Publications by authors named "Antonio Toppino"

13 Publications

  • Page 1 of 1

An innovative therapeutic approach for malignant mesothelioma treatment based on the use of Gd/boron multimodal probes for MRI guided BNCT.

J Control Release 2018 06 3;280:31-38. Epub 2018 May 3.

Department of Molecular Biotechnology and Health Sciences; University of Torino, via Nizza 52, Torino 10126, Italy. Electronic address:

The aim of this study is to develop an innovative imaging guided approach based on Boron Neutron Capture Therapy, for the treatment of mesothelioma, assisted by the quantification of the in vivo boron distribution by MRI. The herein reported results demonstrate that overexpressed Low Density Lipoproteins receptors can be successfully exploited to deliver to mesothelioma cells a therapeutic dose of boron (26 μg/g), significantly higher than in the surrounding tissue (3.5 μg/g). Boron and Gd cells uptake was assessed by ICP-MS and MRI on two mesothelioma (ZL34, AE17) and two healthy (MRC-5 and NMuMg) cell lines. An in vivo model was prepared by subcutaneous injection of ZL34 cells in Nu/Nu mice. After irradiation with thermal neutrons, tumor growth was evaluated for 40 days by MRI. Tumor masses of boron treated mice showed a drastic reduction of about 80-85%. The obtained results appear very promising providing patients affected by this rare disease with an improved therapeutic option, exploiting LDL transporters.
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http://dx.doi.org/10.1016/j.jconrel.2018.04.043DOI Listing
June 2018

The hydroboration reaction as a key for a straightforward synthesis of new MRI-NCT agents.

Org Biomol Chem 2015 Mar;13(11):3288-97

Department of Chemistry, University of Torino, via P. Giuria 7, 10125, Torino, Italy.

In this study the hydroboration reaction has been exploited to produce in only four steps a new lipophilic GdBNCT/MRI agent (PB01). As a matter of fact, the formation of a new B–C bond to link the decaborane with the lipophilic moiety greatly simplifies the synthesis of PB01 with respect to the previously reported dual agents. The complexes obtained (PB01a and PB01b) have been fully characterised from the relaxometric point of view and, after disaggregation with HPβCD, both isomers display high affinity for low density lipoproteins (LDLs) that can be exploited as specific carriers of these therapeutic and diagnostic agents for tumour cells. The LDL loading capacity is different for the two isomers. In fact, LDL can be loaded with 75 and 300 units of PB01a and PB01b, respectively, and for this reason, the isomer PB01b results to be the best candidate to perform MRI guided BNCT.
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http://dx.doi.org/10.1039/c4ob02291bDOI Listing
March 2015

A theranostic approach based on the use of a dual boron/Gd agent to improve the efficacy of Boron Neutron Capture Therapy in the lung cancer treatment.

Nanomedicine 2015 Apr 14;11(3):741-50. Epub 2015 Jan 14.

Department of Molecular Biotechnology and Health Sciences; University of Torino, Torino, Italy.

This study aims at developing an innovative theranostic approach for lung tumor and metastases treatment, based on Boron Neutron Capture Therapy (BNCT). It relies on to the use of low density lipoproteins (LDL) as carriers able to maximize the selective uptake of boron atoms in tumor cells and, at the same time, to quantify the in vivo boron distribution by magnetic resonance imaging (MRI). Tumor cells uptake was initially assessed by ICP-MS and MRI on four types of tumor (TUBO, B16-F10, MCF-7, A549) and one healthy (N-MUG) cell lines. Lung metastases were generated by intravenous injection of a Her2+ breast cancer cell line (i.e. TUBO) in BALB/c mice and transgenic EML4-ALK mice were used as primary tumor model. After neutron irradiation, tumor growth was followed for 30-40 days by MRI. Tumor masses of boron treated mice increased markedly slowly than the control group. From the clinical editor: In this article, the authors described an improvement to existing boron neutron capture therapy. The dual MRI/BNCT agent, carried by LDLs, was able to maximize the selective uptake of boron in tumor cells, and, at the same time, quantify boron distribution in tumor and in other tissues using MRI. Subsequent in vitro and in vivo experiments showed tumor cell killing after neutron irradiation.
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http://dx.doi.org/10.1016/j.nano.2014.12.004DOI Listing
April 2015

Iodine monochloride facilitated deglycosylation, anomerization, and isomerization of 3-substituted thymidine analogues.

Nucleosides Nucleotides Nucleic Acids 2014 ;33(12):786-99

a Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy , The Ohio State University , Columbus , Ohio.

The reaction of thymidine, 3-mono-, and 3,3',5'-trialkylsubstitued thymidine analogues with iodine monochloride (ICl) was investigated. Treatment with ICl resulted in rapid deglycosylation, anomerization, and isomerization of thymidine and 3-substituted thymidine analogues under various reaction conditions leading to the formation of the nucleobases as the major products accompanied by minor formation of α-furanosidic-, α-pyranosidic-, and β-pyranosidic nucleosides. On the other hand, 3,3',5'-trisubstitued thymidine analogues were only deglycosylated and anomerized. These results are similar to those observed for the acidic hydrolysis of the glycoside bond in nucleosides, but were presumably caused by the Lewis acid character of an iodine electrophile.
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http://dx.doi.org/10.1080/15257770.2014.945648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266569PMC
July 2015

Synthesis of a carborane-containing cholesterol derivative and evaluation as a potential dual agent for MRI/BNCT applications.

Org Biomol Chem 2014 Apr;12(15):2457-67

Department of Molecular Biotechnology and Health Sciences, University of Torino, via Nizza 52, 10126, Torino, Italy.

In this study the synthesis and characterization of a new dual, imaging and therapeutic, agent is proposed with the aim of improving the efficacy of Boron Neutron Capture Therapy (BNCT) in cancer treatment. The agent (Gd-B-AC01) consists of a carborane unit (ten boron atoms) bearing a cholesterol unit on one side (to pursue the incorporation into the liposome bi-layer) and a Gd(iii)/1,4,7,10-tetraazacyclododecane monoamide complex on the other side (as a MRI reporter to attain the quantification of the B/Gd concentration). In order to endow the BNCT agent with specific delivery properties, the liposome embedded with the MRI/BNCT dual probes has been functionalized with a pegylated phospholipid containing a folic acid residue at the end of the PEG chain. The vector allows the binding of the liposome to folate receptors that are overexpressed in many tumor types, and in particular, in human ovarian cancer cells (IGROV-1). An in vitro test on IGROV-1 cells demonstrated that Gd-B-AC01 loaded liposomes are efficient carriers for the delivery of the MRI/BNCT probes to the tumor cells. Finally, the BNCT treatment of IGROV-1 cells showed that the number of surviving cells was markedly smaller when the cells were irradiated after internalization of the folate-targeted GdB10-AC01/liposomes.
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http://dx.doi.org/10.1039/c3ob42414fDOI Listing
April 2014

High yielding preparation of dicarba-closo-dodecaboranes using a silver(I) mediated dehydrogenative alkyne-insertion reaction.

Inorg Chem 2013 Aug 5;52(15):8743-9. Epub 2013 Jul 5.

Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4M1, Canada.

The synthesis of 1,2-dicarba-closo-dodecaboranes (ortho-carboranes) is often low yielding which is a critical issue given the increasing use of boron clusters in material science and medicinal chemistry. To address this barrier, a series of Cu, Ag, and Au salts were screened to identify compounds that would enhance the yields of ortho-caboranes produced when treating alkynes with B10H12(CH3CN)2. Using a variety of functionalized ligands including mono- and polyfunctional internal and terminal alkynes, significant increases in yield were observed when AgNO3 was used in catalytic amounts. AgNO3 appears to prevent unwanted reduction/hydroboration of the alkyne prior to carborane formation, and the process is compatible with aryl, halo, hydroxy, nitrile, carbamate, and carbonyl functionalized alkynes.
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http://dx.doi.org/10.1021/ic400928vDOI Listing
August 2013

A carborane-derivative "click" reaction under heterogeneous conditions for the synthesis of a promising lipophilic MRI/GdBNCT agent.

Chemistry 2013 Jan 14;19(2):721-8. Epub 2012 Nov 14.

Dipartimento di Chimica, Università degli Studi di Torino, Via Pietro Giuria, 7, 10125 Torino, Italy.

In this study, the Huisgen reaction has been used to functionalise a carborane cage with a lipophilic moiety and a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) ligand to obtain a new Gd boron neutron-capture therapy (BNCT)/magnetic resonance imaging (MRI) agent. The introduction of the triazole units has been accomplished under both heterogeneous conditions, by the use of a Cu-supported ionic-liquid catalyst, and homogeneous conditions. The ability of the Gd complex of the synthesised ligand to form stable adducts with low-density lipoproteins (LDLs) has been evaluated and then MRI has been performed on tumour melanoma cells incubated in the presence of a Gd-complex/LDL imaging probe. It has been concluded that the high amount of intracellular boron necessary to perform BNCT can be reached even in the presence of a relatively low-boron-containing LDL concentration.
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http://dx.doi.org/10.1002/chem.201201634DOI Listing
January 2013

Boronated compounds for imaging guided BNCT applications.

Anticancer Agents Med Chem 2012 Jun;12(5):543-53

Dipartimento di Chimica Generale e Chimica Organica, Università degli studi di Torino, Via Pietro Giuria, 7, 10125 Torino, Italy.

Boron neutron capture therapy (BNCT) is based on the capture of thermal neutrons by boron 10 ((10)B) nuclei that have been selectively delivered to tumor cells. The amount of 10-30 μg of boron for g of tumor mass is needed to attain an acceptable therapeutic advantage. Despite that the potentialities of BNCT have been demonstrated in several preclinical studies, this technique has not yet been fully accepted in the armory of tools for tumor treatment. This is partly due to the differences in the uptake and distribution of (10)B among patients and also to the uncertainty found in the determination of tumor-to-blood (10)B concentration ratio. Attention is now being payed to use the main imaging techniques to determine the in vivo biodistribution of BNCT agents. Most of the work has been devoted to the most promising BNCT agents, namely BPA, BSH and carborane derivatives. This review surveys studies carried out over the last decade, and outlines the role that NMR, PET and SPECT imaging may have to improve the efficacy of BNCT.
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http://dx.doi.org/10.2174/187152012800617786DOI Listing
June 2012

Synthesis, biological evaluation, and radioiodination of halogenated closo-carboranylthymidine analogues.

Inorg Chem 2012 Jan 16;51(1):629-39. Epub 2011 Dec 16.

Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA.

The synthesis and initial biological evaluation of 3-carboranylthymidine analogues (3CTAs) that are (radio)halogenated at the closo-carborane cluster are described. Radiohalogenated 3CTAs have the potential to be used in the radiotherapy and imaging of cancer because they may be selectively entrapped in tumor cells through monophosphorylation by human thymidine kinase 1 (hTK1). Two strategies for the synthesis of a (127)I-labeled form of a specific 3CTA, previously designated as N5, are described: (1) direct iodination of N5 with iodine monochloride and aluminum chloride to obtain N5-(127)I and (2) initial monoiodination of o-carborane to 9-iodo-o-carborane followed by its functionalization to N5-(127)I. The former strategy produced N5-(127)I in low yields along with di-, tri-, and tetraiodinated N5 as well as decomposition products, whereas the latter method produced only N5-(127)I in high yields. N5-(127)I was subjected to nucleophilic halogen- and isotope-exchange reactions using Na(79/81)Br and Na(125)I, respectively, in the presence of Herrmann's catalyst to obtain N5-(79/81)Br and N5-(125)I, respectively. Two intermediate products formed using the second strategy, 1-(tert-butyldimethylsilyl)-9-iodo-o-carborane and 1-(tert-butyldimethylsilyl)-12-iodo-o-carborane, were subjected to X-ray diffraction studies to confirm that substitution at a single carbon atom of 9-iodo-o-carborane resulted in the formation of two structural isomers. To the best of our knowledge, this is the first report of halogen- and isotope-exchange reactions of B-halocarboranes that have been conjugated to a complex biomolecule. Human TK1 phosphorylation rates of N5, N5-(127)I, and N5-(79/81)Br ranged from 38.0% to 29.6% relative to that of thymidine, the endogenous hTK1 substrate. The in vitro uptake of N5, N5-(127)I, and N5-(79/81)Br in L929 TK1(+) cells was 2.0, 1.8, and 1.4 times greater than that in L929 TK1(-) cells.
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http://dx.doi.org/10.1021/ic202150bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257809PMC
January 2012

MRI-guided neutron capture therapy by use of a dual gadolinium/boron agent targeted at tumour cells through upregulated low-density lipoprotein transporters.

Chemistry 2011 Jul 10;17(30):8479-86. Epub 2011 Jun 10.

Department of Chemistry IFM and Molecular Imaging Center, Università di Torino, Via Nizza 52, 10125 Torino, Italy.

The upregulation of low-density lipoprotein (LDL) transporters in tumour cells has been exploited to deliver a sufficient amount of gadolinium/boron/ligand (Gd/B/L) probes for neutron capture therapy, a binary chemio-radiotherapy for cancer treatment. The Gd/B/L probe consists of a carborane unit (ten B atoms) bearing an aliphatic chain on one side (to bind LDL particles), and a Gd(III)/1,4,7,10-tetraazacyclododecane monoamide complex on the other (for detection by magnetic resonance imaging (MRI)). Up to 190 Gd/B/L probes were loaded per LDL particle. The uptake from tumour cells was initially assessed on cell cultures of human hepatoma (HepG2), murine melanoma (B16), and human glioblastoma (U87). The MRI assessment of the amount of Gd/B/L taken up by tumour cells was validated by inductively coupled plasma-mass-spectrometric measurements of the Gd and B content. Measurements were undertaken in vivo on mice bearing tumours in which B16 tumour cells were inoculated at the base of the neck. From the acquisition of magnetic resonance images, it was established that after 4-6 hours from the administration of the Gd/B/L-LDL particles (0.1 and 1 mmol kg(-1) of Gd and (10)B, respectively) the amount of boron taken up in the tumour region is above the threshold required for successful NCT treatment. After neutron irradiation, tumour growth was followed for 20 days by MRI. The group of treated mice showed markedly lower tumour growth with respect to the control group.
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http://dx.doi.org/10.1002/chem.201003741DOI Listing
July 2011

Heck reaction on protected 3-alkyl-1,2-dien-1-ols: an approach to substituted 3-alkenylindoles, 2-alkoxy-3-alkylidene-2,3-dihydrobenzofuranes and -indolidines.

Org Biomol Chem 2010 May 2;8(9):2020-7. Epub 2010 Mar 2.

Dipartimento di Chimica Generale e Chimica Organica, Università degli studi di Torino, Via Pietro Giuria, 7, 10125 Torino, Italy.

A phosphine-free annulation reaction has been exploited for the preparation of substituted 3-alkenylindoles, 2-alkoxy-3-alkylidene-2,3-dihydrobenzofuranes and -indolidines in good to excellent yields. This has been done by reaction of protected 3-alkyl-1,2-dienols with o-iodophenols or protected o-iodoanilines. Two different heterocyclic skeletons were obtained, depending on the electron-donating properties of the heteroatom involved in the annulation process.
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http://dx.doi.org/10.1039/b925550hDOI Listing
May 2010

Towards improved boron neutron capture therapy agents: evaluation of in vitro cellular uptake of a glutamine-functionalized carborane.

J Biol Inorg Chem 2009 Aug 10;14(6):883-90. Epub 2009 Apr 10.

Department of Chemistry IFM, University of Turin, Turin, Italy.

Sodium borocaptate (BSH) is widely used for boron neutron capture therapy (BNCT) of brain tumors. One drawback is the large uptake by the liver causing a decrease of its availability at the tumor region as well as bringing about toxicity problems. A novel carborane-based compound containing a boron payload very similar to that of BSH has been synthesized and tested on rat glioma (C6) cells, hepatoma tissue culture (HTC) cells, and hepatocytes. The newly synthesized system consists of an o-carborane unit (C(2)B(10)H(11), o-CB) conjugated to a glutamine residue through a proper spacer, namely, o-CB-Gln. As compared with BSH, it showed the same uptake by C6 cells, but a 50% decrease in uptake by HTC cells and an 80% decrease in uptake by healthy hepatocytes. On this basis o-CB-Gln appears an interesting candidate for BNCT of brain tumors as it is expected to have a therapeutic index analogous to that of BSH accompanied by a much lower liver toxicity.
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http://dx.doi.org/10.1007/s00775-009-0500-1DOI Listing
August 2009

Synthesis of Gd(III)-C-palmitamidomethyl-C'-DOTAMA-C(6)-o-carborane: a new dual agent for innovative MRI/BNCT applications.

Org Biomol Chem 2008 Dec 24;6(23):4460-6. Epub 2008 Oct 24.

Dipartimento di Chimica IFM, Università degli Studi di Torino, Via Pietro Giuria, 7, 10125, Torino, Italy.

C-(2-Benzyloxy)-ethyl-C'-N-tert-butoxycarbonyl-aminomethyl-o-carborane (8), a potentially useful intermediate for BNCT, has been synthesised. This intermediate can be readily functionalised with several biological vectors and MRI contrast agents. In this work intermediate 8 has been functionalised with a palmityl chain for lipophilic targeting and with Gd(III)-DOTAMA-C(6)-NH(2) as MRI detector. This combination yielded Gd(III)-C-palmitamidomethyl-C'-DOTAMA-C(6)-o-carborane (14) as a dual MRI-BNCT agent.
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http://dx.doi.org/10.1039/b808804gDOI Listing
December 2008