The cell membrane folate receptor is a potential molecular target for tumor-selective drug delivery. To probe structural requirements for folate receptor targeting with low molecular weight ...radiometal chelates, specifically the role of the amino acid fragment of folic acid (pteroylglutamic acid) in mediating targeting selectivity, the amide-linked conjugate pteroyl-NHCH2CH2OCH2CH2OCH2CH2NH-DTPA was prepared by a three-step procedure from pteroic acid, 2,2‘-(ethylenedioxy)-bis(ethylamine), and t-Bu-protected DTPA. This conjugate, 1-{2-2-(2-(biscarboxymethyl-amino)ethyl)-carboxymethyl-aminoethyl-carboxymethyl-amino}-acetylamino-3,6-dioxa-8-pteroylamino-octane (1), was employed for synthesis of the corresponding 111In(III) radiopharmaceutical. Following intravenous administration to athymic mice, the 111In complex of 1 was found to selectively localize in folate receptor-positive human KB tumor xenografts and to afford prolonged tumor retention of the 111In radiolabel (5.4 ± 0.8, 5.6 ± 1.1, and 3.6 ± 0.6% of the injected dose per gram of tumor at 1, 4, and 24 h, respectively). The observed tumor localization was effectively blocked by co-administration of folic acid with the 111In−1 complex, consistent with a folate receptor-mediated targeting process. In control studies, tumor targeting with this pteroic acid conjugate appears as effective as that seen using 111In−DTPA−folate, a radiopharmaceutical that has progressed to clinical trials for detection of folate receptor-expressing gynecological tumors.
Abstract Introduction: This study was performed to estimate the human radiation dosimetry for 68 GaGa-HBED-CC (PSMA-11) (68 Ga PSMA-11). Methods: Under an RDRC-approved research protocol, we ...evaluated the biodistribution and pharmacokinetics of68 Ga PSMA-11 with serial PET imaging following intravenous administration to nine prostate cancer patients in whom clinical 11 Cacetate PET/CT exams had been independently performed under Expanded Access IND 118,204. List-mode imaging was performed over the initial 0–10 min post-injection with the pelvis in the field-of-view. Whole-body images were acquired, pelvis-to-head, at 15, 60, and 90-min post-injection. Additional images of the pelvis were acquired at 40-min and 115-min, and voided urine collected from each subject at 48-min and 120-min post-injection. Radiation dosimetry estimates were calculated from these data using the OLINDA software package. Results: Renal uptake was high and relatively invariant, ranging from 11% to 14% of the injected dose between 15 and 90-min post-injection. Radioactivity collected in the voided urine accounted for 14% of the injected dose over a period of 120-min. Lymph nodes and skeletal metastases suspicious for prostate cancer recurrence were detected in a greater number of patients using68 Ga PSMA-11 than using11 C–acetate. Conclusion: Kidneys are the critical organ following68 Ga PSMA-11 administration, receiving an estimated dose of 0.413 mGy/MBq. Advances in Knowledge and Implications for Patient Care: This study confirms that the kidneys will be the critical organ following intravenous administration of68 Ga PSMA-11, and provided data consistent with the expectation that68 Ga PSMA-11 will be superior to 11 Cacetate for defining sites of recurrence in prostate cancer patients presenting with biochemical relapse.
A series of four “mixed” bis(thiosemicarbazone) keto aldehyde derivatives containing dissimilar thiosemicarbazone functions were synthesized and evaluated as ligands for preparation of ...radiocopper-labeled radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands CH3CNNHC(S)NH2CHNNHC(S)NHMe (4a), CH3CNNHC(S)NHMeCHNNHC(S)NH2 (4b), CH3CNNHC(S)NH2CHNNHC(S)NMe2 (4c), and CH3CNNHC(S)NHMeCHNNHC(S)NMe2 (4d) were obtained by reaction of thiosemicarbazide, N 4-methylthiosemicarbazide, or N 4,N 4-dimethylthiosemicarbazide with pyruvaldehyde 2-thiosemicarbazones that had been generated by oxidative cleavage of the appropriate pyruvic aldehyde dimethyl acetal 2-thiosemicarbazone. The 67Cu-labeled complexes of ligands 4a − d were prepared and screened in a rat model to assess the potential of each chelate as a 62Cu radiopharmaceutical for imaging with positron emission tomography. In the rat model the 67Cu complexes of ligands 4a−d exhibit significant uptake into the brain and heart after intravenous injection, following trends similar to those previously reported for the related bis(thiosemicarbazone) complexes, Cu−PTS, Cu−PTSM, and Cu−PTSM2 (derived from pyruvaldehyde bis(thiosemicarbazone), pyruvaldehyde bis(N 4-methylthiosemicarbazone), and pyruvaldehyde bis(N 4,N 4-dimethylthiosemicarbazone), respectively). Ultrafiltration studies using solutions of dog and human serum albumin reveal that the 67Cu complexes of ligands 4a−d, like the Cu(II) complex of pyruvaldehyde bis(N 4-methylthiosemicarbazone), interact more strongly with human albumin than dog albumin.
A series of 10 cationic gallium(III) complexes with hexadentate bis(salicylaldimine) ligands were synthesized, characterized, radiolabeled with 67Ga, and screened in a rat model to assess their ...potential as 68Ga radiopharmaceuticals for imaging the heart with positron emission tomography. The tris(salicylaldimine) ligand precursors were synthesized by condensation of either bis(3-aminopropyl)ethylenediamine (BAPEN) or bis(2,2-dimethyl-3-aminopropyl)ethylenediamine (DM-BAPEN) with 3 equiv of a salicylaldehyde derivative containing alkyl, alkoxy, or alkylamino substituents in the 4, 5, or 6 position of the aromatic ring. The cationic six-coordinate gallium(III) bis(salicylaldimine) complexes were obtained by reaction of these tris(salicylaldimines) with tris(acetylacetonato)gallium(III). X-ray crystallographic confirmation of the molecular structure of Ga(4,6-(MeO)2sal)2DM-BAPEN+I- shows the Ga cation to adopt a pseudo-octahedral N4O2 coordination sphere with a trans configuration. All of the 67Ga complexes are lipophilic with measured octanol/water partition coefficients (P) varying from log P = 0.84 to 3.00. These 67Ga-labeled complexes are all found to exhibit significant myocardial uptake following intravenous administration to rats (ranging from 0.34 to 1.08% of the injected dose in myocardium at 1 min postinjection) combined with the desired myocardial retention of tracer.
Four “mixed”
bis(thiosemicarbazone) derivatives of pyruvaldehyde were synthesized that incorporate two dissimilar thiosemicarbazone functions. The corresponding
67Cucopper(II) complexes were ...prepared and evaluated as possible copper radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands, CH
3C=NNHC(S)NHMeCH=NNHC(S)NHEt (1), CH
3C=NNHC(S)NHMeCH=NNHC(S)NEt
2 (2), CH
3C=NNHC(S)NHMeCH=NNHC(S)-
cyclo-N(CH
2)
5 (3), and CH
3C=NNHC(S)NHMeCH=NNHC(S)-
cyclo-N(CH
2)
6 (4), were obtained by reaction of the appropriate thiosemicarbazide derivative with pyruvaldehyde-2-
N
4
-methylthiosemicarbazone (CH
3C=NNHC(S)NHMeCHO). The
67Cu-labeled copper(II) complexes of ligands 1-4 were prepared and screened in a rat model to assess the potential of each chelate as a
62Cu-radiopharmaceutical for imaging with positron emission tomography. The
67Cu-complexes of ligands 1–4 exhibit significant uptake into the brain and heart 1 min following intravenous administration to rats. For the
67Cu-complexes of ligands 2, 3, and 4, the cerebral and myocardial uptake of
67Cu is two-to-threefold lower at 2 h than at 1 min postinjection, due to significant biological clearance of these
67Cu-chelates. However, the
67Cu-complex of 1 affords cerebral and myocardial uptake and retention comparable to that of
67CuCu-PTSM in this model. Although the kinetics of this new agent appear attractive, ultrafiltration studies using solutions of dog and human serum albumin reveal that the
67Cu-complex of ligand 1, like Cu-PTSM, interacts more strongly with human albumin than dog albumin. Thus, this new agent would appear to offer no advantage over Cu-PTSM as a
62Cu-labeled tracer for evaluation of regional tissue perfusion.
This study was performed to estimate the human radiation dosimetry for
GaGa-HBED-CC (PSMA-11) (
Ga PSMA-11).
Under an RDRC-approved research protocol, we evaluated the biodistribution and ...pharmacokinetics of
Ga PSMA-11 with serial PET imaging following intravenous administration to nine prostate cancer patients in whom clinical
Cacetate PET/CT exams had been independently performed under Expanded Access IND 118,204. List-mode imaging was performed over the initial 0-10min post-injection with the pelvis in the field-of-view. Whole-body images were acquired, pelvis-to-head, at 15, 60, and 90-min post-injection. Additional images of the pelvis were acquired at 40-min and 115-min, and voided urine collected from each subject at 48-min and 120-min post-injection. Radiation dosimetry estimates were calculated from these data using the OLINDA software package.
Renal uptake was high and relatively invariant, ranging from 11% to 14% of the injected dose between 15 and 90-min post-injection. Radioactivity collected in the voided urine accounted for 14% of the injected dose over a period of 120-min. Lymph nodes and skeletal metastases suspicious for prostate cancer recurrence were detected in a greater number of patients using
Ga PSMA-11 than using
C-acetate.
Kidneys are the critical organ following
Ga PSMA-11 administration, receiving an estimated dose of 0.413mGy/MBq.
This study confirms that the kidneys will be the critical organ following intravenous administration of
Ga PSMA-11, and provided data consistent with the expectation that
Ga PSMA-11 will be superior to
Cacetate for defining sites of recurrence in prostate cancer patients presenting with biochemical relapse.
Aims were to investigate sensitivity of various human and canine cancer cell lines to hyperthermia and the influence of particular treatment conditions, and to analyze the DNA-damage response and ...mode of cell death in cell line radiosensitized by hyperthermia. Additionally, we were interested in the involvement of HSP70 in radiosensitization.
Radiosensitization by hyperthermia was determined in a panel of human and canine cancer cell lines using clonogenic cell survival assay, as well as levels of heat shock proteins (HSPs) using immunoblotting. The influence of the hyperthermia-radiotherapy time gap, different temperatures and the order of treatments on clonogenicity of hyperthermia-sensitive A549 cells was investigated. Additionally, DNA damage and cell death were assessed by Comet assay and an apoptosis/necrosis assay. Further we induced transient knockdown in A549 cells to test HSP70's involvement in radiosensitization.
Out of eight cell lines tested, only two (A549 and Abrams) showed significant decrease in clonogenic cell survival when pre-treated with hyperthermia at 42°C. Strong induction of HSP70 upon thermoradiotherapy (HT-RT) treatment was found in all cell lines. Transient knockdown of HSP70 in A549 cells did not result in decrease of clonogenic cell survival in response to HT-RT.
Tumor cell-type, temperature and order of treatment play an important role in radiosensitization by hyperthermia. However, hyperthermia has limited potency to radiosensitize canine cancer cells grown in a 2D cell culture setting presented here. DNA damage and apoptosis/necrosis did not increase upon combined treatment and cytosolic levels of HSP70 appear not to play critical role in the radiosensitization of A549 cells.
Hydropower continues to expand globally as the power sector transitions away from carbon-intensive fossil fuels. New dam sites vary widely in the magnitude of their adverse effects on natural ...ecosystems and human livelihoods. Here, we discuss how strategic planning of hydropower expansion can assist decision makers in comparing the benefits of building dams against their socioenvironmental impacts. Advances in data availability and computational analysis now enable accounting for an increasing array of social and environmental metrics at ever-larger spatial scales. In turn, expanding the spatial scale of planning yields more options in the quest to improve both economic and socioenvironmental outcomes. There remains a pressing need to incorporate climate change into hydropower planning. Ultimately, these innovations in evaluating prospective dam sites should be integrated into strategic planning of the entire energy system to ensure that social and environmental disruption of river systems is minimized.
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