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Macrocyclic Co(II) complexes with appended amide-glycinate groups were prepared to develop paramagnetic Co(II) chemical exchange saturation transfer (CEST) agents of reduced overall charge. Complexes with reduced charge and lowered osmolarity are important for their loading into liposomes and to provide complexes that are highly water soluble and well tolerated in animals. Co(L1) has two non-coordinating benzyl groups and two amide-glycinate pendants, whereas Co(L2) has two unsubstituted amide pendants and two amide-glycinate pendants on cyclam (1,4,8,11-tetraazacyclododecane). The 1H NMR spectrum of Co(L1) is consistent with a single cis-pendant isomer with both amide protons in the trans-configuration, as supported by an X-ray crystal structure. Co(L2) has a mixture of different isomers in solution, including the trans-1,4 and 1,8 pendant isomers. The Z-spectrum of Co(L1) shows one highly-shifted CEST peak, whereas Co(L2) exhibits six CEST peaks. Encapsulation of 40 mM Co(L1) in a liposome with osmotically-induced shrinking at 300 mOsm/L produces a liposomal CEST agent with saturation frequency offset of 3 ppm. Addition of the amphiphilic 1,4,7-triazacyclononane-based complex Co(L5) to the liposomal bilayer at 18 mM with Co(L1) encapsulated in the liposome at 50 mM changes the sign and increases the magnitude of the saturation frequency offset to -7.5 ppm at 300 mOsm/L.

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High-spin Fe(III) complexes of 1,4,7-triazacyclononane (TACN) with mixed oxygen donor pendants including hydroxypropyl, phenolate or amide groups are prepared for study as T1 MRI probes. Complexes with two hydroxypropyl pendants and either amide (Fe(TOAB)) or phenolate (Fe(PTOB)) groups are compared to an analog with three hydroxypropyl groups (Fe(NOHP)), in order to study the effect of the third pendant on the coordination sphere as probed by solution chemistry, relaxivity and structural studies. Solution studies show that Fe(PTOB) has two ionizations with the phenol pendant deprotonating with a pKa of 1.7 and a hydroxypropyl pendent with pKa of 6.3. The X-ray crystal structure of [Fe(PTOB)]Br2 features a six-coordinate complex with two bound hydroxypropyl groups, and a phenolate in a distorted octahedral geometry. The Fe(TOAB) complex has a single deprotonation, assigned to a hydroxypropyl group with a pKa value of 7.0. Both complexes are stabilized as high-spin Fe(III) in solution as shown by their effective magnetic moments and Fe(III)/Fe(II) redox potentials of -390 mV and -780 mV versus NHE at pH 7 and 25 °C for Fe(TOAB) and Fe(PTOB) respectively. Both Fe(PTOB) and Fe(TOAB) are kinetically inert to dissociation under a variety of challenges including phosphate/carbonate buffer, one equivalent of ZnCl2, two equivalents of transferrin or 100 mM HCl, or at basic pH values over 24 h at 37 °C. The r1 relaxivity of Fe(TOAB) at 1.4 T, pH 7.4 and 33 °C is relatively low at 0.6 mM-1 s-1 whereas the r1 relaxivity of Fe(PTOB) is more substantial and shows an increase of 2.5 fold to 2.5 mM-1 s-1 at acidic pH. The increase in relaxivity at acidic pH is attributed to protonation of the phenolate group to provide an additional pathway for proton relaxation.

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Fe(III) complexes containing a triamine framework and phenolate or hydroxypyridine donors are characterized and studied as T1 MRI probes. In contrast to most Fe(III) MRI probes of linear chelates reported to date, the ligands reported here are pentadentate to give six-coordinate complexes with a coordination site for inner-sphere water. The crystal structure of the complex containing unsubstituted phenolate donors, Fe(L1)Cl, shows a six-coordinate iron center and contains a chloride ligand that is displaced in water. Two additional derivatives are sufficiently water-soluble for study as MRI probes, including a complex with a hydroxypyridine group, Fe(L2), and a hydroxybenzoic acid group, Fe(L3). The pH potentiometric titrations give protonation constants of 7.2 and 7.5 for Fe(L2) and Fe(L3), respectively, which are assigned to deprotonation of the bound water. Changes in the electronic absorbance spectra of the complexes as a function of pH are consistent with the deprotonation of phenol pendants at acidic pH values. However, the inner-sphere water ligand of Fe(L2) and Fe(L3) does not exchange rapidly on the NMR timescale at pH 6.0 or 7.4, as shown by variable-temperature 17O NMR spectroscopy. The pH-dependent proton relaxivity profiles show a maximum in relaxivity at a near-neutral pH, suggesting that exchange of the protons of the bound water is an important contribution. Competitive binding studies with ethylenediaminetetraacetic acid (EDTA) show effective stability constants for Fe(L2) and Fe(L3) at pH 7.4 with log K values of 21.1 and 20.5, respectively. These two complexes are kinetically inert in carbonate phosphate buffer at 37 °C for several hours but transfer iron to transferrin. Fe(L2) and Fe(L3) show enhanced contrast in T1-weighted imaging analyses in BALB/c mice. These studies show that Fe(L2) clears through mixed renal and hepatobiliary routes, while Fe(L3) has a similar pharmacokinetic clearance profile to a macrocyclic Gd(III) contrast agent.

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Liposomes containing high-spin Fe(III) coordination complexes were prepared towards the production of T1 MRI probes with improved relaxivity. The amphiphilic Fe(III) complexes were anchored into the liposome with two alkyl chains to give a coordination sphere containing mixed amide and hydroxypropyl pendant groups. The encapsulated complex contains a macrocyclic ligand with three phosphonate pendants, [Fe(NOTP)]3-, which was chosen for its good aqueous solubility. Four types of MRI probes were prepared including those with intraliposomal Fe(III) complex (LipoA) alone, amphiphilic Fe(III) complex (LipoB), both intraliposomal and amphiphilic complex (LipoC) or micelles formed with amphiphilic complex. Water proton relaxivities r1 and r2 were measured and compared to a small molecule macrocyclic Fe(III) complex containing similar donor groups. Micelles of the amphiphilic Fe(III) complex had proton relaxivity values (r1 = 2.6 mM-1 s-1) that were four times higher than the small hydrophilic analog. Liposomes with amphiphilic Fe(III) complex (LipoB) have a per iron relaxivity of 2.6 mM-1 s-1 at pH 7.2, 34 °C at 1.4 T whereas liposomes containing both amphiphilic and intraliposomal Fe(III) complexes (lipoC) have r1 of 0.58 mM-1 s-1 on a per iron basis consistent with quenching of the interior Fe(III) complex relaxivity. Liposomes containing only encapsulated [Fe(NOTP)]3- have a lowered r1 of 0.65 mM-1 s-1 per iron complex. Studies show that the biodistribution and clearance of the different types liposomal nanoparticles differ greatly. LipoB is a blood pool agent with a long circulation time whereas lipoC is cleared more rapidly through both renal and hepatobiliary pathways. These clearance differences are consistent with lower stability of LipoC compared to LipoB.

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Co(II) complexes of 1,4,7,10-tetraazacyclododecane (CYCLEN) or 1,4,8,11-tetraazacyclotetradecane (CYCLAM) with 2-hydroxypropyl or carbamoylmethyl (amide) pendants are studied with the goal of developing paramagnetic chemical exchange saturation transfer (paraCEST) agents. Single-crystal X-ray diffraction studies show that two of the coordination cations with hexadentate ligands, [Co(DHP)]2+ and [Co(BABC)]2+, form six-coordinate complexes; whereas two CYCLEN-based complexes with potentially octadentate ligands, [Co(THP)]2+ and [Co(HPAC)]2+, are seven-coordinate with only three of the four pendant groups bound to the metal center. 1H NMR spectra of these complexes suggest that the six-coordinate complexes are present as a single isomer in aqueous solution. For the complexes which are seven-coordinate in the solid state, one is highly fluxional in aqueous solution on the NMR time scale ([Co(HPAC)]2+), whereas the NMR spectrum of [Co(THP)]2+ is consistent with an eight-coordinate complex with all pendants bound. Co(II) complexes of CYCLEN derivatives show CEST effects of low intensity that are assigned to NH or OH groups of the pendants. One complex, [Co(DHP)]2+, shows a highly-shifted CEST peak at 113 ppm versus bulk water, attributed to OH protons. However, the CEST effect is largest for two Co(II) CYCLAM-based complexes with coordinated amide groups that undergo NH proton exchange. All five complexes are inert towards dissociation in buffered solutions containing carbonate and phosphate and towards trans-metalation by excess Zn(II). These data give insight into the production of an intense CEST effect for tetraazamacrocyclic complexes with pendant groups containing NH or OH exchangeable protons. The intense and highly shifted CEST peak(s) of the CYCLAM-based complexes suggest that they are promising for further development as paraCEST agents.

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The presence of multiple oxidation and spin states of first-row transition-metal complexes facilitates the development of switchable MRI probes. Redox-responsive probes capitalize on a change in the magnetic properties of the different oxidation states of the paramagnetic metal ion center upon exposure to biological oxidants and reductants. Transition-metal complexes that are useful for MRI can be categorized according to whether they accelerate water proton relaxation (T1 or T2 agents), induce paramagnetic shifts of 1H or 19F resonances (paraSHIFT agents), or are chemical exchange saturation transfer (CEST) agents. The various oxidation state couples and their properties as MRI probes are summarized with a focus on Co(II)/Co(III) or Fe(II)/Fe(III) complexes as small molecules or as liposomal agents. Solution studies of these MRI probes are reviewed with an emphasis on redox changes upon treatment with oxidants or with enzymes that are physiologically important in inflammation and disease. Finally, we outline the challenges of developing these probes further for in vivo MRI applications.

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Contrast agents are used in approximately 40% of all magnetic resonance imaging (MRI) procedures to improve the quality of the images based on the distribution and dynamic clearance of the agent. To date, all clinically approved contrast agents are Gd(III) coordination complexes that serve to shorten the longitudinal (T1) and transverse (T2) proton relaxation times of water. Recent interest in replacing Gd with biologically relevant metal ions such as Mn or Fe has led to increased interest in the aqueous coordination chemistry of their complexes. In this Account, we focus on high-spin Fe(III) complexes that have been recently reported as MRI contrast agents or probes in our laboratory.The highly Lewis acidic Fe(III) center has distinct coordination chemistry in aqueous solutions, facilitating alternative strategies in the design of MRI probes. To illustrate this, we describe different classes of Fe(III) MRI probes with a focus on macrocyclic complexes and multinuclear complexes such as self-assembled metal organic polyhedra (MOP). Our initial efforts focused on macrocyclic complexes of Fe(III) in order to tune spin and oxidation states with the goal of stabilizing high-spin Fe(III) in reducing biological environments. Our probes feature six-coordinate Fe(III) complexes of 1,4,7-triazacyclononane with hydroxypropyl, phosphonate, or carboxylate pendant groups to produce Fe(III) complexes that shorten proton T1 times predominantly from second-sphere or outer-sphere interactions at neutral pH. Analogues with pentadentate macrocyclic ligands have an inner-sphere water that does not exchange rapidly on the NMR time scale, yet these complexes are effective relaxation agents. Fe(III) macrocyclic complexes in this class can be modified to modulate their biodistribution and pharmacokinetic clearance in mice. The goal of these studies is for the Fe(III) agents to clear as extracellular fluid agents and produce profiles similar to those of Gd agents. Finally, studies of multimeric Fe(III) complexes are of interest to produce probes that give large proton relaxivity. In this approach the two Fe(III) centers are connected through aryl linkers as demonstrated for several macrocyclic complexes. Even more tightly connected Fe(III) centers are produced in a Fe(III) self-assembled cage with relaxivity of 21 mM-1 s-1 at 4.7 T, 37 °C in the presence of serum albumin to which it is tightly bound. This cage enhances contrast of the vasculature as a blood pool agent and accumulates in tumors. Finally, we present our perspectives on the further development of Fe(III) complexes for various applications in MRI.

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A metal-organic polyhedron (MOP) with four paramagnetic Fe(III) centers was studied as a magnetic resonance imaging (MRI) probe. The MOP was characterized in solution by using electron paramagnetic resonance (EPR), UV-visible (UV-vis) spectroscopies, Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry, and in the solid state with single-crystal X-ray diffraction. Water proton T1 relaxation properties were examined in solution and showed significant enhancement in the presence of human serum albumin (HSA). The r1 relaxivities in the absence and presence of HSA were 8.7 mM-1 s-1 and 21 mM-1 s-1, respectively, per molecule (2.2 mM-1 s-1 and 5.3 mM-1 s-1 per Fe) at 4.7 T, 37 °C. In vivo studies of the iron MOP show strong contrast enhancement of the blood pool even at a low dose of 0.025 mmol/kg with prolonged residence in vasculature and clearance through the intestinal tract of mice. The MOP binds strongly to serum albumin and shows comparable accumulation in a murine tumor model as compared to a covalently linked Gd-HSA contrast agent.

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Fe(III) macrocyclic complexes containing a macrocycle and three pendant groups including phosphonate (NOTP =1,4,7-triazacyclononane-1,4,7-triyl-tris(methylenephosphonic acid), carboxylate (NOTA = 1,4,7 - triazacyclononane - N,N',N″ - triacetate) or hydroxypropyl (NOHP =(2S,2'S,2"S)-1,1',1″-(1,4,7-triazonane-1,4,7-triyl)tris(propan-2-ol)) were studied in order to compare the effect of these donor groups on solution chemistry and water proton relaxivity. All three complexes, Fe(NOTP), Fe(NOHP) and Fe(NOTA), display a large degree of kinetic inertness to dissociation in the presence of phosphate and carbonate, under acidic conditions of 100 mM HCl or 1 M HCl or to trans-metalation with Zn(II). The r1 proton relaxivity of the complexes at 1.4 T, 33 °C is compared over the pH range of 1 to 10. At pH 7.4, 33 °C, 1.4 T, Fe(NOHP) has the largest relaxivity (1.5 mM-1 s-1), Fe(NOTP) is second at 1.0 mM-1 s-1, whereas Fe(NOTA) is the lowest at 0.61 mM-1 s-1. Fe(NOTP), Fe(NOHP) and Fe(NOTA) all show an increase in relaxivity at very acidic pH values (< 3) that is consistent with an acid-catalyzed process. Variable temperature 17O NMR studies at near neutral pH are consistent with the absence of an inner-sphere water molecule for Fe(NOTP) and Fe(NOHP), supporting second-sphere or outer-sphere water contributions to proton relaxation. Fe(NOTP) shows contrast enhancement in T1 weighted MRI studies in mice and clears through a renal pathway.

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Four high-spin Fe(III) macrocyclic complexes, including three dinuclear and one mononuclear complex, were prepared toward the development of more effective iron-based magnetic resonance imaging (MRI) contrast agents. All four complexes contain a 1,4,7-triazacyclononane macrocyclic backbone with two hydroxypropyl pendant groups, an ancillary aryl or biphenyl group, and a coordination site for a water ligand. The pH potentiometric titrations support one or two deprotonations of the complexes, most likely deprotonation of hydroxypropyl groups at near-neutral pH. Variable-temperature 17O NMR studies suggest that the inner-sphere water ligand is slow to exchange with bulk water on the NMR time scale. Water proton T1 relaxation times measured for solutions of the Fe(III) complexes at pH 7.2 showed that the dinuclear complexes have a 2- to 3-fold increase in r1 relaxivity in comparison to the mononuclear complex per molecule at field strengths ranging from 1.4 T to 9.4 T. The most effective agent, a dinuclear complex with macrocycles linked through para-substitution of an aryl group (Fe2(PARA)), has an r1 of 6.7 mM-1 s-1 at 37 °C and 4.7 T or 3.3 mM-1 s-1 per iron center in the presence of serum albumin and shows enhanced blood pool and kidney contrast in mice MRI studies.

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Paramagnetic liposomes containing Fe(III) complexes were prepared by incorporation of mononuclear (Fe(L1) or Fe(L3)) or dinuclear (Fe2(L2)) coordination complexes of 1,4,7-triazacyclononane macrocycles containing 2-hydroxypropyl pendant groups. Two different types of paramagnetic liposomes were prepared. The first type, LipoA, has the mononuclear Fe(L1) complex loaded into the internal aqueous core. The second type, LipoB, has the amphiphilic Fe(L3) complex inserted into the liposomal bilayer and the internal aqueous core loaded with either Fe(L1) (LipoB1) or Fe2(L2) (LipoB2). LipoA enhances both T1 and T2 water proton relaxation rates. Treatment of LipoA with osmotic gradients to produce a nonspherical liposome produces a liposome with a chemical exchange saturation transfer effect as shown by an asymmetry analysis but only at high osmolarity. LipoB1, which contains an amphiphilic complex in the liposomal bilayer, produced a broadened Z-spectrum upon treatment of the liposome with osmotic gradients. The r1 relaxivity of LipoB1 and LipoB2 were higher than the r1 relaxivity of LipoA on a per Fe basis, suggesting an important contribution from the amphiphilic Fe(III) center. The r1 relaxivities of paramagnetic liposomes are relatively constant over a range of magnetic field strengths (1.4-9.4 T), with the ratio of r2/r1 substantially increasing at high field strengths. MRI studies of LipoB1 in mice showed prolonged contrast enhancement in blood compared to the clinically employed Gd(DOTA), which was injected at a 2-fold higher dose per metal than the Fe(III)-loaded liposomes.

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Four high-spin macrocyclic Co(II) complexes with hydroxypropyl or amide pendants and appended coumarin or carbostyril fluorophores were prepared as CEST (chemical exchange saturation transfer) MRI probes. The complexes were studied in solution as paramagnetic CEST (paraCEST) agents and after loading into Saccharomyces cerevisiae yeast cells as cell-based CEST (cellCEST) agents. The fluorophores attached to the complexes through an amide linkage imparted an unusual pH dependence to the paraCEST properties of all four complexes through of ionization of a group that was attributed to the amide NH linker. The furthest shifted CEST peak for the hydroxypropyl-based complexes changed by ∼90 ppm upon increasing the pH from 5 to 7.5. At acidic pH, the Co(II) complexes exhibited three to four CEST peaks with the most highly shifted CEST peak at 200 ppm. The complexes demonstrated substantial paramagnetic water proton shifts which is a requirement for the development of cellCEST agents. The large shift in the proton resonance was attributed to an inner-sphere water at neutral pH, as shown by variable temperature 17O NMR spectroscopy studies. Labeling of yeast with one of these paraCEST agents was optimized with fluorescence microscopy and validated by using ICP mass spectrometry quantitation of cobalt. A weak asymmetry in the Z-spectra was observed in the yeast labeled with a Co(II) complex, toward a cellCEST effect, although the Co(II) complexes were toxic to the cells at the concentrations necessary for observation of cellCEST.

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Complexes of Fe(III) that contain a triazacyclononane (TACN) macrocycle, two pendant hydroxyl groups, and a third ancillary pendant show promise as MRI contrast agents. The ancillary group plays an important role in tuning the solution relaxivity of the Fe(III) complex and leads to large changes in MRI contrast enhancement in mice. Two new Fe(III) complexes, one with a third coordinating hydroxypropyl pendant, Fe(L2), and one with an anionic non-coordinating sulfonate group, Fe(L1)(OH2), are compared. Both complexes have a deprotonated hydroxyl group at neutral pH and electrode potentials representative of a stabilized trivalent iron center. The r1 relaxivity of the Fe(L1)(OH2) complex is double that of the saturated complex, Fe(L2), at 4.7 T, 37 °C in buffered solutions. However, variable-temperature 17O-NMR experiments show that the inner-sphere water of Fe(L1)(OH2) does not exchange rapidly with bulk water under these conditions. The pendant sulfonate group in Fe(L1)(OH2) confers high solubility to the complex in comparison to Fe(L2) or previously studied analogues with benzyl groups. Dynamic MRI studies of the two complexes showed major differences in their pharmacokinetics clearance rates compared to an analogue containing a benzyl ancillary group. Rapid blood clearance and poor binding to serum albumin identify Fe(L1)(OH2) for development as an extracellular fluid contrast agent.

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Three paramagnetic CoII macrocyclic complexes containing 2-hydroxypropyl pendant groups, 1,1',1'',1'''-(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrayl)tetrakis- (propan-2-ol) ([Co(L1)]2+ , 1,1'-(4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)bis(propan-2-ol) ([Co(L2)]2+ ), and 1,1'-(4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)bis(octadecan-2-ol) ([Co(L3)]2+ ) were synthesized to prepare transition metal liposomal chemical exchange saturation transfer (lipoCEST) agents. In solution, ([Co(L1)]2+ ) forms two isomers as shown by 1 H NMR spectroscopy. X-ray crystallographic studies show one isomer with 1,8-pendants in cis-configuration and a second isomer with 1,4-pendants in trans-configuration. The [Co(L2)]2+ complex has 1,8-pendants in a cis-configuration. Remarkably, the paramagnetic-induced shift of water 1 H NMR resonances in the presence of the [Co(L1)]2+ complex is as large as that observed for one of the most effective LnIII water proton shift agents. Incorporation of [Co(L1)]2+ into the liposome aqueous core, followed by dialysis against a solution of 300 mOsm L-1 produces a CEST peak at 3.5 ppm. Incorporation of the amphiphilic [Co(L3)]2+ complex into the liposome bilayer produces a more highly shifted CEST peak at -13 ppm. Taken together, these data demonstrate the feasibility of preparing CoII lipoCEST agents.

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Yeast-derived ß-glucan particles (GPs) are a class of microcarriers under development for the delivery of drugs and imaging agents to immune-system cells for theranostic approaches. However, the encapsulation of hydrophilic imaging agents in the porous GPs is challenging. Here, we show that the unique coordination chemistry of FeIII -based macrocyclic T1 MRI contrast agents permits facile encapsulation in GPs. Remarkably, GPs labeled with the simple FeIII complexes are stable under physiologically relevant conditions, despite the absence of amphiphilic groups. In contrast to the free FeIII coordination complex, the labeled FeIII -GPs have lowered T1 relaxivity and act as a silenced form of the contrast agent. Addition of a fluorescent tag to the FeIII complex produces a bimodal agent to further enable tracking of the nanoparticles and to monitor release. Treatment of the iron-labeled GPs with a maltol chelator or with mildly acidic conditions releases the intact iron complex and restores enhanced T1 relaxation of the water protons.

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A newly discovered isomer of Co(ii) (1,4,8,11-tetrakis(carbamoylmethyl)-1,4,8,11-tetraazacyclotetradecane = CCRM) produces four highly paramagnetically shifted chemical exchange saturation transfer (CEST) peaks. The 1,8-pendants of the complex are bound in a trans-arrangement to produce a Co(ii) complex of increased kinetic inertness. The isomers have a stabilized Co(ii) center (E1/2 of 540 to 550 mV versus SHE). Both the 1,8 and the 1,4-isomer are excellent pH probes in solution and in tissue homogenate by virtue of their highly paramagnetically shifted amide protons. These isomers produce both a ratiometric pH readout as well as amide proton exchange rate constants that correlate to pH.

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Early studies suggested that FeIII complexes cannot compete with GdIII complexes as T1 MRI contrast agents. Now it is shown that one member of a class of high-spin macrocyclic FeIII complexes produces more intense contrast in mice kidneys and liver at 30 minutes post-injection than does a commercially used GdIII agent and also produces similar T1 relaxivity in serum phantoms at 4.7 T and 37 °C. Comparison of four different FeIII macrocyclic complexes elucidates the factors that contribute to relaxivity in vivo including solution speciation. Variable-temperature 17 O NMR studies suggest that none of the complexes has a single, integral inner-sphere water that exchanges rapidly on the NMR timescale. MRI studies in mice show large in vivo differences of three of the FeIII complexes that correspond, in part, to their r1 relaxivity in phantoms. Changes in overall charge of the complex modulate contrast enhancement, especially of the kidneys.

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Labeling of cells with paramagnetic metal complexes produces changes in MRI properties that have applications in cell tracking and identification. Here we show that fungi, specifically the budding yeast Saccharomyces cerevisiae, can be loaded with Fe(III) T1 contrast agents. Two Fe(III) macrocyclic complexes based on 1,4,7-triazacyclononane, with two pendant alcohol groups are prepared and studied as T1 relaxation MRI probes. To better visualize uptake and localization in the yeast cells, Fe(III) complexes have a fluorescent tag, consisting of either carbostyril or fluoromethyl coumarin. The Fe(III) complexes are robust towards dissociation and produce moderate T1 effects, despite lacking inner-sphere water ligands. Fluorescence microscopy and MRI T1 relaxation studies provide evidence of uptake of an Fe(III) complex into Saccharomyces cerevisiae upon electroporation.

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