Novel 175Yb-Poly (L-Lactic Acid) Microspheres for Transarterial Radioembolization of Unrespectable Hepatocellular Carcinoma.

Novel biodegradable Poly (L-lactic acid) (PLLA) microspheres containing ytterbium were designed for intra-tumoral radiotherapy, especially for radioembolization. 175Yb possess both therapeutic beta and diagnostic gamma radiations. In this work, a process of making ready radiomicrospheres 175Yb (acac)3-loaded PLLA for more consideration has been investigated. The radiomicrospheres were prepared with approximate size of 20-40 µm, and radionuclidic purity > 92%. The radiomicrospheres were stable in-vitro for up to 72 h in normal saline, and also in human serum albumin (HSA). Biodistribution in mice bearing 4T1 tumor showed specific radionuclide uptake over 48 h. Tumor necrosis was also observed at the injection site up to 12 days after injection. These data indicated that 175Yb-PLLA microspheres could be prepared and considered further for radiomicrospheres tumor therapy.

177Lu/153Sm-Ethylenediamine Tetramethylene Phosphonic Acid Cocktail: A Novel Palliative Treatment for Patients with Bone Metastases.

Background: Production of effective, low-cost, and efficient radiopharmaceuticals is an important task and requires further research and clinical studies. In this clinical trial, safety and efficacy of 177Lu/153Sm-ethylenediamine tetramethylene phosphonic acid (EDTMP) cocktail has been evaluated for pain relief of bone metastases. Materials and Methods: Twenty-five patients with the mean age of 55.5 ± 15.8 years participated in this study. Patients received a total dose of 37 MBq/kg. Pain and performance assessments were followed using a Brief Pain Inventory form. Complete blood count and renal and liver function tests were also performed up to 12 weeks postadministration. Results: Eighteen patients (72%) demonstrated complete pain relief (relief = 100%) and approximately all patients (96%) experienced significant improvement in their quality of life. No grade IV hematological toxicity was observed during the 12-week follow-up period, and grade III toxicity was seen in 1 patient only. In addition, no abnormalities were seen in renal and liver function during the follow-up period. Conclusions: There were no considerable complications after administration of 177Lu/153Sm EDTMP; this cocktail seems to be a safe and effective treatment for bone pain palliation in patients with skeletal metastases and improves the quality of life.

Highly Stable 177Lu-Organic Framework as a Potential Agent for Treatment of Metastatic Bone.

In this paper, the metal organic framework (MOF) concept is contributed to rearrange the bone-seeking agent composed of carrier-free lutetium-177 (Lu-177), 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraaminomethylenephosphonate (DOTMP) and cupper (II) (Cu (II)) for preparation of a potential agent for treatment of bone metastases. The product was characterized (infra-red spectroscopy, IR, and X-ray diffraction analysis) and quality-controlled (radio-thin layer chromatography, (RTLC)). The stability and in vitro hydroxyapatite binding was checked up to 1.5 month at 37 °C in human serum. Radio-MOF crystals and radio-MOF particles that were obtained by varying the synthesizing conditions (including pH and temperature) showed similar IR patterns and similar elemental analysis results. The final product was synthesized at pH = 8, stirring at room temperature (yield >99%, RTLC, particle size: 90 ± 20 nm). Biodistribution study experiments showed interesting bone-seeking (%ID/g: 8.5%) affinity of the prepared formula with no significant liver or lung uptake. Also high accumulation of radio-complex in bone tissue was estimated by the modeling of the radiation dose delivery using radiation dose assessment resource software. This novel radio-MOF with promising therapeutic results is the first study of the usage of the MOF concept to provide a high payload of Lu-177 for treatment of bone metastases. As it was expected, the most important outcome of the paper was higher bone-uptake rates rather than conventional 177Lu-DOTMP.

Preparation and evaluation of 188 Re sulfide colloidal nanoparticles loaded biodegradable poly (L-lactic acid) microspheres for radioembolization therapy.

Radioembolization with radioactive microspheres has been an effective method for the treatment of liver lesions. The aim of this study was to prepare carrier-free 188 Re loaded poly (L-lactic acid) (PLLA) microspheres through 188 Re sulfide colloidal nanoparticles (188 Re-SC nanoparticles). The formation of 188 Re-SC nanoparticles was confirmed by ultraviolet-visible spectrophotometry. The labeling yield of 188 Re-SC nanoparticles was verified using the RTLC method. Effects of synthesis parameters on morphology and size of prepared 188 Re-sulfide colloidal-PLLA microspheres (188 Re-SC-PLLA microspheres) were studied by scanning electron microscopy. In vitro stability of 188 Re-SC-PLLA microspheres was investigated in normal saline at room temperature and in human serum at 37°C. In vivo distribution studies and gamma camera imaging were performed in healthy BALB/c mice. The microspheres could be prepared with sizes between 13 and 48 µm (modal value 29 µm) and radiolabeling efficiency >99%. After incubation, the microspheres were found stable in vitro up to 72 hours. The biodistribution after intravenous injection in healthy BALB/c mice showed high accumulation in lung as a first capture pathway organ for microsphere followed by great retention over 48 hours for these microspheres. These data show that 188 Re-SC-PLLA microspheres are suitable candidate for clinical studies.

Absorbed doses in humans from 188Re-Rituximab in the free form and bound to superparamagnetic iron oxide nanoparticles: Biodistribution study in mice.

Absorbed doses to human organs from 188Re-Rituximab in the free form and bound to superparamagnetic iron oxide nanoparticles were predicted from results of the radiopharmaceutical biodistribution studies in mice by the RADAR method. Overall, equivalent and effective doses to human organs from the radiopharmaceutical on the nanoparticles were higher because of the enhanced permeability and retention effect. Liver, spleen and kidneys received higher equivalent doses than other organs (5.29, 3.70 and 3.06mSv/MBq, respectively, for the free radiopharmaceutical and 6.12, 3.96 and 3.93mSv/MBq for the drug on the nanoparticles).

Preparation and evaluation of APTES-PEG coated iron oxide nanoparticles conjugated to rhenium-188 labeled rituximab.

Radioimmuno-conjugated (Rhenium-188 labeled Rituximab), 3-aminopropyltriethoxysilane (APTES)-polyethylene glycol (PEG) coated iron oxide nanoparticles were synthesized and then characterized. Therapeutic effect and targeting efficacy of complex were evaluated in CD20 express B cell lines and tumor bearing Balb/c mice respectively. To reach these purposes, superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized using coprecipitation method and then their surface was treated with APTES for increasing retention time of SPIONs in blood circulation and amine group creation. In the next step, N-hydroxysuccinimide (NHS) ester of polyethylene glycol maleimide (NHS-PEG-Mal) was conjugated to the APTES-treated SPIONs. After radiolabeling of Rituximab antibody with Rhenium-188 (T1/2=16.9h) using synthesized N2S4 chelator, it was attached to the APTES-PEG-MAL-SPIONs surface through thiol-maleimide coupling reaction. In vitro evaluation of the 188ReN2S4-Rituximab-SPION-complex thus obtained revealed that at 24 and 48h post-treatment effective cancer cell killing had been achieved. Bio-distribution study in tumor bearing mice showed capability of this complex for targeted cancer therapy. Active and passive tumor targeting strategies were applied through incorporated anti-CD20 (Rituximab) antibody and also enhanced permeability and retention (EPR) effect of solid tumors for nanoparticles respectively.

Production, quality control, and determination of human absorbed dose of no carrier added 177 Lu-risedronate for bone pain palliation therapy.

In this study, the radiocomplexation of risedronic acid, a potent bisphosphonate with a no carrier added (NCA) 177 Lu, was investigated and followed by quality control studies, biodistribution evaluation, and dosimetry study for human based on biodistribution data in Wistar rats. The moderate energy ß- emitter, 177 Lu (T½  = 6.7 days, Eßmax  = 497 keV), has been considered as a potential agent for development of bone-seeking radiopharmaceuticals. Because the specific activity of the radiolabeled carrier molecules should be high, the NCA radionuclides have an effective role in nuclear medicine. Many researchers illustrated an NCA 177 Lu production; among these separation techniques, extraction chromatography has been considered more capable than other methods. The NCA 177 Lu was produced with specific activity of 48 Ci/mg and radionuclidic purity of 99.99% by the irradiation of enriched 176 Yb target in thermal neutron flux of 4 × 1013  n·cm-2 ·s-1 for 14 days. The NCA 177 Lu was mixed to a desired amount of sodium risedronate (15 mg/mL, 200 µL) and incubated with stirring at 95°C for 30 minutes. The radiochemical purity of 177 Lu-risedronate was determined by radio thin-layer chromatography, and high radiochemical purities (>97%) were obtained under optimized reaction conditions. The complex was injected to Wistar rats, and complex biodistribution was performed 4 hours to 7 days postinjections showing high bone uptake (9.8% ± 0.24% ID/g at 48 hours postinjection). Also, modeling the radiation dose delivery by RADAR software for the absorbed dose evaluation of each human organ showed a major accumulation of the radiocomplex in bone tissue.

Production and quality control 177Lu (NCA)-DOTMP as a potential agent for bone pain palliation.

Skeletal uptake of radiolabeled-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetramethylene phosphoric acid (e.g., 177Lu-DOTMP) complex, is used for bone pain palliation. The moderate energy of ß-emitting 177Lu (T½ = 6.7 d, Eßmax = 497keV) has been considered as a potential radionuclide for development of the bone-seeking radiopharmaceutical. Since the specific activity of the radiolabeled carrier molecules should be high, the "no-carrier-added radionuclides" have sig-nificant roles in nuclear medicine. Many researchers illustrated no-carrier-added 177Lu production; among these separation techniques such as ion exchange chromatography, reversed phase ion-pair, and electrochemical method, extraction chromatography has been considered more capable than other methods. In order to optimize the conditions, some effective factors on separation of Lu/Yb were investigated by EXC. The NCA 177Lu, produced by this method, was mixed with 300 µl of DOTMP solution (20 mg in 1 mL of 0.5 M NaHCO3, pH = 8) and incu-bated under stirring at room temperature for 45 min. Radiochemical purity of the 177Lu-DOTMP complex was determined using radio-thin-layer chromatography (RTLC) method. The complex was injected to wild-type rats and biodistribution was then studied for seven days. The NCA 177Lu was produced with specific activ-ity of 48 Ci/mg and with a radinuclidic purity of 99.99% through irradiation of enriched 176Yb target (1 mg) in a thermal neutron flux of 4 × 1013 n.cm-2.s-1 for 14 days. 177Lu-DOTMP was obtained with high radiochemical purities (> 98%) under optimized reaction conditions. The radiolabeled complex exhibited excellent stability at room temperature. Biodistribution of the radiolabeled complex studies in rats showed favorable selective skeletal uptake with rapid clearance from blood along with insignificant accumulation within the other nontargeted organs.

Development of an electrochemical 188W/188Re generator as a technique for separation and purification of 188Re in radiopharmaceutical applications.

In this study, a simple electrochemical procedure adaptable for using low specific activity 188W for separation and purification of 188Re from 188W to obtain no carrier added (NCA) 188Re is developed. The electrochemical parameters were optimized to maximize the 188Re electrodeposition yield with minimal 188W contamination. Two cycle electrolysis procedure was developed. The first electrochemical cell was used for separation of 188Re and in the second electrochemical cell, separation and purification of 188Re with >90% deposition yield of 188Re and minimal contamination of 188W (<10-4%) was achieved. The overall electrodeposition yield of 188Re was >90% with >99% radionuclidic purity and >99% radiochemical purity suitable for radiopharmaceutical applications. Furthermore, the performance of the generator remained consistent during a period of 69 days, one half-life of 188W, when the electrochemical separation procedure was performed frequently, at least once in 5 days.

Effect of low molecular weight organic acids on the uptake of 226Ra by corn (Zea mays L.) in a region of high natural radioactivity in Ramsar-Iran.

To study the benefit of including citric and oxalic acid treatments for phytoremediation of 226Ra contaminated soils a greenhouse experiment with corn was conducted. A soil was sampled from a region of high natural 226Ra radioactivity in Ramsar, Iran. After cultivation of corn seed and using organic acid treatments at 1, 10 and 100 mM concentrations, plants (shoots and roots) were harvested, digested and prepared to measure 226Ra activity. Simultaneously, sequential selective extraction were performed to estimate the partitioning of 226Ra among geochemical extraction. Results showed that the maximum uptake of 226Ra in plants was observed in citric acid (6.3%) and then oxalic acid (6%) at 100 mM concentration. These treatments increased radium uptake by a factor of 1.5 than the control. Enhancement of radium uptake by plants was related to soil pH reduction of organic acids in comparison to control. Also, the maximum uptake of this radionuclide in all treatments was obtained in roots compared to shoots. 226Ra fractionations results revealed that 91.8% of radium was in the residual phase of the soil and the available fractions were less than 2%. As the main percent of 226Ra was in the residual phase of the soil in this region, it seems that organic acids had not significant effect on the uptake of 226Ra for phytoremediation by corn in this condition.

Synthesis of a stabilized 177Lu-siRNA complex and evaluation of its stability and RNAi activity.

PURPOSE: Serum and intracellular instability limits the therapeutic applications of short interfering RNA (siRNA) as a radiopharmaceutical. Chemical modifications like phosphorothioate (PS) substitution and 2'-O-methoxy (2'-O-Me) modifications could eliminate such limitations. In this study, the effects of PS and 2'-O-Me modifications at the backbone of siRNA on serum stability and RNA interference activity were investigated. MATERIALS AND METHODS: Fully PS and 2'-O-Me-modified type 1 insulin-like growth factor receptor (IGF-1R) siRNA was radiolabeled with lutetium-177 ((177)Lu) through p-SCN-Bn-DTPA as a chelator. After purification with Vivaspin and PD-10 columns, the radiolabs were examined for stability in serum by instant thin-layer chromatography and polyacrylamide gel electrophoresis. The level of IGF-1R in response to the modified and labeled IGF-1R siRNA was examined using RT-PCR and ELISA assay in colon cancer cells. The effects of such siRNA on the prevention of proliferation of colon cancer cells and its apoptosis were investigated using MTT assay and Annexin-V/propidium iodide double staining, respectively. Cellular accumulation quantities of the labeled and modified IGF-1R siRNA were determined using a γ-counter by taking advantage of (177)Lu as a γ-emitter. RESULTS: Both the modified (177)Lu-siRNA complex and the modified nonlabeled siRNA showed significant stability in serum. The levels of IGF-1R mRNA and protein significantly decreased with both the labeled and nonlabeled IGF-1R siRNAs, but no such reduction in IGF-1R was observed with luciferase siRNA (P<0.01). Proliferation decreased significantly and apoptosis increased in the cells treated with modified (177)Lu-IGF-1R siRNA in comparison with either (177)Lu or labeled luciferase siRNA (P<0.001). CONCLUSION: Uniform chemically modified siRNAs can form stable complexes with Lu that pronounce its cytotoxic effect through apoptosis in colon cancer cells.

Production, biodistribution assessment and dosimetric evaluation of (177)Lu-TTHMP as an agent for bone pain palliation.

OBJECTIVES: Recently, bone-avid radiopharmaceuticals have been shown to have potential benefits for the treatment of widespread bone metastases. Although (177)Lu-triethylene tetramine hexa methylene phosphonic acid (abbreviated as (177)Lu-TTHMP), as an agent for bone pain palliation, has been evaluated in previous studies, there are large discrepancies between the obtained results. In this study, production, quality control, biodistribution, and dose evaluation of (177)Lu-TTHMP have been investigated and compared with the previously reported data. METHODS: TTHMP was synthesized and characterized, using spectroscopic methods. Radiochemical purity of the (177)Lu-TTHMP complex was determined using instant thin-layer chromatography (ITLC) and high performance liquid chromatography (HPLC) methods. The complex was injected to wild-type rats and biodistribution was studied for 7 days. Preliminary dose evaluation was investigated based on biodistribution data in rats. RESULTS: (177)Lu was prepared with 2.6-3 GBq/mg specific activity and radionuclide purity of 99.98%. (177)Lu-TTHMP was successfully prepared with high radiochemical purity (>99%). The complex showed rapid bone uptake, while accumulation in other organs was insignificant. Dosimetric results showed that all tissues received almost insignificant absorbed doses in comparison with bone tissues. CONCLUSION: Based on the obtained results, this radiopharmaceutical can be a good candidate for bone pain palliation therapy in skeletal metastases.

Preliminary dosimetric evaluation of (166)Ho-TTHMP for human based on biodistribution data in rats.

In this work, the absorbed dose to each organ of human for (166)Ho-TTHMP was evaluated based on biodistribution studies in rats by a RADAR method and was compared with (166)Ho-DOTMP as the only clinically used Ho-166 bone marrow ablative agent. The highest absorbed dose for this complex is observed in red marrow with 0.922mGy/MBq. The results show that (166)Ho-TTHMP has considerable characteristics compared to (166)Ho-DOTMP and can be a good candidate for bone marrow ablation in patients with multiple myeloma.

Development of (166)Holmium-1,2 Propylene Di-amino Tetra (Methy1enephosphonicacid) as a Possible Bone Palliation Agent.

(166)Holmium-1,2-propylene di-amino tetra (methy1enephosphonicacid) ((166) Ho-PDTMP) complex was prepared successfully using an in-house synthesized PDTMP ligand and (166) HoCl 3 . Ho-166 chloride was obtained by thermal neutron irradiation (1 × 10 (13) n/cm (2) /s) of natural Ho (NO 3 ) 3 samples (specific activity = 3-5 GBq/mg), dissolved in acidic media. Radiochemical purity of (166) Ho-PDTMP was checked by instant thin layer chromatography (>99%). Stability studies of the complex in the final preparation and in the presence of human serum were performed up to 72 h. The biodistribution of (166) Ho-PDTMP and (166) HoCl 3 in wild-type rats was checked in animal tissues up to 48 h. The produced (166) Ho-PDTMP properties suggest a possible new bone palliative therapeutic to overcome the metastatic bone pains.

Production, quality control, biodistribution assessment and preliminary dose evaluation of (177)Lu-PDTMP as a possible bone palliative agent.

OBJECTIVES: In this study, production, quality control, and biodistribution studies of a newly developed therapeutic compound have been presented and are followed by dosimetric evaluation for use in humans based on biodistribution data in wild-type rats. MATERIALS AND METHODS: The Lu-1,2-propylene di-amino tetramethylenephosphonic acid (Lu-PDTMP) complex was prepared successfully using synthesized PDTMP ligand and LuCl3. LuCl3 was obtained by thermal neutron irradiation (4×10 n/cm/s) of enriched Lu2O3 samples. The radiochemical purity of Lu-PDTMP was checked by instant thin-layer chromatography. Stability studies of the complex in the final preparation and in the presence of human serum were performed for up to 72 h. The biodistribution of Lu-PDTMP and LuCl3 in wild-type rats was checked in animal tissues for up to 7 days. The absorbed dose of each human organ was calculated by means of the medical internal radiation dose method. RESULTS: Lu was produced with a specific activity of 100-110 GBq/mg. Lu-PDTMP was prepared with high radiochemical purity of greater than 99% and specific activity of 278 GBq/mmol. The complex demonstrated significant stability at room temperature. The agent demonstrated major accumulation in the bone tissue and a high target/nontarget uptake ratio. Dosimetric results showed that all tissues receive an insignificant absorbed dose in comparison with bone tissue. CONCLUSION: The results showed that Lu-PDTMP has considerably better properties compared with clinically used bone-seeking radiopharmaceuticals and therefore can be a good candidate for bone pain palliative therapy in skeletal metastases; however, further biological studies in other mammals are still needed.

Development of (177)Lu-phytate Complex for Radiosynovectomy.

OBJECTIVE(S): In this work a new possible agent for radiosynovectomy has been targeted for articular pain palliation. MATERIALS AND METHODS: Lu-177 of 2.6-3 GBq/mg specific activity was obtained by irradiation of natural Lu2O3 sample with thermal neutron flux of 4 × 10(13) n.cm(-2).s(-1). The product was converted into chloride form which was further used for labeling of (177)Lu-phytate complex and checked using ITLC (MeOH: H2O: acetic acid, 4: 4: 2, as mobile phase). The complex stability and viscosity were checked in the final solution up to seven days. The prepared complex solution (100 µCi/100 µl) was injected intra-articularly to male rat knee joint. Leakage of radioactivity from injection site and its distribution in organs were investigated up to seven days. RESULTS: The complex was successfully prepared with high radiochemical purity (>99.9 %). Approximately, the whole injected dose has remained in injection site seven days after injection. CONCLUSION: The complex was proved to be a feasible agent for cavital radiotherapy in oncology and rheumatology.

Production, Quality Control and Biological Evaluation of (166)Ho-PDTMP as a Possible Bone Palliation Agent.

OBJECTIVE(S): In this study, (166)Ho-1,2-propylene di-amino tetra(methy1enephosphonicAcid) ((166)Ho-PDTMP) complex was prepared as a bone palliation agent. MATERIALS AND METHODS: The complex was successfully prepared using an in-house synthesized EDTMP ligand and (166)HoCl3. Ho-166 chloride was obtained by thermal neutron irradiation (1 × 1013 n.cm-2.s-1) of natural Ho(NO3)3 samples followed by radiolabeling and stability studies. Biodistribution in wild type rats was also peformed. RESULTS: The complex was prepared with the specific activity of 278 GBq/mg and high radiochemical purity (>99%, checked by ITLC). (166)Ho-PDTMP complex was stabilized in the final preparation and in the presence of human serum (>90%) up to 72 hr. The biodistribution of (166)Ho-PDTMP in wild-type rats demonstrated significant bone uptake was up to 48 hr compared to (166)HoCl3. CONCLUSION: The produced (166)Ho-PDTMP properties suggest a possible new bone palliative therapeutic to overcome the metastatic bone pains.

Optimization of 90 Y-antiCD20 preparation for radioimmunotherapy.

CONTEXT: The advent of monoclonal antibodies such as Rituximab, in recent years, has brought about decisive progress in the treatment of aggressive and indolent non-Hodgkin's lymphoma. AIMS: A further tried and tested improvement to the unmodified antibody has been its coupling to the beta-emitters Y-90. The optimization of 90 Y-antiCD20 radioimmunoconjugate production and quality control methods for future clinical studies in the country was targeted in this work. MATERIALS AND METHODS: The antibody was labeled with 90 Y-yttrium chloride (185 MBq) after conjugation with freshly prepared ccDTPA. Y-90 chloride was obtained by thermal neutron flux (4 × 10 13 n/cm 2 /s) of a natural Y 2 O 3 sample, dissolved in acidic media. Radiolabeling was completed in 24 h by the addition of DTPA-Rituximab conjugate at room temperature. STATISTICAL ANALYSIS USED: All values were expressed as mean ± standard deviation (mean ± SD), and the data were compared using Student's t-test. Statistical significance was defined as P < 0.05. RESULTS: Radiochemical purity of 96% was obtained by using ITLC method for the final radioimmunoconjugate (specific activity = 440-480 MBq/mg). The final isotonic 90 Y-Rituximab complex was checked by gel electrophoresis for protein integrity retention. Biodistribution studies in normal rats were carried out to determine the radioimmunoconjugate distribution up to 72 h. CONCLUSION: The results showed that 90 Y-DTPA-Rituximab could be considered for further evaluation in animals and possibly in humans as a radiopharmaceutical for use in radioimmunotherapy against non-Hodgkin's lymphomas. Because of the importance of developing anti-lymphoma B agents in nuclear medicine for country use, an optimized radiolabeling method has been introduced.

Demonstration of dose dependent cytotoxic activity in SW480 colon cancer cells by ¹77Lu-labeled siRNA targeting IGF-1R.

PURPOSE: The radiolabeling of targeting biomolecules with gamma emitter radionuclides for tracing and beta emitters for therapy involves the conjugation of such biomolecules to the chelating agents to form complexes with the radionuclide of interest. In this study, radioconjugate of IGF-1R siRNA with lutetium-177 ((177)Lu) was produced, and the anti-proliferation and apoptosis effects elicited by this (177)Lu-siRNA complex in the SW480 colon cancer cells were evaluated. METHODS: IGF-1R and Luciferase siRNAs were conjugated with p-SCN-Bn-DTPA, and then radiolabeled with (177)Lu. The effects of labeled and non-labeled IGF-1R siRNAs on IGF-1R expression were assessed with RT-PCR analysis and ELISA assay. IGF-1R siRNAs induced cell death and apoptosis were investigated using MTT assay and Annexin-V/propidium iodide (PI) double staining, respectively. RESULTS: Combined purification using Vivaspin and PD-10 columns resulted in a radiochemical purity of 97.32% ± 1.97%. Knockdown effect of the labeled IGF-1R siRNA was not significantly different from the non-labeled duplex of the same sequence (P<0.05), but it was significant compared to the Luciferase siRNAs (P<0.001). Proliferation decreased significantly, but apoptosis increased in the cells treated with the (177)Lu-IGF-1R siRNA in comparison with either (177)Lu or IGF-1R siRNA (P<0.001). CONCLUSION: Radioconjugate of IGF-1R siRNA, p-SCN-Bn-DTPA and (177)Lu was successfully produced and characterized as radiopharmaceutical. The present study demonstrates the involvement of (177)Lu-labeled IGF-1R siRNA in the inhibition of cell growth and induction of apoptosis in colon cancer cells.

Low-energy conformers of pamidronate and their intramolecular hydrogen bonds: a DFT and QTAIM study.

Extensive DFT and ab initio calculations were performed to characterize the conformational space of pamidronate, a typical pharmaceutical for bone diseases. Mono-, di- and tri-protic states of molecule, relevant for physiological pH range, were investigated for both canonical and zwitterionic tautomers. Semiempirical PM6 method were used for prescreening of the single bond rotamers followed by geometry optimizations at the B3LYP/6-31++G(d,p) and B3LYP/6-311++G(d,p) levels. For numerous identified low energy conformers the final electronic energies were determined at the MP2/6-311++G(2df,2p) level and corrected for thermal effects at B3LYP level. Solvation effects were also considered via the COSMO and C-PCM implicit models. Reasonable agreement was found between bond lengths and angle values in comparison with X-ray crystal structures. Relative equilibrium populations of different conformers were determined from molecular partition functions and the role of electronic, vibrational and rotational degrees of freedom on the stability of conformers were analyzed. For no level of theory is a zwitterionic structure stable in the gas-phase while solvation makes them available depending on the protonation state. Geometrically identified intramolecular hydrogen bonds were analyzed by QTAIM approach. All conformers exhibit strong inter-phosphonate hydrogen bonds and in most of them the alkyl-amine side chain is folded on the P-C-P backbone for further hydrogen bond formation.