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PubMed1992

Model studies directed toward the boron neutron-capture therapy of cancer: boron delivery to murine tumors with liposomes.

The successful treatment of cancer by boron neutron-capture therapy (BNCT) requires the selective concentration of boron-10 within malignant tumors. The potential of liposomes to deliver boron-rich compounds to tumors has been assessed by the examination of the biodistribution of boron delivered by liposomes in tumor-bearing mice. Small unilamellar vesicles with mean diameters of 70 nm or less, composed of a pure synthetic phospholipid (distearoyl phosphatidylcholine) and cholesterol, have been found to stably encapsulate high concentrations of water-soluble ionic boron compounds. The hydrolytically stable borane anions B10H10(2-), B12H11SH2-, B20H17OH4-, B20H19(3-), and the normal form and photoisomer of B20H18(2-) were encapsulated in liposomes as their soluble sodium salts. The tissue concentration of boron in tumor-bearing mice was measured at several time points over 48 h after i.v. injection of emulsions of liposomes containing the borane anions. Although the boron compounds used do not exhibit an affinity for tumors and are normally rapidly cleared from the body, liposomes were observed to selectively deliver the borane anions to tumors. The highest tumor concentrations achieved reached the therapeutic range (greater than 15 micrograms of boron per g of tumor) while maintaining high tumor-boron/blood-boron ratios (greater than 3). The most favorable results were obtained with the two isomers of B20H18(2-). These boron compounds have the capability to react with intracellular components after they have been deposited within tumor cells by the liposome, thereby preventing the borane ion from being released into blood.

Animals↗
PubMed1982

Boradeption: a new procedure for transferring water-insoluble agents across cell membranes.

A new process has been developed which is called "Boradeption" to signify boronic acid--dependent phase transfer of water-insoluble agents. Highly fluorescent boronic acid dervatives, FluoroBoras, are solubilized with a physiologically compatible carrier buffer containing a receptor group for boronate adduct formation. The system can be used to stain living cells. In another variation of the Boradeption concept, an insoluble reporter molecule containing a boronate receptor is solubilized with a carrier buffer containing a boronic acid functional group. The boronate-receptor complexes, which are in dynamic equilibrium, can be designed as vital stains and reagents for a variety of biological and medical applications.

Animals↗
PubMedDate not supplied

Synthesis of cetuximab-immunoliposomes via a cholesterol-based membrane anchor for targeting of EGFR.

The objective of the present study was to construct epidermal growth factor receptor (EGFR) targeting cetuximab-immunoliposomes (ILs) for targeted delivery of boron compounds to EGFR(+) glioma cells for neutron capture therapy. The ILs were synthesized by using a novel cholesterol-based membrane anchor, maleimido-PEG-cholesterol (Mal-PEG-Chol), to incorporate cetuximab into liposomes by either surface conjugation or a post-insertion method. For post-insertion, the transfer efficiency of MAb conjugates from micelles to liposome was examined at varying temperatures, mPEG2000-DSPE ratios, and micelle-to-liposome lipid ratios. Following this, the cetuximab-ILs were evaluated for targeted delivery of the encapsulated boron anion, dodecahydro-closo-dodecaborate (2-) (B12H122-), to human EGFR gene transfected F98EGFR glioma cells as potential delivery agents for boron neutron capture therapy (BNCT). In addition, cellular uptake of cetuximab-ILs, encapsulating a fluorescence dye, was analyzed by confocal fluorescence microscopy and flow cytometry, and boron content was quantified by ICP-MS. Much greater ( approximately 8-fold) cellular uptake of boron was obtained using cetuximab-ILs in EGFR(+) F98EGFR compared with nontargeted human IgG-ILs. On the basis of these observations, we have concluded that cholesterol can serve as an effective anchor for MAb in liposomes, and cetuximab-ILs are potentially useful delivery vehicles for BNCT of gliomas.

Antibodies, Monoclonal↗
PubMed1995

Monte Carlo simulation of the biological effects of boron neutron capture irradiation with d(14)+Be neutrons in vitro.

It was shown that radiation effects in tumor cells treated with fast neutrons may be increased by the neutron capture reaction 10B(n, alpha)7Li. The classic approach for macroscopic dosimetry in fast-neutron therapy cannot be applied to the dose in boron neutron capture therapy (BNCT). The effectiveness of BNCT in killing tumor cells depends on the number of 10B atoms delivered to the tumor, the subcellular distribution of 10B and the thermal neutron fluence at the site of the tumor. Monte Carlo calculations of the energy depositions of short-range particles with high LET coming from 10B disintegrations were performed and compared to the observed biological effects. The simulation allows us to study the influence of the localization of intracellular 10B in the nucleus, cytoplasma, plasma membrane or extracellular space. The biological response function which describes the probability of the lethal effect produced by a single particle track through the cell nucleus was found by comparing the calculated microscopic dose distribution spectra for single events with the survival observed experimentally. Calculations for a human melanoma cell population treated as a monolayer in the presence or absence of boron with d(14)+Be neutrons will be demonstrated. Two different boron compounds enriched in 10B were investigated in this study: boric acid (H3 10BO3) and p-dihydroxyboryl phenylalanine (BPA). The study shows that a high fraction of BPA enters the cytoplasm while boric acid was found only in the extracellular space. The computer simulations indicate that BPA yields a higher potential effectiveness for inactivation of melanoma cells than boric acid.

Boron Neutron Capture Therapy↗
PubMed1995

A novel approach to the microdosimetry of neutron capture therapy. Part I. High-resolution quantitative autoradiography applied to microdosimetry in neutron capture therapy.

A novel approach to the microdosimetry of neutron capture therapy has been developed using high-resolution quantitative autoradiography (HRQAR) and two-dimensional Monte Carlo simulation. This approach has been applied using actual cell morphology (nuclear and cytoplasmic cell structures) and the measured microdistribution of boron-10 in a transplanted murine brain tumor (GL261) containing p-boronophenylalanine (BPA) as the boron compound. The 2D Monte Carlo transport code for the alpha and 7Li charged particles from the 10B(n,alpha)7Li reactions has been developed as a surrogate to a full 3D approach to calculate a variety of different microdosimetric parameters. The HRQAR method and the surrogate 2D Monte Carlo approach are described in detail and examples of their use are presented.

Animals↗
PubMed2004

Boronphenylalanine insertion in cationic liposomes for Boron Neutron Capture Therapy.

Cationic liposomes are widely used as carriers of biomolecules specifically targeted to the cell nucleus. p-Boronphenylalanine (BPA) is a powerful anti-tumor agent for Boron Neutron Capture Therapy (BNCT). In this paper, (1)H and (13)C NMR was used to study the insertion of BPA in mixed liposomes, made up by the positively charged 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the zwitterionic 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The boronated drug was distributed between the water phase and the liposomes. The location site of BPA into the lipid bilayer was investigated and the boron-substituted aromatic ring was found inserted in the hydrophobic region, whereas the amino acidic group was oriented towards the aqueous environment. Further information was given by proton spin-lattice relaxation rates.

Boron Compounds↗
PubMed1995

Biodistribution of boron sulfhydryl for boron neutron capture therapy in patients with intracranial tumors.

The biodistribution of boron sulfhydryl (BSH) was evaluated for boron neutron capture therapy of brain tumors. A selective boron delivery to the neoplasm is a prerequisite for successful therapy. The uptake of BSH after intravenous administration was analyzed in neoplastic and normal tissues in 61 patients undergoing craniotomies for intracranial tumors. The patients received 10 to 100 mg of BSH/kg (5-50 mg of 10B/kg) body weight, 2 to 72 hours before surgery. The tumor boron concentrations ranged from 0.2 ppm (micrograms/g) in a low-grade glioma to 19.5 ppm in a high-grade glioma. The tumor to blood boron ratio rose above 1 in 15 of 24 high-grade intracerebral tumors, 18 h or more after BSH infusion. The boron concentration in high-grade tumors was heterogeneous. Low-grade intracerebral tumors showed a low boron concentration with a tumor to blood ratio below 1. Extracerebral tumors, mainly meningiomas, showed boron concentrations comparable with high-grade tumors, with a tumor to blood ratio above 1 in 10 of 17 patients. The boron concentrations in skin and muscle compared roughly with the blood values. Boron did not enter normal brain in any significant amount. In high-grade tumors, tumor to brain ratios were above 2. Low boron concentrations in normal brain make BSH safe for a Phase I normal tissue tolerance study. Computed tomographic contrast enhancement was evaluated to tumor boron uptake for 30 patients. Tumor enhancement on computed tomography does not permit the prediction of individual tumor boron concentrations; however, the absence of a contrast enhancement was always associated with low boron uptake.

Adult↗
PubMed2003

Inhibition of the enzymatic activity of prostate-specific antigen by boric acid and 3-nitrophenyl boronic acid.

BACKGROUND: Prostate specific antigen (PSA) is a well-established marker of prostate cancer, but it can also degrade extracellular matrix proteins such as fibronectin and could be involved in tumor progression and metastasis. In this study, we have addressed the use of boric acid and 3-nitrophenyl boronic acid (NPBA) as PSA inhibitors in vitro. METHODS: The inhibition of PSA by boric acid was studied by using specific fluorogenic substrates. Fibronectin, a biologically relevant substrate for PSA, was used as a substrate in a zymographic assay, and the degradation of fibronectin by PSA in the presence of boric acid and NPBA was followed by Western Blot. RESULTS: Low concentrations of boric acid partially inhibited the proteolytic activity of PSA toward a synthetic fluorogenic substrate. Also, by Western blot, we have found significant inhibition in the proteolysis of fibronectin by PSA in the presence of boric acid as well as NPBA. Results indicate that the boronated compounds used in this study can be used for the modulation of PSA activity. CONCLUSION: PSA activity is inhibited in vitro by boric acid and NPBA. If degradation of fibronectin by PSA were, in fact, an important step in the progression of prostate cancer, then borate-induced inhibition of PSA activity should help reduce the development and proliferation of prostate carcinomas.

Blotting, Western↗
PubMed2006

The potential of transferrin-pendant-type polyethyleneglycol liposomes encapsulating decahydrodecaborate-(10)B (GB-10) as (10)B-carriers for boron neutron capture therapy.

PURPOSE: To evaluate GB-10-encapsulating transferrin (TF)-pendant-type polyethyleneglycol (PEG) liposomes as tumor-targeting (10)B-carriers for boron neutron capture therapy. METHODS AND MATERIALS: A free mercaptoundecahydrododecaborate-(10)B (BSH) or decahydrodecaborate-(10)B (GB-10) solution, bare liposomes, PEG liposomes, or TF-PEG liposomes were injected into SCC VII tumor-bearing mice, and (10)B concentrations in the tumors and normal tissues were measured by gamma-ray spectrometry. Meanwhile, tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all intratumor proliferating cells, then injected with these (10)B-carriers containing BSH or GB-10 in the same manner. Right after thermal neutron irradiation, the response of quiescent (Q) cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. The frequency in the total tumor cells was determined from the BrdU nontreated tumors. RESULTS: Transferrin-PEG liposomes showed a prolonged retention in blood circulation, low uptake by reticuloendothelial system, and the most enhanced accumulation of (10)B in solid tumors. In general, the enhancing effects were significantly greater in total cells than Q cells. In both cells, the enhancing effects of GB-10-containing (10)B-carriers were significantly greater than BSH-containing (10)B-carriers, whether loaded in free solution or liposomes. In both cells, whether BSH or GB-10 was employed, the greatest enhancing effect was observed with TF-PEG liposomes followed in decreasing order by PEG liposomes, bare liposomes, and free BSH or GB-10 solution. In Q cells, the decrease was remarkable between PEG and bare liposomes. CONCLUSIONS: In terms of biodistribution characteristics and tumor cell-killing effect as a whole, including Q cells, GB-10 TF-PEG liposomes were regarded as promising (10)B-carriers.

Animals↗
PubMed2004

Dose response of the AIA rabbit stifle joint to boron neutron capture synovectomy.

This study assessed the treatment with boron neutron capture synovectomy of synovitis in the antigen-induced arthritis (AIA) model. A boron compound, potassium dodecahydrododeca-borate (K(2)B(12)H(12)), was injected into stifle joints of 24 AIA and 12 normal rabbits and activated by neutron bombardment of the joint to achieve doses from 800 to 81,000 RBE-cGy. Synovial ablation in the AIA joint was accomplished at doses of 6,000 to 7,000 RBE-cGy with no adverse effects to skin or extracapsular tissues.

Animals↗
PubMed1999

Pharmacological uses and perspectives of heavy water and deuterated compounds.

Since the discovery of D20 (heavy water) and its use as a moderator in nuclear reactors, its biological effects have been extensively, although seldom deeply, studied. This article reviews these effects on whole animals, animal cells, and microorganisms. Both "solvent isotope effects," those due to the special properties of D20 as a solvent, and "deuterium isotope effects" (DIE), which result when D replaces H in many biological molecules, are considered. The low toxicity of D20 toward mammals is reflected in its widespread use for measuring water spaces in humans and other animals. Higher concentrations (usually >20% of body weight) can be toxic to animals and animal cells. Effects on the nervous system and the liver and on formation of different blood cells have been noted. At the cellular level, D20 may affect mitosis and membrane function. Protozoa are able to withstand up to 70% D20. Algae and bacteria can adapt to grow in 100% D2O and can serve as sources of a large number of deuterated molecules. D2O increases heat stability of macromolecules but may decrease cellular heat stability, possibly as a result of inhibition of chaperonin formation. High D2O concentrations can reduce salt- and ethanol-induced hypertension in rats and protect mice from gamma irradation. Such concentrations are also used in boron neutron capture therapy to increase neutron penetration to boron compounds bound to malignant cells. D2O is more toxic to malignant than normal animal cells, but at concentrations too high for regular therapeutic use. D2O and deuterated drugs are widely used in studies of metabolism of drugs and toxic substances in humans and other animals. The deuterated forms of drugs often have different actions than the protonated forms. Some deuterated drugs show different transport processes. Most are more resistant to metabolic changes, especially those changes mediated by cytochrome P450 systems. Deuteration may also change the pathway of drug metabolism (metabolic switching). Changed metabolism may lead to increased duration of action and lower toxicity. It may also lead to lower activity, if the drug is normally changed to the active form in vivo. Deuteration can also lower the genotoxicity of the anticancer drug tamoxifen and other compounds. Deuteration increases effectiveness of long-chain fatty acids and fluoro-D-phenylalanine by preventing their breakdown by target microorganisms. A few deuterated antibiotics have been prepared, and their antimicrobial activity was found to be little changed. Their action on resistant bacteria has not been studied, but there is no reason to believe that they would be more effective against such bacteria. Insect resistance to insecticides is very often due to insecticide destruction through the cytochrome P450 system. Deuterated insecticides might well be more effective against resistant insects, but this potentially valuable possibility has not yet been studied.

Animals↗
PubMed2002

Synthesis and DNA-binding properties of cationic 2,2':6',2' '-terpyridineplatinum(II) complexes containing 1,2- and 1,7-dicarba-closo-dodecaborane(12).

The first examples of DNA metallointercalators containing a dicarba-closo-dodecaborane(12) (carborane) moiety are presented. Treatment of the labile platinum(II) complex [Pt(OTf)(terpy)](+) (terpy = 2,2':6',2' '-terpyridine) with the 1,2-carborane monothiol derivatives 1-HS(CH(2))(n)-1,2-C(2)B(10)H(11) (n = 0, 1) or the novel 1,7-carborane ligand, 1-HSCH(2)-1,7-C(2)B(10)H(11), affords the stable, brightly colored species [Pt(1-S(CH(2))(n)-1,Z-C(2)B(10)H(11))(terpy)](+) (Z = 2, n = 0, 1; Z = 7, n = 1) in good yield and purity. Preliminary DNA-binding experiments with calf-thymus DNA indicate an intercalative interaction by the platinum(II) complexes at high r(f) values.

Animals↗
PubMed2004

Combination of boron neutron capture therapy and external beam radiotherapy for brain tumors.

PURPOSE: Boron neutron capture therapy (BNCT) has been used clinically as a single modality treatment for high-grade gliomas and melanomas metastatic to the brain. The purpose of the present study was to determine whether its efficacy could be enhanced by an X-ray boost administered after BNCT. Two brain tumor models were used, the F98 glioma as a model for primary brain tumors and the MRA 27 human melanoma as a model for metastatic brain tumors. METHODS AND MATERIALS: For biodistribution studies, either 10(5) F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats or 10(6) MRA 27 melanoma cells were implanted intracerebrally into National Institutes of Health (NIH)-rnu nude rats. Biodistribution studies were performed 11-13 days after implantation of the F98 glioma and 20-24 days after implantation of the MRA 27 melanoma. Animals bearing the F98 glioma received a combination of two boron-containing drugs, sodium borocaptate at a dose of 30 mg/kg and boron phenylalanine (BPA) at a dose of 250 mg/kg. MRA 27 melanoma-bearing rats received BPA (500 mg/kg) containing an equivalent amount of 10B (27 mg B/kg). The drugs were administered by either intracarotid or i.v. injection. RESULTS: The tumor boron concentration after intracarotid injection was approximately 50% greater in the F98 glioma and MRA 27 melanoma after intracarotid injection (20.8 and 36.8 microg/g, respectively) compared with i.v. injection (11.2 and 19.5 microg/g, respectively). BNCT was carried out at the Brookhaven National Laboratory Medical Research Reactor approximately 14 days after tumor implantation of either the F98 glioma or the MRA 27 melanoma. Approximately 7-10 days after BNCT, subsets of animals were irradiated with 6-MV photons, produced by a linear accelerator at a total dose of 15 Gy, delivered in 5-Gy daily fractions. F98 glioma-bearing rats that received intracarotid or i.v. sodium borocaptate plus BPA, followed 2.5 h later by BNCT and 7-10 days later by X-rays, had similar mean survival times (61 days and 53 days, respectively, p = 0.25), and the non X-irradiated, BNCT-treated animals had a mean survival time of 52 and 40 days, respectively, for intracarotid vs. i.v. injection; the latter was equivalent to that of the irradiated animals. The corresponding survival time for MRA 27 melanoma-bearing rats that received intracarotid or i.v. BPA, followed by BNCT and then X-irradiation, was 75 and 82 days, respectively (p = 0.5), 54 days without X-irradiation (p = 0.0002), 37 days for X-irradiation alone, and 24 days for untreated controls. In contrast to the data obtained with the F98 glioma, MRA 27 melanoma-bearing rats that received i.v. BPA, followed by BNCT, had a highly significant difference in mean survival time compared with the irradiated controls (54 vs. 37 days, p = 0.008). CONCLUSION: Our data are the first to suggest that a significant therapeutic gain may be obtained when BNCT is combined with an X-ray boost. Additional experimental studies are required to determine the optimal combination of X-radiation and neutron doses and whether it is more advantageous to administer the photon boost before or after BNCT.

Animals↗
PubMed1997

Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of either sodium borocaptate or boronophenylalanine with or without blood-brain barrier disruption.

The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy could be enhanced by means of intracarotid (i.c.) injection of sodium borocaptate (BSH) or boronophenylalanine (BPA) with or without blood-brain barrier disruption (BBB-D). For biodistribution studies, F98 glioma-bearing rats were injected i.v. or i.c. with either BSH (30 mg of boron/kg of body weight) or BPA (24 mg of boron/kg of body weight) with or without mannitol-induced, hyperosmotic BBB-D and killed 2.5 h later. The highest tumor boron concentrations for BSH and BPA were attained following i.c. injection with BBB-D (48.6 and 94.0 microg/g, respectively) compared to i.c. (30.8 and 42.7 microg/g) and i.v. injection (12.9 and 20.8 microg). Using the same doses of BSH and BPA, therapy experiments were initiated 14 days after intracerebral implantation of F98 glioma cells. Animals were irradiated 2.5 h after i.v. or i.c. administration of the capture agent with or without BBB-D using a collimated beam of thermal neutrons at the Brookhaven Medical Research Reactor. The median survival times of rats given BSH or BPA i.c. were 52 and 69 days, respectively, for rats with BBB-D; 39 and 48 days for rats without BBB-D; 33 and 37 days for i.v. injected rats; 29 days for irradiated controls; and 24 days for untreated controls. i.c. injection of either BSH or BPA resulted in highly significant enhancement (P = 0.01 and P = 0.0002, respectively) of survival times compared to i.v. injection, and this was further augmented by BBB-D (P = 0.02 and P = 0.04, respectively) compared to i.c. injection. Normal brain tissue tolerance studies were carried out with non-tumor-bearing rats, which were treated in the same way as tumor-bearing animals. One year after irradiation, the brains of these animals showed only minimal radiation-induced changes in the choroid plexus, but no differences were discernible between irradiated controls and those that had BBB-D followed by i.c. injection of either BSH or BPA. Our data clearly show that the route of administration, as well as BBB-D, can enhance the uptake of BSH and BPA, and, subsequently, the efficacy of boron neutron capture therapy.

Alpha Particles↗
PubMed2004

Structural characterization of cationic liposomes loaded with sugar-based carboranes.

In this article we report the physicochemical characterization of cationic liposomes loaded with orthocarborane and two of its sugar-containing derivatives. Carboranes are efficient boron delivery agents in boron neutron capture therapy, an anti-cancer treatment based on neutron absorption by 10B nuclei. Cationic liposomes were prepared using the positively charged DOTAP and the zwitterionic DOPE, as a helper lipid. These liposomes are currently used in gene therapy for their ability in targeting the cell nucleus; therefore they can be considered appropriate vectors for boron neutron capture therapy, in the quest of reducing the high boron amount that is necessary for successful cancer treatment. Boron uptake was determined by an original in situ method, based on neutron absorption. The structural properties of the loaded liposomes were studied in detail by the combined use of small angle x-ray scattering and small angle neutron scattering. These techniques established the global shape and size of liposomes and their bilayer composition. The results were discussed in term of molecular properties of the hosted drugs. Differences found in the insertion modality were correlated with the preparation procedure or with the specific shape and lipophilic-hydrophilic balance of each carborane.

Boranes↗
PubMed1996

Boron neutron capture irradiation of the rat spinal cord: histopathological evidence of a vascular-mediated pathogenesis.

A histopathological study was carried out on the spinal cord of rats after boron neutron capture (BNC) irradiation. Rats were irradiated with thermal neutrons alone or in combination with borocaptate sodium (BSH) or p-boronophenylalanine (BPA). Spinal cords were examined 1 year after irradiation, or at earlier times in rats developing myelopathy. Considered overall, the pathology of the spinal cord after BNC irradiation was comparable with that reported previously after X irradiation of the spinal cord in the identical strain of rat. When BSH was used as the neutron capture agent, the biologically effective dose of radiation delivered to the CNS parenchyma was a factor of -2.7 lower than that delivered to the vascular endothelium. In effect, the blood vessels were selectively irradiated using this BNC modality. The resultant pathology was similar to that observed after irradiation with thermal neutrons alone or in the presence of BPA, situations in which the CNS vasculature was not selectively irradiated. This points to the vascular endothelium as being the critical target cell population, damage to which results in the development of the lesions seen in the spinal cord after BNC irradiation and, by inference, after irradiation with more conventional modalities.

Alpha Particles↗
PubMed2000

A Monte Carlo dosimetry-based evaluation of the 7Li(p,n)7Be reaction near threshold for accelerator boron neutron capture therapy.

Advanced methods of boron neutron capture therapy (BNCT) use an epithermal neutron beam in conjunction with tumor-targeting boron compounds for irradiation of glioblastomas and metastatic melanomas. A common neutron-producing reaction considered for accelerator-based BNCT is 7Li(p,n)7Be, whose cross section increases very rapidly within several tens of keV of the reaction threshold at 1.88 MeV. Operation in the proton energy region near threshold will have an appreciable thick target neutron yield, but the neutrons produced will have relatively low energies that require little moderation to reach the epithermal range desirable for BNCT. Because of its relatively low projected accelerator cost and the portability of the neutron source/target assembly, BNCT based on the near-threshold technique is considered an attractive candidate for widespread hospital use. A systematic Monte Carlo N-Particle (MCNP) investigation of the dosimetric properties of near-threshold neutron beams has been performed. Results of these studies indicate that accelerator proton energies between 1.93 and 1.99 MeV, using 5 cm of H2O moderator followed by thin 6Li and Pb shields, can provide therapeutically useful beams with treatment times less than one hour and accelerator currents less than 5 mA.

Beryllium↗