Papers by Celia Fernandes
International Journal of Molecular Sciences
Although 99mTc is not an ideal Auger electron (AE) emitter for Targeted Radionuclide Therapy (TRT... more Although 99mTc is not an ideal Auger electron (AE) emitter for Targeted Radionuclide Therapy (TRT) due to its relatively low Auger electron yield, it can be considered a readily available “model” radionuclide useful to validate the design of new classes of AE-emitting radioconjugates. With this in mind, we performed a detailed study of the radiobiological effects and mechanisms of cell death induced by the dual-targeted radioconjugates 99mTc-TPP-BBN and 99mTc-AO-BBN (TPP = triphenylphosphonium; AO = acridine orange; BBN = bombesin derivative) in human prostate cancer PC3 cells. 99mTc-TPP-BBN and 99mTc-AO-BBN caused a remarkably high reduction of the survival of PC3 cells when compared with the single-targeted congener 99mTc-BBN, leading to an augmented formation of γH2AX foci and micronuclei. 99mTc-TPP-BBN also caused a reduction of the mtDNA copy number, although it enhanced the ATP production by PC3 cells. These differences can be attributed to the augmented uptake of 99mTc-TPP-BB...
Major advancements have been made in treating cardiovascular disease. However, improving diagnosi... more Major advancements have been made in treating cardiovascular disease. However, improving diagnosis is crucial, because the detection of the early stages of disease would allow preventative approaches therapy. Myocardial perfusion imaging is in clinical use for decades and is an effective tool for diagnosis, and longterm follow-up of patients with suspected or known coronary artery disease. The technetium-based agents, 99mTc-sestamibi and 99mTc-tetrofosmin, are widely used myocardial blood flow tracers. However, since both present drawbacks in their biodistribution properties, there is now resurgence in the study of both neutral and cationic technetium agents to further improve the characteristics of perfusion radiopharmaceuticals. Despite all the success of perfusion imaging, a unique strength of nuclear imaging is its ability to provide tools for imaging processes at molecular and cellular levels in intact organisms under a wide variety of physiologic conditions. Advances in new specific imaging agents that identify myocardium injury and cellular dysfunction may contribute to the improvement of diagnosis and eventually better therapeutic approaches. In this communication, we will review perfusion agents and their biological mechanism of uptake. We will also discuss examples of target-specific radiopharmaceuticals for cardiac imaging, including advances in pre-clinical imaging approaches.
Pharmaceutics, Feb 8, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Journal of Inorganic Biochemistry, Jul 1, 2016
Heterobimetallic complexes with the evolutionary, well-preserved, histidyl-alanylvalinyl (HAV) se... more Heterobimetallic complexes with the evolutionary, well-preserved, histidyl-alanylvalinyl (HAV) sequence for cadherin targeting, an organometallic Ru core with anticancer activity and a radioactive moiety for imaging may hold potential as theranostic agents for cancer. Visible-light irradiation of the HAVAY-NH 2 pentapeptide in the presence of [( 5-Cp)Ru( 6-naphthalene)] + resulted in the formation of a full sandwich type complex, ( 6-Tyr-RuCp)-HAVAY-NH 2 in aqueous solution, where the metal ion is connected to the Tyr (Y) unit of the peptide. Conjugation of this complex to 2,2'-(7-(1-carboxy-4-((4isothiocyanatobenzyl)amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODA-GA) and subsequent metalation of the resulting product with stable (nat Ga) and radioactive (67 Ga) isotope yielded nat Ga/ 67 Ga-NODA-GA-[( 6-Tyr-RuCp)-HAVAY-NH 2 ]. The nonradioactive compounds were characterized by NMR spectroscopy and Mass Spectrometry. The cellular uptake and cytotoxicity of the radioactive and non-radioactive complexes, respectively, were evaluated in various human cancer cell lines characterized by different levels of Nor E-cadherins expression. Results from these studies indicate moderate cellular uptake of the radioactive complexes. However, the inhibition of the cell proliferation was not relevant. Highlights VIS-irradiation of [( 5-Cp)Ru( 6-naphtalene)] +-HAVAY-NH 2 system Formation of a full sandwich peptide conjugate via 6-coordination of the Tyr residue Modification of the peptide via the N-terminus with a macrocycle to bind 67 Ga Synthesis, characterisation, biological test of the heterobimetallic (Ga/Ru) complex
Dalton Transactions, 2009
International Journal of Pharmaceutics, Dec 1, 2016
We aimed at exploring block copolymer micelles (BCMs) for the simultaneous delivery of radiation/... more We aimed at exploring block copolymer micelles (BCMs) for the simultaneous delivery of radiation/ chemotherapy to cancer cells. To achieve that goal, we have prepared and characterized a novel type of docetaxel (DTX) loaded and non-loaded BCMs. The micelles were decorated with pyrazolyl-diamine chelating units to stabilize the matched pair 99m Tc/Re for image-guided delivery of therapeutic drugs. The in vitro studies have shown that DTX release is pH-dependent increasing at lower pH values. Antiproliferative studies in different cancer cell lines showed that DTX-loaded BCMs present relevant antiproliferative activity. In comparison to free DTX, the loaded-micelles exhibited higher anti-proliferative activity for the same DTX concentration, which mean that a similar therapeutic outcome may be achieved with reduced side effects. The pyrazolyl-diamine-functionalized micelles were labeled with fac-[ 99m Tc(CO) 3 (H 2 O) 3 ] + in high radiochemical yield and purity. The radiolabeled micelles are stable in phosphate buffer and in cell culture media. Cellular uptake studies in different cancer cell lines indicate a cell type and time-dependent uptake, in agreement with the anti-proliferative activity. Early biodistribution studies in healthy BALB/c mice has shown prolonged circulation lifetime in the bloodstream and relevant in vivo stability, important features when considering an effective DTX delivery system and image-guided delivery agent for cancer theranostics.
Nuclear Medicine and Biology, Feb 1, 2016
Radiolabeled bisphosphonates (BPs) have been used for bone imaging and delivery of β(-) emitting ... more Radiolabeled bisphosphonates (BPs) have been used for bone imaging and delivery of β(-) emitting radionuclides for bone pain palliation. As a β(-) emitter, (188)Re has been considered particularly promising for bone metastases therapy. Aimed at finding innovative bone-seeking agents for systemic radiotherapy of bone metastases, we describe herein novel organometallic compounds of the type fac-[(188)Re(CO)3(k(3)-L)], (L=BP-containing chelator), their in vitro and in vivo stability, and their cellular damage in MDAMB231 cells, a metastatic breast cancer cell line. After synthesis and characterization of the novel organometallic compounds of the type fac-[(188)Re(CO)3(k(3)-L)] their radiochemical purity and in vitro stability was assessed by HPLC. In vivo stability and pharmacokinetic profile were evaluated in mice and the radiocytotoxic activity and DNA damage were assessed by MTT assay and by the cytokinesis-block micronucleus (CBMN) assay, respectively. Among all complexes, (188)Re3 was obtained with high radiochemical purity (>95%) and high specific activity and presented high in vitro and in vivo stability. Biodistribution studies of (188)Re3 in Balb/c mice showed fast blood clearance, high bone uptake (16.1±3.3% IA/g organ, 1h p.i.) and high bone-to-blood and bone-to-muscle radioactivity ratios, indicating that it is able to deliver radiation to bone in a very selective way. The radiocytotoxic effect elicited by (188)Re3 in the MDAMB231 cells was dependent on its concentration, and was higher than that induced by identical concentrations of [(188)ReO4](-). Additionally, (188)Re3 elicited morphological changes in the cells and induced DNA damage by the increased number of MN observed. Altogether, our results demonstrate that (188)Re3 could be considered an attractive candidate for further preclinical evaluation for systemic radionuclide therapy of bone metastases considering its ability to deliver radiation to bone in a very selective way and to induce radiation damage.
Dalton Transactions, 2016
Doxorubicin is a clinical benchmark drug, which is applied in the treatment of numerous cancers. ... more Doxorubicin is a clinical benchmark drug, which is applied in the treatment of numerous cancers. Known for its accumulation in the nucleus and ability to intercalate into DNA, it targets quickly dividing i.e. hypermitotic cells. Through this mechanism, it could be an ideal structural motif for a new class of imaging agents, given that the new entity approximates the in vitro profile of the parent drug. Here we describe design, synthesis and biological activity of a small array of Doxorubicin-metalloconjugates (M = 99m Tc, Re). We demonstrate that the conjugates preferably accumulate in the nuclear compartment, tightly bind to DNA and retain an appreciable cytotoxicity. Moreover, the Re conjugates effectively act as inhibitors of the human Topoisomerase II enzyme, which is the widely accepted mechanism of action of the parent drug. Since the conjugates effectively mimic the in vitro behavior of native Doxorubicin, the 99m Tc compounds are prospective imaging agents. † Electronic supplementary information (ESI) available. See
Pharmaceutics, Mar 22, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Dalton Transactions, 2015
Pharmaceutics
Several gastrin-releasing peptide receptor (GRPR) antagonists with improved in vivo behavior have... more Several gastrin-releasing peptide receptor (GRPR) antagonists with improved in vivo behavior have been recently developed and tested in the clinic. However, despite the generally mild side effects of peptide receptor radionuclide therapy (PRRT), toxicity has been observed due to high doses delivered to nontarget tissues, especially in the kidneys and pancreas. Previous experiences with radiolabeled peptides opened a unique opportunity to explore GRPR pretargeting using clickable bombesin antagonists. Toward this goal, we used clickable DOTA-like radiocomplexes which have been previously evaluated by our group. We functionalized a potent GRPR antagonist with a clickable TCO moiety using two different linkers. These precursors were then studied to select the compound with the highest GRPR binding affinity and the best pharmacokinetics to finally explore the advantages of the devised pretargeting approach. Our results provided an important proof of concept toward the development of bio...
Molecules, 2021
For effective Auger therapy of cancer, the Auger-electron emitters must be delivered to the tumor... more For effective Auger therapy of cancer, the Auger-electron emitters must be delivered to the tumor cells in close proximity to a radiosensitive cellular target. Nuclear DNA is considered the most relevant target of Auger electrons to have augmented radiotoxic effects and significant cell death. However, there is a growing body of evidence that other targets, such as the mitochondria, could be relevant subcellular targets in Auger therapy. Thus, we developed dual-targeted 99mTc(I) tricarbonyl complexes containing a triphenylphosphonium (TPP) moiety to promote accumulation of 99mTc in the mitochondria, and a bombesin peptide to provide specificity towards the gastrin releasing peptide receptor (GRPr) overexpressed in prostate cancer cells. The designed dual-targeted complex, 99mTc-TPP-BBN, is efficiently internalized by human prostate cancer PC3 cells through a specific GRPr-mediated mechanism of uptake. Moreover, the radioconjugate provided an augmented accumulation of 99mTc in the mi...
Cancer Drug Resistance, 2020
Number of new cases in 2018, both sexes, all ages Total: 18 078 957 cases Lung 2 093 876 (11.6%) ... more Number of new cases in 2018, both sexes, all ages Total: 18 078 957 cases Lung 2 093 876 (11.6%) Breast 2 088 849 (11.6%) Colorectum 1 849 518 (10.2%) Prostate 1 276 106 (7.1%) Stomach 1 033 701 (5.7%) Liver 841 080 (4.7%) Oesophagus 572 034 (3.2%) Cervix uteri 569 847 (3.2%) Other cancers 7 753 946 (42.9%) Number of deaths in 2018, both sexes, all ages Total: 9 555 027 deaths Lung 1 761 007 (18.4%) Colorectum 880 792 (9.2%) Stomach 782 685 (8.2%) Liver 781 631 (8.2%) Breast 626 679 (6.6%) Oesophagus 508 585 (5.3%) Pancreas 432 242 (4.5%) Prostate 358 989 (3.8%) Other cancers 3 422 417 (35.8%) Cancer incidence and mortality statistics worldwide and by region Incidence Mortality Both sexes Males Females Both sexes Males Females New cases Cum. risk 0-74 (%) New cases Cum. risk 0-74 (%) New cases Cum. risk 0-74 (%) Deaths Cum. risk 0-74 (%) Deaths Cum. risk 0-74 (%) Deaths Cum. risk *Latin America and the Caribbean 672
Radiochimica Acta, 2015
The oestrogen receptor (ER) is an important tumour target for molecular imaging and radionuclide ... more The oestrogen receptor (ER) is an important tumour target for molecular imaging and radionuclide therapy due to its overexpression in many malignant cells as compared to normal cells. Aiming to find new functional molecular imaging/therapeutic agents for ER positive tumours, we have synthesized a new estradiol derivative substituted at the 16-
Journal of Drug Delivery Science and Technology, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ChemMedChem, Jul 19, 2017
A straightforward synthetic route for a new multifunctional 1,4,7,10-tetraazacyclododecane-1,4,7,... more A straightforward synthetic route for a new multifunctional 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivative is described. To demonstrate the versatility of this pro-chelator for the preparation of radiolabeled hybrid compounds containing two different biological targeting moieties, an antitumor agent (e.g., a DNA-intercalating agent) and an estrogen receptor (ER) ligand (e.g., LXXLL-based peptide) were regiospecifically conjugated to the DOTA derivative. The bifunctional probe was radiolabeled with the auger electron emitter indium-111, and the resulting radioconjugate was demonstrated to induce DNA damage in vitro, which, along with the nuclear internalization exhibited in breast cancer cells, might enhance its therapeutic activity. This favorable in vitro performance suggests that these hybrid compounds could be attractive probes for theranostic applications.
Bioconjugate chemistry, Jan 16, 2015
We present the combination of the clinically well-proven chemotherapeutic agent, Doxorubicin, and... more We present the combination of the clinically well-proven chemotherapeutic agent, Doxorubicin, and 99mTc - an Auger - and internal conversion electron emitter - into a dual-action agent for therapy. Chemical conjugation of Doxorubicin to 99mTc afforded a construct which autonomously ferries a radioactive payload into the cell nucleus. At this site, damage is exerted by dose deposition from Auger radiation. The 99mTc-conjugate exhibited a dose-dependent inhibition of survival in a selected panel of cancer cells and an in vivo study in healthy mice evidenced a biodistribution which is comparable to that of the parent drug. The homologous Re-conjugate was found to effectively bind to DNA, inhibited human Topoisomerase II and exhibited cytotoxicity in vitro. The collective in vitro and in vivo data demonstrate that the presented metallo-conjugates closely mimic native Doxorubicin.
Nuclear Medicine and Biology, 2012
The overexpression of epidermal growth factor receptor (EGFR) in tumors underlines the recent int... more The overexpression of epidermal growth factor receptor (EGFR) in tumors underlines the recent interest in EGFR as attractive target for the development of new cancer imaging agents. EGFR-tyrosine kinase inhibitors (EGFR-TKIs) based on the anilinoquinazoline scaffold have been explored as potential probes for EGFR imaging. However, up to now, no optimal radiotracer is available. Herein, we report the synthesis and biological evaluation of three novel halogenated 6-substituted 4-anilinoquinazoline based EGFR-TKIs. Radiosynthesis ( 125 I and 18 F) of the corresponding analogues was also performed. Methods: 6a, 6b and 8 were obtained by reaction of 6-amino-4-anilinoquinazoline (5) with 3-/4-iodobenzoyl and 4-fluorobenzoyl chlorides. Inhibition of EGFR autophosphorylation and A431 cellular proliferation were assessed by Western blot and MTT assays. 125 I-anilinoquinazolines [ 125 I]6a/b were prepared via destannylation of the corresponding tributylstannyl precursors with [ 125 I]NaI. Cellular uptake studies were conducted in A431 cells. Optimization of the radiosynthesis of the 18 F-anilinoquinazoline [ 18 F]8 was attempted by nucleophilic substitution of the trimethylammonium-and nitro-6-substituted 4-anilinoquinazoline precursors. Results: 6a, 6b and 8 were synthesized in high chemical yield. All of them are inhibitors of EGFR autophosphorylation (0.1bIC 50 b1 μM) and A431 cell proliferation (IC 50 b3.5 μM). [ 125 I]6a/b, obtained in high radiochemical purity and specific activity, were highly taken up by A431 cells. Biodistribution profile in mice indicated fast blood clearance and hepatobiliary excretion. Despite all attempts, [ 18 F]8 was only formed in 4% yield, hampering further biological evaluation. Conclusions: This study suggests that these quinazoline derivatives can act as EGFR-TKI, warranting further modifications in the chemical structure in order to be explored as potential molecular imaging agents for single photon emission computerized tomography and positron emission tomography.
Journal of Organometallic Chemistry, 2009
In recent years, the coordination and organometallic chemistry of rhenium and technetium has dese... more In recent years, the coordination and organometallic chemistry of rhenium and technetium has deserved an increasingly growing interest, reflecting the importance of these d-transition elements in the biomedical field. In fact, technetium-99m still is the most widely used radionuclide ...
Inorganica Chimica Acta, 2003
New oxorhenium complexes with 2-(diphenylphosphanyl)-N -(2-thioethyl)benzamide (H 2 PNS) and trim... more New oxorhenium complexes with 2-(diphenylphosphanyl)-N -(2-thioethyl)benzamide (H 2 PNS) and trimethyl-, triethyl-and triphenyl-hydroxyl silylated monodentate thiols are reported. These new complexes have been prepared by reacting [N n Bu 4 ][Re(O)Cl 4 ] with the tridentate H 2 PNS and the corresponding silylated thiol at room temperature. The characterization of the complexes involved elemental analysis, 31 P and 1 H NMR spectroscopies and X-ray crystallographic analysis for the triethyl-silylated Re complex.
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Papers by Celia Fernandes