A Compact Piezo-Inertia Actuator Utilizing the Double-Rocker Flexure Hinge Mechanism.

With a simple structure and control method, the piezo-inertia actuator is a preferred embodiment in the field of microprecision industry. However, most of the previously reported actuators are unable to achieve a high speed, high resolution, and low deviation between positive and reverse velocities at the same time. To achieve a high speed, high resolution, and low deviation, in this paper we present a compact piezo-inertia actuator with a double rocker-type flexure hinge mechanism. The structure and operating principle are discussed in detail. To study the load capacity, voltage characteristics, and frequency characteristics of the actuator, we made a prototype and conducted a series of experiment. The results indicate good linearity in both positive and negative output displacements. The maximum positive and negative velocities are about 10.63 mm/s and 10.12 mm/s, respectively, and the corresponding speed deviation is 4.9%. The positive and negative positioning resolutions are 42.5 nm and 52.5 nm, respectively. In addition, the maximum output force is 220 g. These results show that the designed actuator has a minor speed deviation and good output characteristics.

Evolution of the Morphology and Magnetic Properties of Flaky FeSiAl/MFe2O4 (M = Mn, Co, Ni, Cu, Zn) Composites.

Nanosized spinel ferrites MFe2O4 (M = Mn, Co, Ni, Cu, Zn)-coated flaky FeSiAl alloy composites were synthesized successfully. Nano-ferrites preferentially grow into nanoplatelets due to induced or restricted growth on the flaky surface of FeSiAl. With annealing temperature increasing, the ferrites' nanosheets thicken gradually and then grow into irregular particles. The annealing temperature not only affects the nanosized morphology and coating but also the magnetic properties of flaky FeSiAl composites. The saturation magnetization of CuFe2O4- or NiFe2O4-coated FeSiAl is approximate 69 emu/g, where the value of MnFe2O4-, CoFe2O4- and ZnFe2O4-coated FeSiAl show a decreasing trend generally from 64 emu/g to 55.7 emu/g annealing at 800 °C, respectively. The saturation magnetization of flaky FeSiAl composites was improved with the increased annealing temperature, except for those coated with ZnFe2O4 and NiFe2O4. These results are useful for improving the comprehensive properties of ferrite-coated flaky FeSiAl alloy composites.

Comparison of conjugation strategies of cross-bridged macrocyclic chelators with cetuximab for copper-64 radiolabeling and PET imaging of EGFR in colorectal tumor-bearing mice.

Epidermal growth-factor receptor (EGFR) is overexpressed in a wide variety of solid tumors and has served as a well-characterized target for cancer imaging and therapy. Cetuximab was the first mAb targeting EGFR approved by the FDA for the treatment of metastatic colorectal and head and neck cancers. Previous studies showed that (64)Cu (T1/2 = 12.7 h; ß(+) (17.4%)) labeled DOTA-cetuximab showed promise for PET imaging of EGFR-positive tumors; however the in vivo stability of this compound has been questioned. In this study, two recently developed cross-bridged macrocyclic chelators (CB-TE1A1P and CB-TE1K1P) were conjugated to cetuximab using standard NHS coupling procedures and/or strain-promoted azide-alkyne cycloaddition (SPAAC) methodologies. The radiolabeling and in vitro/vivo evaluation of the resulting cetuximab conjugates were compared. Improved Cu-64 labeling efficiency and high specific activity (684 kBq/µg, decay corrected to the end of bombardment) were obtained with the CB-TE1K1P-PEG4-click-cetuximab conjugate. Saturation binding assays indicated that the prepared cetuximab conjugates had comparable affinity (1.32-2.00 nM) in the HCT116 human colorectal tumor cell membranes. In the subsequent in vivo evaluation, (64)Cu-CB-TE1K1P-PEG4-click-cetuximab demonstrated more rapid renal clearance with a higher tumor/nontumor ratio than other (64)Cu-labeled cetuximab conjugates, and it shows the greatest promise for imaging and therapy of EGFR-positive tumors.

Roles of Atox1 and p53 in the trafficking of copper-64 to tumor cell nuclei: implications for cancer therapy.

Owing to its cytotoxicity, free copper is chelated by protein side chains and does not exist in vivo. Several chaperones transport copper to various cell compartments, but none have been identified that traffic copper to the nucleus. Copper-64 decays by ß (+) and ß (-) emission, allowing positron emission tomography and targeted radionuclide therapy for cancer. Because the delivery of (64)Cu to the cell nucleus may enhance the therapeutic effect of copper radiopharmaceuticals, elucidation of the pathway(s) involved in transporting copper to the tumor cell nucleus is important for optimizing treatment. We identified Atox1 as one of the proteins that binds copper in the nucleus. Mouse embryonic fibroblast cells, positive and negative for Atox1, were used to determine the role of Atox1 in (64)Cu transport to the nucleus. Mouse embryonic fibroblast Atox1(+/+) cells accumulated more (64)Cu in the nucleus than did Atox1(-/-) cells. HCT 116 colorectal cancer cells expressing p53 (+/+) and not expressing p53 (-/-) were used to evaluate the role of this tumor suppressor protein in (64)Cu transport. In cells treated with cisplatin, the uptake of (64)Cu in the nucleus of HCT 116 p53(+/+) cells was greater than that in HCT 116 p53(-/-) cells. Atox1 expression increased in HCT 116 p53(+/+) and p53(-/-) cells treated with cisplatin; however, Atox1 localized to the nuclei of p53(+/+) cells more than in the p53(-/-) cells. The data presented here indicate that Atox1 is involved in copper transport to the nucleus, and cisplatin affects nuclear transport of (64)Cu in HCT 116 cells by upregulating the expression and the nuclear localization of Atox1.

The role of p53 in combination radioimmunotherapy with 64Cu-DOTA-cetuximab and cisplatin in a mouse model of colorectal cancer.

UNLABELLED: Radioimmunotherapy has been successfully used in the treatment of lymphoma but thus far has not demonstrated significant efficacy in humans beyond disease stabilization in solid tumors. Radioimmunotherapy with (64)Cu was highly effective in a hamster model of colorectal cancer, but targeted radiotherapies with this radionuclide have since not shown as much success. It is widely known that mutations in key proteins play a role in the success or failure of cancer therapies. For example, the KRAS mutation is predictive of poor response to anti-epidermal growth factor receptor therapies in colorectal cancer, whereas p53 is frequently mutated in tumors, causing resistance to multiple therapeutic regimens. METHODS: We previously showed that nuclear localization of (64)Cu-labeled DOTA-cetuximab was enhanced in p53 wild-type tumor cells. Here, we examine the role of p53 in the response to radioimmunotherapy with (64)Cu-DOTA-cetuximab in KRAS-mutated HCT116 tumor-bearing mice, with and without cisplatin, which upregulates wild-type p53. RESULTS: Experiments with HCT116 cells that are p53 +/+ (p53 wild-type) and -/- (p53 null) grown in cell culture demonstrated that preincubation with cisplatin increased expression of p53 and subsequently enhanced localization of (64)Cu from (64)Cu-acetate and (64)Cu-DOTA-cetuximab to the tumor cell nuclei. Radioimmunotherapy studies in p53-positive HCT116 tumor-bearing mice, receiving either radioimmunotherapy alone or in combination with cisplatin, showed significantly longer survival in mice receiving unlabeled cetuximab or cisplatin alone or in combination (all, P < 0.01). In contrast, the p53-negative tumor-bearing mice treated with radioimmunotherapy alone or combined with cisplatin showed no survival advantage, compared with control groups (all, P > 0.05). CONCLUSION: Together, these data suggest that (64)Cu specifically delivered to epidermal growth factor receptor-positive tumors by cetuximab can suppress tumor growth despite the KRAS status and present opportunities for personalized clinical treatment strategies in colorectal cancer.

Chemistry and theranostic applications of radiolabeled nanoparticles for cardiovascular, oncological, and pulmonary research.

Labeling nanoparticles with radionuclides has been widely used to form multifunctional and multivalency agents for various biomedical applications. A variety of nanostructures including inorganic, organic and lipid nanoparticles have been labeled with positron or gamma emitting radioisotopes through versatile radiochemistry in a number of disease models to track their in vivo fate, image biomarkers, and monitor treatment response. This review briefly summarizes the recent applications of nanoparticles labeled with radionuclides for oncological, cardiovascular, and pulmonary theranostics.

Preparation and biological evaluation of (64)Cu labeled Tyr(3)-octreotate using a phosphonic acid-based cross-bridged macrocyclic chelator.

Somatostatin receptors (SSTr) are overexpressed in a wide range of neuroendocrine tumors, making them excellent targets for nuclear imaging and therapy, and radiolabeled somatostatin analogues have been investigated for positron emission tomography imaging and radionuclide therapy of SSTr-positive tumors, especially of the subtype-2 (SSTr2). The aim of this study was to develop a somatostatin analogue, Tyr(3)-octreotate (Y3-TATE), conjugated to a novel cross-bridged macrocyclic chelator, 11-carboxymethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4-methanephosphonic acid (CB-TE1A1P). Unlike traditional cross-bridged macrocycles, such as 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), CB-TE1A1P-Y3-TATE was radiolabeled with (64)Cu in high purity and high specific activity using mild conditions. Saturation binding assays revealed that (64)Cu-CB-TE1A1P-Y3-TATE had comparable binding affinity but bound to more binding sites in AR42J rat pancreatic tumor cell membranes than (64)Cu-CB-TE2A-Y3-TATE. Both radiopharmaceuticals showed comparable uptake in SSTr2 positive tissues in AR42J tumor-bearing rats. (64)Cu-CB-TE1A1P-Y3-TATE demonstrated improved blood clearance compared to (64)Cu-CB-TE2A-Y3-TATE, as the tumor/blood ratios of (64)Cu-CB-TE1A1P-Y3-TATE were shown to be significantly higher than those of (64)Cu-CB-TE2A-Y3-TATE at 4 and 24 h postinjection. (64)Cu-CB-TE1A1P-Y3-TATE, in spite of a relatively high kidney uptake, accumulated less in nontarget organs such as liver, lung, and bone. Small animal PET/CT imaging of (64)Cu-CB-TE1A1P-Y3-TATE in AR42J tumor bearing rats validated significant uptake and good contrast in the tumor. This study suggests that CB-TE1A1P is a promising bifunctional chelator for (64)Cu-labeled for Y3-TATE, owing to high binding affinity and target tissue uptake, the ability to radiolabel the agent at lower temperatures, and improved tumor/nontarget organ ratios over (64)Cu-CB-TE2A-Y3-TATE.