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Radioimmunotherapy (RIT) aims to selectively deliver radionuclides emitting α-particles, β-particles or Auger electrons to tumors by conjugation to monoclonal antibodies (mAbs) that recognize tumor-associated antigens/receptors. The approach has been most successful for treatment of non-Hodgkin's B-cell lymphoma but challenges have been encountered in extending these promising results to the treatment of solid malignancies. These challenges include the low potency of β-particle emitters such as 131 I, 177 Lu or 90 Y which have been commonly conjugated to the mAbs, due to their low linear energy transfer (LET=0.1-1.0keV/μm). Furthermore, since the β-particles have a 2-10mm range, there has been dose-limiting non-specific toxicity to hematopoietic stem cells in the bone marrow (BM) due to the cross-fire effect. Conjugation of mAbs to α-particle-emitters (e.g. 225 Ac, 213 Bi, 212 Pb or 211 At) or Auger electron-emitters (e.g. 111 In, 67 Ga, 123 I or 125 I) would increase the potency of RIT due to their high LET (50-230keV/μm and 4 to 26keV/μm, respectively). In addition, α-particles have a range in tissues of 28-100μm and Auger electrons are nanometer in range which greatly reduces or eliminates the cross-fire effect compared to β-particles, potentially reducing their non-specific toxicity to the BM. In this review, we describe the results of preclinical and clinical studies of RIT of cancer using radioimmunoconjugates emitting α-particles or Auger electrons, and discuss the potential of these high LET forms of radiation to improve the outcome of cancer patients., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: Modular nanotransporters (MNTs) are a polyfunctional platform designed to achieve receptor-specific delivery of short-range therapeutics into the cell nucleus by receptor-mediated endocytosis, endosome escape, and targeted nuclear transport. This study evaluated the potential utility of the MNT platform in tandem with Auger electron emitting 111 In for cancer therapy., Methods: Three MNTs developed to target either melanocortin receptor-1 (MC1R), folate receptor (FR), or epidermal growth factor receptor (EGFR) that are overexpressed on cancer cells were modified with p-SCN-Bn-NOTA and then labeled with 111 In in high specific activity. Cytotoxicity of the 111 In-labeled MNTs was evaluated on cancer cell lines bearing the appropriate receptor target (FR: HeLa, SK-OV-3; EGFR: A431, U87MG.wtEGFR; and MC1R: B16-F1). In vivo micro-single-photon emission computed tomography/computed tomography imaging and antitumor efficacy studies were performed with intratumoral injection of MC1R-targeted 111 In-labeled MNT in B16-F1 melanoma tumor-bearing mice., Results: The three NOTA-MNT conjugates were labeled with a specific activity of 2.7 GBq/mg with nearly 100% yield, allowing use without subsequent purification. The cytotoxicity of 111 In delivered by these MNTs was greatly enhanced on receptor-expressing cancer cells compared with 111 In nontargeted control. In mice with B16-F1 tumors, prolonged retention of 111 In by serial imaging and significant tumor growth delay (82% growth inhibition) were found., Conclusion: The specific in vitro cytotoxicity, prolonged tumor retention, and therapeutic efficacy of MC1R-targeted 111 In-NOTA-MNT suggest that this Auger electron emitting conjugate warrants further evaluation as a locally delivered radiotherapeutic, such as for ocular melanoma brachytherapy. Moreover, the high cytotoxicity observed with FR- and EGFR-targeted 111 In-NOTA-MNT suggests further applications of the MNT delivery strategy should be explored., Competing Interests: The authors report no conflicts of interest in this work.

For many years in radiobiology and radiotherapy predominated the conviction that cellular DNA is the main target for ionizing radiation, however, the view has changed in the past 20 years. Nowadays, it is assumed that not only directed (targeted) radiation effect, but also an indirect (non-targeted) effect may contribute to the result of radiation treatment. Non-targeted effect is relatively well recognized after external beam irradiation in vitro and in vivo, and comprises such phenomena like radiation-induced bystander effect (RIBE), genomic instability, adaptive response and abscopal (out of field) effect. These stress-induced and molecular signaling mediated phenomena appear in non-targeted cells as variety responses resembling that observed in directly hit cells. Bystander effects can be both detrimental and beneficial in dependence on dose, dose-rate, cell type, genetic status and experimental condition. Less is known about radionuclide-induced non-targeted effects in radionuclide therapy, although, based on characteristics of the radionuclide radiation, on experiments in vitro utilizing classical and 3-D cell cultures, and preclinical study on animals it seems obvious that exposure to radionuclide is accompanied by various bystander effects, mostly damaging, less often protective. This review summarizes existing data on radionuclide induced bystander effects comprising radionuclides emitting beta- and alpha-particles and Auger electrons used in tumor radiotherapy and diagnostics. So far, separation of the direct effect of radionuclide decay from crossfire and bystander effects in clinical targeted radionuclide therapy is impossible because of the lack of methods to assess whether, and to what extent bystander effect is involved in human organism. Considerations on this topic are also included.

Introduction: Gold nanoparticles (AuNP; 30nm) were modified with polyethylene glycol (PEG) chains linked to trastuzumab for binding to HER2-positive breast cancer (BC) cells and diethylenetriaminepentaacetic acid (DTPA) for complexing the Auger electron-emitter, 111 In (trastuzumab-AuNP- 111 In). Our objective was to determine the cytotoxicity of trastuzumab-AuNP- 111 In on HER2-positive BC cells in vitro and evaluate its tumor growth inhibition properties and normal tissue toxicity in vivo following intratumoral (i.t.) injection in mice with s.c. HER2-overexpressing BC xenografts., Methods: Binding and internalization of trastuzumab-AuNP- 111 In or non-targeted AuNP- 111 In in SK-BR-3 (1-2×10 6 HER2/cell) and MDA-MB-361 (5×10 5 HER2/cell) human BC cells were studied. The surviving fraction (SF) of SK-BR-3 or MDA-MB-361 cells exposed to trastuzumab-AuNP- 111 In or AuNP- 111 In was determined. DNA double-strand breaks (DSBs) were assayed by probing for γ-H2AX. Tumor growth was monitored over 70days in CD1 athymic mice with s.c. MDA-MB-361 xenografts after i.t. injection of 10MBq (0.7mg; 2.6×10 12 AuNP) of trastuzumab-AuNP- 111 In and normal tissue toxicity was assessed by monitoring body weight, complete blood cell (CBC) counts and serum alanine aminotransferase (ALT) and creatinine (Cr)., Results: Trastuzumab-AuNP- 111 In was specifically bound by SK-BR-3 and MDA-MB-361 cells. Trastuzumab-AuNP- 111 In was more efficiently internalized than AuNP- 111 In and localized to a peri-nuclear region. The SF fraction of SK-BR-3 cells was reduced by 1.8-fold by treatment with 3nM (7MBq/mL) of trastuzumab-AuNP- 111 In. The SF of MDA-MB-361 cells was reduced by 3.7-fold at 14.4nM (33.6MBq/mL). In comparison, non-targeted AuNP- 111 In at these concentrations reduced the SF of SK-BR-3 or MDA-MB-361 cells by 1.2-fold (P=0.03) and 1.7-fold (P<0.0001), respectively. DNA DSBs were greater in SK-BR-3 and MDA-MB-361 cells exposed to trastuzumab-AuNP- 111 In compared to AuNP- 111 In, but unlabeled trastuzumab-AuNP did not increase DNA DSBs. Local i.t. injection of trastuzumab-AuNP- 111 In in CD1 athymic mice with s.c. MDA-MB-361 tumors arrested tumor growth for 70days. There was no apparent normal tissue toxicity. The radiation absorbed dose deposited in the tumor by trastuzumab-AuNP- 111 In was 60.5Gy, while normal organs received <0.9Gy., Conclusion: These results are promising for further development of trastuzumab-AuNP- 111 In as a novel Auger electron-emitting radiation nanomedicine for local treatment of HER2-positive BC., Advances in Knowledge and Implications for Patient Care: A local radiation treatment for HER2-positive BC based on AuNP modified with trastuzumab and labeled with the Auger electron-emitter, 111 In was developed and shown to arrest tumor growth with no normal tissue toxicity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To understand the biological effect of external and internal exposure from 137 Cs, DNA damage spectrum induced by directly emitted electrons (γ-rays, internal conversion electrons, Auger electrons) from 137 Cs was compared with that induced by 137 Cs γ-rays., Methods: Monte Carlo track simulation method was used to calculate the microscopic energy deposition pattern in liquid water. Simulation was performed for the two simple target systems in microscale. Radiation sources were placed inside for one system and outside for another system. To simulate the energy deposition by directly emitted electrons from 137 Cs placed inside the system, the multiple ejections of electrons after internal conversion were considered. In the target systems, induction process of DNA damage was modeled and simulated for both direct energy deposition and the water radical reaction on the DNA. The yield and spatial distribution of simple and complex DNA damage including strand breaks and base lesions were calculated for irradiation by electrons and γ-rays from 137 Cs., Results: The simulation showed that the significant difference in DNA damage spectrum was not caused by directly ejected electrons and γ-rays from 137 Cs., Conclusions: The result supports the existing perception that the biological effects by internal and external exposure by 137 Cs are equivalent.

Purpose DNA ligands labelled with 125 I induce cytotoxic DNA double-strand breaks (DSB), suggesting a potential for Auger endoradiotherapy. Since the 60-day half-life of 125 I is suboptimal for therapy, we have investigated another Auger-emitter 124 I, with shorter half-life (4.18 days), and the additional feature of positron-emission, enabling positron emission tomography (PET) imaging. The purpose of this study was to compare the two radionuclides on the basis of DNA DSB per decay. Materials and methods Using a 124 I- (or 125 I)-labelled minor groove binding DNA ligand, we investigated DNA breakage using the plasmid DNA assay. Biodistribution of the conjugate of the labelled ligand with transferrin was investigated in nude mice bearing a K562 human lymphoma xenograft. Results The probability of DSB per decay was 0.58 and 0.85 for 124 I and 125 I, respectively, confirming the therapeutic potential of the former. The crystal structure of the ligand DNA complex shows the iodine atom deep within the minor groove, consistent with the high efficiency of induced damage. Biodistribution studies, including PET imaging, showed distinctive results for the conjugate, compared to the free ligand and transferrin, consistent with receptor-mediated delivery of the ligand. Conclusions Conjugation of 124 I-labelled DNA ligands to tumor targeting peptides provides a feasible strategy for Auger endoradiotherapy, with the advantage of monitoring tumor targeting by PET imaging.

To identify the emergence of the recognition of the potential of the Auger effect for clinical application, and after tracing the salient milestones towards that goal, to evaluate the status quo and future prospects. It was not until 40 years after the discovery of Auger electrons, that the availability of radioactive DNA precursors enabled the biological power, and the clinical potential, of the Auger effect to be appreciated. Important milestones on the path to clinical translation have been identified and reached, but hurdles remain. Nevertheless the potential is still evident, and there is reasonable optimism that the goal of clinical translation is achievable.

Introduction: (111)In-DTPA-NLS-CSL360 radioimmunoconjugates (RIC) recognize the overexpression of the interleukin-3 receptor α-subchain (CD123) relative to the β-subchain (CD131) on leukemia stem cells (LSC). Our aim was to study Auger electron radioimmunotherapy (RIT) of acute myeloid leukemia (AML) with (111)In-DTPA-NLS-CSL360 in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice or NOD-Rag1(null)IL2rγ(null) (NRG) mice engrafted with CD123(+) human AML-5 cells., Methods: The toxicity of three doses of (111)In-DTPA-NLS-CSL360 (3.3-4.8MBq; 11-15μg each) injected i.v. every two weeks was studied in non-engrafted NOD/SCID or NRG mice pre-treated with 200cGy of γ-radiation required for AML engraftment. Engraftment efficiency of (1-5)×10(6) cells AML-5 cells inoculated i.v. into NOD/SCID or NRG mice was assessed by flow cytometric analysis for human CD45(+) (hCD45(+)) cells in the bone marrow (BM) and spleen. AML-5 engrafted mice were treated with two or three doses (3.7MBq; 10μg each) every two weeks of (111)In-DTPA-NLS-CSL360, non-specific (111)In-DTPA-NLS-hIgG, unlabeled CSL360 (10μg) or normal saline. The percentage of hCD45(+) cells in the BM and spleen were measured at one week after completion of treatment., Results: (111)In-DTPA-NLS-CSL360 in combination with 200cGy of γ-radiation caused an initial transient decrease in body weight in NOD/SCID but not in NRG mice. There were no hematological, liver or kidney toxicities. The spleen exhibited 13-fold lower engraftment efficiency than the BM in NOD/SCID mice inoculated with 1×10(6) cells but both organs were highly (>85%) engrafted in NRG mice. Unexpectedly, (111)In-DTPA-NLS-CSL360 or non-specific (111)In-DTPA-NLS-hIgG caused a paradoxical 1.5-fold increase (P<0.0001) in the proportion of hCD45(+) cells in the BM of NOD/SCID mice compared to normal saline treated mice. (111)In-DTPA-NLS-CSL360 reduced hCD45(+) cells in the spleen by 3.0-fold compared to (111)In-DTPA-NLS-hIgG (P=0.0015) but the proportion of hCD45(+) cells was not significantly different than in normal saline treated mice. Unlabeled CSL360 decreased the percentage of hCD45(+) cells in the BM (P=0.004) or spleen (P=0.007) in NOD/SCID mice by 1.6-fold and 2.5-fold, respectively. (111)In-DTPA-NLS-CSL360 or unlabeled CSL360 did not decrease the proportion of hCD45(+) cells in the BM or spleen of NRG mice, due to a much higher leukemic burden., Conclusion: (111)In-DTPA-NLS-CSL360 and (111)In-DTPA-NLS-hIgG caused a paradoxical increase in the proportion of hCD45(+) cells in the BM of NOD/SCID mice. This may be due to a priming effect on the BM niche that promotes expansion of engrafted hCD45(+) cells, analogous to γ-radiation required for AML engraftment. There appears to be a competition between this effect and the cytotoxic effects of the Auger electrons on leukemia cells. The effectiveness of (111)In-DTPA-NLS-CSL360 on reducing hCD45(+) cells in the BM or spleen of NOD/SCID and NRG mice was dependent on the leukemic burden., Advances in Knowledge and Implications for Patient Care: This study demonstrates for the first time a paradoxical radiation priming effect of RIT on enhancing the hCD45(+) cell population in the BM and spleen of NOD/SCID or NRG mice. Our results have important implications for preclinical evaluation of radioimmunotherapies for patients with AML., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A comprehensive investigation of the emission characteristics for electrons induced by X-rays of a few hundred eV at grazing-incidence angles on an atomically clean Cu(111) sample during laser excitation is presented. Electron energy spectra due to intense infrared laser irradiation are investigated at the BESSY II slicing facility. Furthermore, the influence of the corresponding high degree of target excitation (high peak current of photoemission) on the properties of Auger and photoelectrons liberated by a probe X-ray beam is investigated in time-resolved pump and probe measurements. Strong electron energy shifts have been found and assigned to space-charge acceleration. The variation of the shift with laser power and electron energy is investigated and discussed on the basis of experimental as well as new theoretical results.

Chimeric IgG1 monoclonal antibody CSL360 recognizes the CD123(+)/CD131(-) phenotype expressed by leukemic stem cells (LSC). Auger electron-emitting (111)In-DTPA-NLS-CSL360 radioimmunoconjugates incorporating nuclear translocation sequence (NLS) peptides bound specifically to Raji cells transfected with CD123 and exhibited a KD of 11nmols/L in a competition receptor-binding assay using CD123-transfected CHO cells. (111)In-DTPA-NLS-CSL360 was bound, internalized and transported to the nucleus of human AML-5 myeloid leukemia cells. The clonogenic survival of AML-5 cells was reduced by (111)In-DTPA-NLS-CSL360 up to 3.7-fold. Isotype control (111)In-DTPA-chIgG1 was 2-fold less cytotoxic, and unlabeled CSL360, DTPA-NLS-CSL360 or free (111)In acetate did not decrease cell survival. These results are promising for further evaluation of (111)In-DTPA-NLS-CSL360 for Auger electron radioimmunotherapy of AML targeting the critical LSC subpopulation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: The present review article aims to provide an overview of the available radionuclides for palliative treatment of bone metastases beyond (89)Sr and (153)Sm. In addition, it aims to review and summarize the clinical outcomes associated with the palliative treatment of bone metastases using different radiopharmaceuticals., Materials and Methods: A literature search was conducted on Science Direct and PubMed databases (1990 - 2015). The following search terms were combined in order to obtain relevant results: "bone", "metastases", "palliative", "care", "therapy", "treatment", "radiotherapy", "review", "radiopharmaceutical", "phosphorus-32", "strontium-89", "yttrium-90", "tin-117m", "samarium-153", "holmium-166", "thulium-170", "lutetium-177", "rhenium-186", "rhenium-188" and "radium-223". Studies were included if they provided information regarding the clinical outcomes., Results and Conclusions: A comparative analysis of the measured therapeutic response of different radiopharmaceuticals, based on previously published data, suggests that there is a lack of substantial differences in palliative efficacy among radiopharmaceuticals. However, when the comparative analysis adds factors such as patient's life expectancy, radionuclides' physical characteristics (e.g. tissue penetration range and half-life) and health economics to guide the rational selection of a radiopharmaceutical for palliative treatment of bone metastases, (177)Lu and (188)Re-labeled radiopharmaceuticals appear to be the most suitable radiopharmaceuticals for treatment of small and medium/large size bone lesions, respectively., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

High power, high radiance, broadband light sources emitting in the 2.0–2.5 μm wavelength range are important for optical sensing of biomolecules such as glucose in aqueous solutions. Here we demonstrate and analyze superluminescent diodes with output centered at 2.4 μm (range ~2.2–2.5 μm) from GaInAsSb/AlGaAsSb quantum wells in a separate confinement structure. Pulsed wave output of 1 mW (38 kW cm2 Sr−1) is achieved at room temperature for 40 μm × 2 mm devices. Superluminescence is evidenced in superlinear increase in emission, spectral narrowing, and angular narrowing of light output with increasing current injection. Optical output is analyzed and modeled with rate equations. Potential routes for future improvements are explored, such as additional Auger suppression and photonic mode engineering. [ABSTRACT FROM AUTHOR]

Secondary electron emission with very low kinetic energy (KE) has been measured in the Ne 1s photoexcitation region. A new decay channel for Auger transitions following Ne 1s to 3p excitation has been identified using a two-dimensional mapping technique, in which slow Auger electron signals are displayed as functions of electron kinetic energy and photon energy. Electrons with about 0.68 eV KEs have been ascribed to multiplet exchange Auger electrons from the 2p−2(1S)3d state. This state is formed through the resonant Auger transition from the 1s−13p state, in which the excited 3p electron changes its azimuthal quantum number. Another cascade Auger decay of multiplet exchanging was found as electron emission of about 2.0 eV KEs; 2p−2(1S)4p → 2p−2(3P) + e−. Several cascade decays were found to occur via the photoexcitation into 1s−14p and 1s−15p states. [ABSTRACT FROM AUTHOR]

In order to improve the dynamical conditions for possible formation of quasi-Fermi level separation between states in the conduction band, upon external illumination of an quantum dot based solar cells, we employ methods of quantum engineering to design the type II alignment, using a GaAsSb barrier buffer underneath InAs/GaAs QD. By changing the Sb amount in the buffer region, we predict an increase of the interband radiative time to the same time scale as interband radiative time, with simultaneous increase of the Auger electron cooling to ∼0.1 ns. [ABSTRACT FROM AUTHOR]

Our objective was to evaluate the cytotoxicity toward HER2-positive human breast cancer (BC) cells of trastuzumab modified site-specifically with a metal-chelating polymer (MCP) that presents multiple DTPA chelators for complexing (111)In. (111)In emits subcellular range Auger electrons that induce multiple lethal DNA double-strand breaks (DSBs) in cells. MCPs were synthesized with a polyglutamide backbone with 24 or 29 pendant DTPA groups, with or without nuclear translocation sequence (NLS) peptide modification and a terminal hydrazide group for reaction with aldehydes generated by sodium periodate (NaIO4)-oxidation of glycans on the Fc-domain of trastuzumab. Trastuzumab was site-specifically modified with two DTPA and labeled with (111)In for comparison (trastuzumab-NH-Bn-DTPA-(111)In). The maximum specific activity (SA) for labeling trastuzumab-Hy-MCP with (111)In was 90-fold greater than for trastuzumab-NH-Bn-DTPA-(111)In [8.9 MBq/μg (1.5 × 10(6) MBq/μmol) vs 0.1 MBq/μg (1.2 × 10(4) MBq/μmol)]. Trastuzumab-Hy-MCP-(111)In was bound, internalized, and imported into the nucleus of SK-BR-3 cells. NLS peptide modification of MCPs did not increase nuclear importation. A greater density of DNA DSBs was found for BC cells exposed to high SA (5.5 MBq/μg) than low SA (0.37 MBq/μg) radioimmunoconjugates. At 20 nmol/L, high SA trastuzumab-Hy-MCP-(111)In was 6-fold more effective at reducing the clonogenic survival (CS) of HER2 overexpressed and HER2 gene-amplified SK-BR-3 cells (1.3 × 10(6) receptors/cell) than low SA MCP-radioimmunoconjugates (CS = 1.8 ± 1.3 vs 10.9 ± 0.7%; P = 0.001). Low SA trastuzumab-NH-Bn-DTPA-(111)In (20 nmol/L) reduced the CS of SK-BR-3 cells to 15.8 ± 2.1%. The CS of ZR-75-1 cells with intermediate HER2 density (4 × 10(5) receptors/cell) but without HER2 gene amplification was reduced to 20.5 ± 4.3% by high SA trastuzumab-Hy-MCP-(111)In (20 nmol/L). The CS of HER2-overexpressed (5 × 10(5) HER2/cell) but trastuzumab-resistant TrR1 cells was decreased to 17.1 ± 1.6% by high SA trastuzumab-Hy-MCP-(111)In. Unlabeled trastuzumab (20 nmol/L) was 18-fold less potent than high SA trastuzumab-Hy-MCP-(111)In at reducing the CS of SK-BR-3 cells (CS = 37.0 ± 5.3%) and 3-fold less effective against Zr-75-1 cells (CS = 53.1 ± 9.8%). Unlabeled trastuzumab had no effect on the survival of TrR1 cells. We conclude that increasing the SA for labeling with (111)In by site-specific conjugation of MCPs to trastuzumab greatly amplified the cytotoxic potency against HER2-overexpressed and gene-amplified BC cells and extended its cytotoxicity to cells with intermediate HER2 expression but without gene amplification and to cells that are HER2 overexpressed but trastuzumab-resistant.

A correction to the article "Auger Processes in the 21st Century" that was published in the 2008 issue is presented.

Highly mismatched semiconductor alloys such as GaNxAs1 − x and GaBixAs1 − x have several novel electronic properties, including a rapid reduction in energy gap with increasing x and also, for GaBiAs, a strong increase in spin-orbit-splitting energy with increasing Bi composition. We review here the electronic structure of such alloys and their consequences for ideal lasers. We then describe the substantial progress made in the demonstration of actual GaInNAs telecommunication (telecom) lasers. These have characteristics comparable to conventional InP-based devices. This includes a strong Auger contribution to the threshold current. We show, however, that the large spin-orbit-splitting energy in GaBiAs and GaBiNAs could lead to the suppression of the dominant Auger recombination loss mechanism, finally opening the route to efficient temperature-stable telecomm and longer wavelength lasers with significantly reduced power consumption. [ABSTRACT FROM AUTHOR]

This study proposes a novel scanning-probe-based approach to induce local interdiffusion at buried interfaces. Scanning-probe oxidation (SPO) was performed on a thin TiN layer on a Si substrate with ethanol menisci. The diffusion of Si and Ti at the interface was observed using Auger electron analysis and photoelectron spectroscopy and mapping. The results of photoelectron spectroscopy revealed that SPO converted the TiN layer into TiNxOy. The significant conductivity of TiNxOy was verified by conductive atomic force microscopy. Joule heating in the conductive TiNxOy induced Si diffusion in the amorphous TiNxOy layer. [ABSTRACT FROM AUTHOR]

Background: The androgen receptor (AR) plays a dominant role in the pathogenesis of prostate cancer. 5-Radioiodo-3'-O-(17β-succinyl-5α-androstan-3-one)-2'-deoxyuridin-5'-yl phosphate (RISAD-P) is an AR-targeting reagent developed for noninvasive assessment of AR and proliferative status of the AR-expressing tumors, and for molecular radiotherapy with Auger electron-emitting radionuclides. In this study, the preclinical toxicity and targeting potential of RISAD-P was evaluated., Methods: Effects of nonradioactive ISAD-P and RISAD-P labeled with (123) I, (124) I, and (125) I were evaluated in male mice. Expanded-acute single dose toxicity studies, hematologic toxicity, liver and kidney function, pharmacokinetics, biodistribution, and imaging studies were conducted. Imaging and pilot therapy studies were conducted in transgenic mice., Results: RISAD-P is not toxic at doses projected for clinical use. Its tissue distribution compares favorably with the distribution reported for (18) F-dihydrotestosterone derivatives. RISAD-P has excellent prostate cancer targeting properties. One hour after (125) IRISAD-P administration, nearly 10% of the injected dose is associated with prostate tumor. The tumor clearance is biphasic and plateaus between 24 and 48 hr post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range with values of 170, 250, 1,240 Gy × MBq(-1)  × g(-1) for (125) I-, (123) I-, and (124) I-labeled RISAD-P, respectively. The transient uptake of radioactivity is observed in the genitourinary tract and stomach. Without the potassium iodide blockade, thyroid uptake is also observed., Conclusions: Biodistribution, toxicity, and radiation dosimetry studies suggest that RISAD-P holds characteristics of a promising candidate for imaging of AR expression and tumor proliferation, as well as molecular radiotherapy for metastatic or locally, regionally advanced prostate cancer., (© 2014 Wiley Periodicals, Inc.)

Background: The androgen receptor (AR) axis, the key growth and survival pathway in prostate cancer, remains a prime target for drug development. 5-Radioiodo-3'-O-(17β-succinyl-5α-androstan-3-one)-2'-deoxyuridin-5'-yl phosphate (RISAD-P) is the AR-seeking reagent developed for noninvasive assessment of AR and proliferative status, and for molecular radiotherapy of prostate cancer with Auger electron-emitting radionuclides., Methods: RISAD-P radiolabeled with 123I, 124I, and 125I were synthesized using a common stannylated precursor. The cellular uptake, subcellular distribution, and radiotoxicity of 123I-, 124I-, and (125) IRISAD-P were measured in LNCaP, DU145, and PC-3 cell lines expressing various levels of AR., Results: The uptake of RISAD-P by prostate cancer cells is proportional to AR levels and independent of the radionuclide. The intracellular accumulation of radioactivity is directly proportional to the extracellular concentration of RISAD-P and the duration of exposure. Initially, RISAD-P is trapped in the cytoplasm. Within 24 hr, radioactivity is associated exclusively with DNA. The RISAD-P radiotoxicity is determined by the radionuclide; however, the cellular responses are directly proportional to the AR expression levels. LNCaP cells expressing high levels of AR are killed at the rate of up to 60% per day after a brief 1 hr RISAD-P treatment. For the first time, the AR expression in PC-3 and DU 145 cells, generally reported as AR-negative, was quantitated by the ultra sensitive RISAD-P-based method., Conclusions: RISAD-P is a theranostic drug, which targets AR. Its subcellular metabolite participates in DNA synthesis. RISAD-P is a promising candidate for imaging of the AR expression and tumor proliferation as well as molecular radiotherapy of prostate cancer., (© 2014 Wiley Periodicals, Inc.)

Gold nanoparticles (GNP) enhance the absorbance of photons thereby increasing emission of Auger-/photoelectrons in the nm-μm range. Yet, a major disadvantage is their diameter-dependent cellular uptake with an optimum of ~50 nm which may not offer optimal radiosensitization. A method was developed to enhance the uptake of small GNP. GNP (10nm) were linked to DNA and transferred into HeLa cells by transient transfection (GNP-DT). Treatment of cells with GNP-DT resulted in a strong perinuclear focal accumulation, whereas this was dimmer and sparser for GNP-T (lacking DNA) and close to background levels in GNP-treated cells. Only GNP-DT showed a significant radiosensitizing effect (p=0.005) on clonogenic survival using clinically relevant megavolt x-rays. Our novel method markedly increases the uptake/retention and alters the localization of small GNP in cells compared to unmodified GNP. This work finally enables studying the radiosensitizing effects of differentially sized GNP., From the Clinical Editor: In an effort to increase the radiosensitization of HeLa cells, his paper discusses a transient transfection-based method to enhance gold nanoparticle intracellular delivery., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: The somatostatin receptor, which is overexpressed by many neuroendocrine tumors, is a well-known target for molecular imaging and peptide receptor radionuclide therapy. Recently, (57)Co-labeled DOTATOC, an octreotide analog, was shown to have the highest affinity yet found for somatostatin receptor subtype 2. The aim of this study was to evaluate the biologic effects of novel cobalt-labeled octreotide analogs targeting the somatostatin receptor to identify promising candidates for molecular imaging and Auger electron-based radionuclide therapy., Methods: Cobalt-labeled DOTATATE, DOTATOC, and DOTANOC were prepared with (57)Co or (58m)Co for SPECT or Auger electron-based therapy, respectively. The cellular uptake and intracellular distribution of the radioligands were characterized with the pancreatic tumor cell line AR42J in vitro, including assessment of the therapeutic effects of (58m)Co-DOTATATE via DNA double-strand break and proliferation assays. Comparisons with the therapeutic effects of (111)In- and (177)Lu-DOTATATE were also performed. Tumor uptake and normal tissue uptake were characterized in a subcutaneous pancreatic tumor mouse model., Results: All 3 cobalt-conjugated peptides resulted in time-dependent and receptor-specific uptake, with a high level (≥88%) of cellular internalization in vitro of the total cell-associated radioactivity. The DNA double-strand break yield showed a dose-dependent increase with activity, whereas cell survival showed a dose-dependent decrease. (58m)Co-DOTATATE was significantly more efficient in cell killing per cumulated decay than (111)In- and (177)Lu-DOTATATE. The in vivo pharmacokinetic studies showed a high level of receptor-specific tumor uptake., Conclusion: All cobalt-labeled radioligands showed a high level of receptor-specific uptake both in vitro and in vivo in tumor-bearing mice. Furthermore, (58m)Co-DOTATATE showed considerable therapeutic effects in vitro and, thus, could be an effective agent for eradicating disseminated tumor cells and micrometastases., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)