Terbium offers 4 clinically interesting radioisotopes with complementary physical decay characteristics: 149 Tb, 152 Tb, 155 Tb, and 161 Tb. The identical chemical characteristics of these radioisotopes allow the preparation of radiopharmaceuticals with identical pharmacokinetics useful for PET ( 152 Tb) and SPECT diagnosis ( 155 Tb) and for a-( 149 Tb) and b 2 -particle ( 161 Tb) therapy. The goal of this proof-of-concept study was to produce all 4 terbium radioisotopes and assess their diagnostic and therapeutic features in vivo when labeled with a folate-based targeting agent. Methods: 161 Tb was produced by irradiation of 160 Gd targets with neutrons at Paul Scherrer Institute or Institut LaueLangevin. After neutron capture, the short-lived 161 Gd decays to 161 Tb. 149 Tb, 152 Tb, and 155 Tb were produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. The isotopes were purified by means of cation exchange chromatography. For the in vivo studies, we used the DOTA-folate conjugate cm09, which binds to folate receptor (FR)-positive KB tumor cells. Therapy experiments with 149 Tb-cm09 and 161 Tb-cm09 were performed in KB tumor-bearing nude mice. Diagnostic PET/ CT ( 152 Tb-cm09) and SPECT/CT ( 155 Tb-cm09 and 161 Tbcm09) studies were performed in the same tumor mouse model. Results: Carrier-free terbium radioisotopes were obtained after purification, with activities ranging from approximately 6 MBq (for 149 Tb) to approximately 15 GBq (for 161 Tb). The radiolabeling of cm09 was achieved in a greater than 96% radiochemical yield for all terbium radioisotopes. Biodistribution studies showed high and specific uptake in FR-positive tumor xenografts (23.8% 6 2.5% at 4 h after injection, 22.0% 6 4.4% at 24 h after injection, and 18.4% 6 1.8% at 48 h after injection). Excellent tumor-to-background ratios at 24 h after injection (tumor to blood, ;15; tumor to liver, ;5.9; and tumor to kidney, ;0.8) allowed the visualization of tumors in mice using PET ( 152 Tb-cm09) and SPECT ( 155 Tb-cm09 and 161 Tb-cm09). Compared with no therapy, a-( 149 Tb-cm09) and b 2 -particle therapy ( 161 Tb-cm09) resulted in a marked delay in tumor growth or even complete remission (33% for 149 Tb-cm09 and 80% for 161 Tb-cm09) and a significantly increased survival. Conclusion: Because of its physical half-lives (T 1/2 ), decay properties, and energies, the lanthanide terbium is one of the few elements that features 4 clinically interesting radioisotopes (Table 1). 149 Tb has a half-life of 4.12 h and emits shortrange a-particles at an energy (E a ) of 3.967 MeV with an intensity of 17%. It is the only a-emitter among radiolanthanides with a suitable half-life for application in radionuclide therapy. 152 Tb (T 1/2 , 17.5 h) emits positrons of an average energy of 1.080 MeV with an intensity of 17%. The radionuclide would be useful for patient-specific dosimetry using PET before the application of therapeutic radiolanthanides. 155 Tb (T 1/2 , 5.32 d) decays by electron cap...
Tumor targeting with folic acid radioconjugates has been proposed as a promising strategy for radionuclide therapy of folate receptor α (FR)-positive cancer. Recently, it was shown that modification of radiofolates with an albumin-binding entity increased the tumor-to-kidney ratios of accumulated radioactivity in mice. The goal of this study was to evaluate the lead compound cm10 and compare it with new albumin-binding folate conjugates. Compound cm12 was designed with a long spacer consisting of a PEG-11 entity, and compound cm13 contained a short alkane chain between the albumin-binding moiety and folic acid. All of the derivatives were labeled with Lu (t = 6.65 days, E = 134 keV; E = 113 keV, 208 keV), a clinically established radionuclide for therapeutic purposes. The evaluation revealed that all of the albumin-binding radiofolates exhibited increased in vitro stability compared with the reference compound (Lu-cm14) without albumin binder. Serum protein binding, determined with an ultrafiltration assay, was high (>88%) for the derivatives with albumin-binding entities. The FR-binding affinity was in the same range (K = 4.0-7.5 nM) for all of the radiofolates, independent of the albumin-binding entity and spacer length. FR-specific uptake was proven in vitro using FR-positive KB tumor cells. In vivo studies with KB-tumor-bearing mice were performed in order to assess the tissue distribution profile of the novel radiofolates. Lu-cm13 showed high tumor uptake at late time points (13.3 ± 2.94% IA/g, 48 h p.i.) and tumor-to-kidney ratios (0.59 ± 0.03, 48 h p.i.) in the same range asLu-cm10 (0.55 ± 0.07, 48 h p.i.). However, the tumor-to-kidney ratio of Lu-cm12 (0.28 ± 0.07, 48 h p.i.) was reduced compared withLu-cm10 and Lu-cm13. The results of this study indicate that the spacer entity between folic acid and the albumin binder is of critical importance with regard to the tissue distribution profile of the radiofolate. The PEG spacer compromised the beneficial effects of the lead compound, but the design with a short alkane spacer appeared to be promising. Future studies will focus on the design of radiofolates with lipophilic and more rigid spacer entities, which may allow a further improvement of their tissue distribution profiles.
IntroductionTriamcinolone acetonide (TA) is used for osteoarthritis management to reduce pain, and pre-clinical studies have shown that TA limits osteophyte formation. Osteophyte formation is known to be facilitated by synovial macrophage activation. TA injections might influence macrophage activation and subsequently reduce osteophytosis. Although widely applied in clinical care, the mechanism through which TA exerts this effect remains unknown. In this animal study, we investigated the in vivo effects of TA injections on macrophage activation, osteophyte development and joint degeneration. Furthermore, in vitro macrophage differentiation experiments were conducted to further explain working mechanisms of TA effects found in vivo.MethodsOsteoarthritis was induced in rat knees using papain injections and a running protocol. Untreated and TA-treated animals were longitudinally monitored for 12 weeks with in vivo micro–computed tomography (μCT) to measure subchondral bone changes. Synovial macrophage activation was measured in vivo using folate receptor β (FRβ)-targeted single-photon emission computed tomography/computed tomography. Articular cartilage was analyzed at 6 and 12 weeks with ex vivo contrast-enhanced μCT and histology. To further explain the outcomes of our in vivo study, TA on macrophages was also studied in vitro. These cultured macrophages were either M1- or M2-activated, and they were analyzed using fluorescence-activated cell sorting for CD163 and FRβ expression as well as for messenger RNA (mRNA) expression of interleukin (IL)-10.ResultsOur in vivo study showed that intra-articular injections with TA strongly enhanced FRβ+ macrophage activation. Despite stimulated macrophage activation, osteophyte formation was fully prevented. There was no beneficial effect of TA against cartilage degradation or subchondral bone sclerosis. In vitro macrophage cultures showed that TA strongly induced monocyte differentiation towards CD163+ and FRβ+ macrophages. Furthermore, TA-stimulated M2 macrophages showed enhanced IL-10 expression at the mRNA level.ConclusionsTA injections potently induce a CD163+- and FRβ+-activated macrophage with anti-inflammatory characteristics such as reduced IL-10 production in vitro and lack of osteophytosis in vivo.
The acrosome reaction was determined in aliquots from ejaculates of 74 patients undergoing in-vitro fertilization at the University of Giessen, Germany, by means of the triple-stain technique. The percentage of acrosome-reacted spermatozoa after low-temperature induction of the acrosome reaction was not significantly related with the fertilization rate (H test, P = 0.693, SJ test, P = 0.366). However, all patients showing < 13.0% acrosome-reacted spermatozoa had poor fertilization rates. Highly significant differences between patients could be detected by correlating the inducibility of the acrosome reaction with the fertilization rate (H test, P = 0.018; SJ test, P = 0.004); patients with high fertilization rates showed a corresponding high inducibility of acrosome reactions. From our results, it is evident that percentages of acrosome-reacted spermatozoa < 13.0% or an inducibility of the acrosome reaction of < 7.5% are indicative of subfertility.
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