The OLIGOPEPTIDE TRANSPORTER 3 (OPT3) has recently been identified as a component of the systemic network mediating iron (Fe) deficiency responses in Arabidopsis. Reduced expression of OPT3 induces an over accumulation of Fe in roots and leaves, due in part by an elevated expression of the IRON-REGULATED TRANSPORTER 1. Here we show however, that opt3 leaves display a transcriptional program consistent with an Fe overload, suggesting that Fe excess is properly sensed in opt3 leaves and that the OPT3-mediated shoot-to-root signaling is critical to prevent a systemic Fe overload. We also took advantage of the tissue-specific localization of OPT3, together with other Fe-responsive genes, to determine the timing and location of early transcriptional events during Fe limitation and resupply. Our results show that the leaf vasculature responds more rapidly than roots to both Fe deprivation and resupply, suggesting that the leaf vasculature is within the first tissues that sense and respond to changes in Fe availability. Our data highlight the importance of the leaf vasculature in Fe homeostasis by sensing changes in apoplastic levels of Fe coming through the xylem and relaying this information back to roots via the phloem to regulate Fe uptake at the root level.

Introduction Targeted radiotherapy using the bifunctional chelate approach with 186/188Re(V) is challenging because of the susceptibility of monooxorhenium(V)-based complexes to oxidize in vivo at high dilution. A monoamine-monoamide dithiol (MAMA)-based bifunctional chelating agent was evaluated with both rhenium and technetium to determine its utility for in vivo applications. Methods A 222-MAMA chelator, 222-MAMA(N-6-Ahx-OEt) bifunctional chelator, and 222- MAMA(N-6-Ahx-BBN(7-14)NH2) were synthesized, complexed with rhenium, radiolabeled with 99mTc and 186Re (carrier added and no carrier added), and evaluated in initial biological distribution studies. Results An IC50 value of 2.0 ± 0.7 nM for natReO-222-MAMA(N-6-Ahx-BBN(7-14)NH2) compared to [125I]-Tyr4-BBN(NH2) was determined through competitive cell binding assays with PC-3 tumor cells. In vivo evaluation of the no-carrier added 99mTc-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed little gastric uptake and blockable pancreatic uptake in normal mice. Conclusions The 186ReO-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed stability in biological media, which indicates that the 222-N2S2 chelator is appropriate for chelating 186/188Re in radiopharmaceuticals involving peptides. Additionally, the in vitro cell studies showed that the ReO-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex (macroscopically) bound to PC3-tumor cell surface receptors with high affinity. The 99mTc analog was stable in vivo and exhibited pancreatic uptake in mice that was blockable, indicating BB2r targeting.

Gadolinium vanadate (GdVO4) core and core + 2 shell nanocrystals (NCs) were evaluated for in vitro retention of 225Ac, 227Th, and their first decay daughters, 221Fr and 223Ra, respectively. GdVO4 NCs with a tetragonal crystal system (zircon-type) and spherical morphology were obtained by precipitation of GdCl3 and Na3VO4 using sodium citrate as a complexing agent. The growth of two nonradioactive GdVO4 shells on both Gd(225Ac)VO4 and Gd(227Th)VO4 core NCs was demonstrated by an increase of 0.7 nm and 2 nm in the crystallite size, respectively. The maximum leakage of 225Ac was 15% and 2.4% from core and core + 2 shells, whereas the leakage of 227Th was 3% and 1.5%, respectively. The presence of two nonradioactive GdVO4 shells increased the retention of 221Fr and 223Ra by 20% and 15% with respect to core NCs. Furthermore, a longitudinal proton relaxivity, r1 = 0.9289 s−1 mM−1, confirmed their potential application as contrast agents for magnetic resonance imaging. In summary, GdVO4 NCs show promising capabilities as radionuclide carriers with partial retention of decay daughters and as contrast agents for theranostic applications.

Unwanted targeting of healthy organs caused by the relocation of radionuclides from the target site has been one of the limiting factors in the widespread application of targeted alpha therapy in patient regimens. GdVO4 nanoparticles (NPs) were developed as platforms to encapsulate α-emitting radionuclides 223Ra, 225Ac, and 227Th, and retain their decay daughters at the target site. Polycrystalline GdVO4 NPs with different morphologies and a zircon-type tetragonal crystal structure were obtained by precipitation of GdCl3 and Na3VO4 in aqueous media at room temperature. The ability of GdVO4 crystals to host multivalent ions was initially assessed using La, Cs, Bi, Ba, and Pb as surrogates of the radionuclides under investigation. A decrease in Ba encapsulation was obtained after increasing the concentration of surrogate ions, whereas the encapsulation of La cations in GdVO4 NPs was quantitative (∼100%). Retention of radionuclides was assessed in vitro by dialyzing the radioactive GdVO4 NPs against deionized water. While 227Th was quantitatively encapsulated (100%), a partial encapsulation of 223Ra (∼75%) and 225Ac (>60%) was observed in GdVO4 NPs. The maximum leakage of 221Fr (1st decay daughter of 225Ac) was 55.4 ± 3.6%, whereas for 223Ra (1st decay daughter of 227Th) the maximum leakage was 73.0 ± 4.0%. These results show the potential of GdVO4 NPs as platforms of α-emitting radionuclides for their application in targeted alpha therapy.