve the dose distributions and biological effects achievable with photons and electrons. Protons, neutrons, pions, boron-neutron capture therapy, and charged-nuclei therapy (with argon, carbon, helium [alpha particles], neon, nitrogen, and silicon) have been assessed for their physical, biological, and clinical effects. In the 90 years since protons and neutrons were discovered, investigations of particle therapy for cancer have helped to elucidate many fundamental radiobiological ideas, such as linear energy transfer, relative biological effectiveness, oxygen effect, and oxygen enhancement. Particle therapy has contributed to our understanding of medical ethics when neutron therapy became intertwined with the debate over standards of informed consent in radiation experiments in humans during the cold war era. Particle teletherapy and brachytherapy continue to show promise in some clinical situations. In the future, the insights of molecular biology might clarify the ideal particles for clinical situations.

Brachytherapy↗

PubMed2003

In vitro evaluation of 213Bi-rituximab versus external gamma irradiation for the treatment of B-CLL patients: relative biological efficacy with respect to apoptosis induction and chromosomal damage.

External source radiotherapy and beta radioimmunotherapy (RIT) are effective treatments for lymphoid malignancies. The development of RIT with alpha emitters is attractive because of the high linear energy transfer (LET) and short path length, allowing higher tumour cell kill and lower toxicity to healthy tissues. We assessed the relative biological efficacy (RBE) of alpha RIT (in vitro) compared to external gamma irradiation with respect to induction of apoptosis in B chronic lymphocytic leukaemia (B-CLL) and induction of chromosomal damage in healthy donor B and T lymphocytes. The latter was measured by a micronucleus assay. 213Bi was eluted from a 225Ac generator and conjugated to CD20 antibody (rituximab) with CHX-A"-DTPA as a chelator. B-CLL cells from five patients were cultured for 24 h in RPMI/10% FCS while exposed to 213Bi conjugated to CD20 antibody or after external 60Co gamma irradiation. Binding assays were performed in samples of all patients to calculate the total absorbed dose. Apoptosis was scored by flow cytometric analyses of the cells stained with annexin V-FITC and 7-AAD. Apoptosis was expressed as % excess over spontaneous apoptosis in control. Full dose range experiments demonstrated 213Bi-conjugated CD20 antibody to be more effective than equivalent doses of external gamma irradiation, but showed that similar plateau values were reached at 10 Gy. The RBE for induction of apoptosis in B-CLL was 2 between 1.5 and 7 Gy. The micronucleus yield in lymphocytes of healthy volunteers was measured to assess the late toxicity caused by induction of chromosomal instability. While gamma radiation induced a steady increase in micronucleus yields in B and T cells, the damage induced by 213Bi was more dramatic, with RBE ranging from 5 to 2 between 0.1 Gy and 2 Gy respectively. In contrast to gamma irradiation, 213Bi inhibited mitogen-stimulated mitosis almost completely at 2 Gy. In conclusion, high-LET targeted alpha particle exposure killed B-CLL cells more effectively than did external gamma irradiation at a low dose (RBE=2), while a plateau was reached at a high dose. Long-term toxicity on healthy B and T lymphocytes was systematically higher for the alpha emitter (RBE=5 to 2).

Aged↗

PubMed1999

Boron neutron capture therapy of brain tumors: an emerging therapeutic modality.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10, a stable isotope, is irradiated with low-energy thermal neutrons to yield alpha particles and recoiling lithium-7 nuclei. For BNCT to be successful, a large number of 10B atoms must be localized on or preferably within neoplastic cells, and a sufficient number of thermal neutrons must be absorbed by the 10B atoms to sustain a lethal 10B (n, alpha) lithium-7 reaction. There is a growing interest in using BNCT in combination with surgery to treat patients with high-grade gliomas and possibly metastatic brain tumors. The present review covers the biological and radiobiological considerations on which BNCT is based, boron-containing low- and high-molecular weight delivery agents, neutron sources, clinical studies, and future areas of research. Two boron compounds currently are being used clinically, sodium borocaptate and boronophenylalanine, and a number of new delivery agents are under investigation, including boronated porphyrins, nucleosides, amino acids, polyamines, monoclonal and bispecific antibodies, liposomes, and epidermal growth factor. These are discussed, as is optimization of their delivery. Nuclear reactors currently are the only source of neutrons for BNCT, and the fission reaction within the core produces a mixture of lower energy thermal and epithermal neutrons, fast or high-energy neutrons, and gamma-rays. Although thermal neutron beams have been used clinically in Japan to treat patients with brain tumors and cutaneous melanomas, epithermal neutron beams now are being used in the United States and Europe because of their superior tissue-penetrating properties. Currently, there are clinical trials in progress in the United States, Europe, and Japan using a combination of debulking surgery and then BNCT to treat patients with glioblastomas. The American and European studies are Phase I trials using boronophenylalanine and sodium borocaptate, respectively, as capture agents, and the Japanese trial is a Phase II study. Boron compound and neutron dose escalation studies are planned, and these could lead to Phase II and possibly to randomized Phase III clinical trials that should provide data regarding therapeutic efficacy.

Boron Neutron Capture Therapy↗

PubMedDate not supplied

Measurement of dose distributions of linear energy transfer in matter irradiated by fast neutrons.

A detector has been developed and used to measure dose distributions versus linear energy transfer to thin gas targets in spherical geometry from fast neutron irradiation of tissue-equivalent plastic and carbon. The detector is a hemispherical proportional counter with a Cs(T1) scintillator at the center of the hemisphere. The coincidence of the proportional counter signals constrain the measurements to charged particles traversing the radius of the hemisphere. The charged particle energy deposition distributions are directly measured for a known pathlength. The A-150 kerma factor was measured at a neutron energy of 14.8 MeV and is in agreement with tabulated values. The carbon kerma factor measurements are less than the tabulated value at 14.8 MeV. The alpha-particle production in carbon was measured for neutron energies from 14.1 to 14.8 MeV and is compared with existing data.

Energy Transfer↗

PubMed2004

Aspects of the geographical variations of naturally occurring 210Pb/210Po in permanent teeth of juveniles in the UK.

PURPOSE: To study geographical variations in the level of naturally occurring 210Pb-supported 210Po in permanent teeth of juveniles in the UK. MATERIALS AND METHODS: Permanent teeth extracted from 278 juveniles for orthodontic purposes were obtained from 48 counties in the UK. 210Po activity concentration was measured on the outer enamel surface using TASTRAK alpha-particle-sensitive plastic track detectors. RESULTS: Geometric mean +/- SE activity concentrations in teeth from urban, suburban and rural areas, excluding the high radon area of Devon, were 8.41 + 0.25/-0.24, 7.76 + 0.37/-0.35 and 7.20 +0.49/-0.46 Bq kg(-1), respectively. Overall, there was no significant association between alpha-activity on the outer enamel surface of permanent teeth and proximity to the major UK motorways. However, when the data were considered with respect to the prevailing south-westerly wind on the western side of the UK, a statistically significant association with respect to donors living downwind (on the easterly side) of the motorways was found. This effect was greater for sections of the M5 and M6 motorways that traverse urban areas. 210Po levels in teeth were also associated with domestic radon concentration. This effect was comparable with that from traffic and urban pollution. CONCLUSIONS: Higher levels of 210Pb-supported 210Po are seen in permanent teeth of juveniles near sources of increased exposure in the UK. Inhalation uptake is an important pathway of exposure, especially with respect to domestic radon exposure. The results might be important in assessing integrated exposure to 210Po in the skeleton and consequent high linear energy transfer dose to bone marrow.

Adolescent↗

PubMed2006

Boron containing macromolecules and nanovehicles as delivery agents for neutron capture therapy.

Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive boron-10 is irradiated with low energy thermal neutrons to yield high linear energy transfer (LET) alpha particles ((4)He) and recoiling lithium -7((7)Li) nuclei. For BNCT to be successful, a sufficient number of (10)B atoms ( approximately 10(9) atoms/cell) must be selectively delivered to the tumor and enough thermal neutrons must be absorbed by them to sustain a lethal (10)B(n, alpha) (7)Li capture reaction. BNCT primarily has been used to treat patients with brain tumors, and more recently those with head and neck cancer. Two low molecular weight (LMW) boron delivery agents currently are being used clinically, sodium borocaptate and boronophenylalanine. However, a variety of high molecular weight (HMW) agents consisting of macromolecules and nanovehicles have been developed. This review will focus on the latter which include: monoclonal antibodies, dendrimers, liposomes, dextrans, polylysine, avidin, folic acid, and epidermal and vascular endothelial growth factors (EGF and VEGF). Procedures for introducing boron atoms into these HMW agents and their chemical properties will be discussed. In vivo studies on their biodistribution will be described, and the efficacy of a subset of them, which have been used for BNCT of tumors in experimental animals, will be discussed. Since brain tumors currently are the primary candidates for treatment by BNCT, delivery of these HMW agents across the blood-brain barrier presents a special challenge. Various routes of administration will be discussed including receptor-facilitated transcytosis following intravenous administration, direct intratumoral injection and convection enhanced delivery by which a pump is used to apply a pressure gradient to establish bulk flow of the HMW agent during interstitial infusion. Finally, we will conclude with a discussion relating to issues that must be addressed if these HMW agents are to be used clinically.

Animals↗