processes Article Labeling of Hinokitiol with 90Y for Potential Radionuclide Therapy of Hepatocellular Carcinoma Christelle Bouvry 1,2, Valérie Ardisson 1, Nicolas Noiret 3, Etienne Garin 1,4 and Nicolas Lepareur 1,4,* 1 Comprehensive Cancer Center Eugène Marquis, F-35042 Rennes, France; [email protected] (C.B.); [email protected] (V.A.); [email protected] (E.G.) 2 CNRS, ISCR (Institut des Sciences Chimiques de Rennes)—UMR 6226, University Rennes, F-35000 Rennes, France 3 ENSCR, CNRS, ISCR (Institut des Sciences Chimiques de Rennes)—UMR 6226, University Rennes, F-35000 Rennes, France; [email protected] 4 Inrae, Inserm, Institut NUMECAN (Nutrition, Métabolismes et Cancer)—UMR_A 1341, University Rennes, UMR_S 1241, F-35033 Rennes, France * Correspondence: [email protected]; Tel.: +33-029-925-3144 Abstract: Hepatocellular carcinoma (HCC), the most common form of primary liver tumors, is the fifth cancer in the world in terms of incidence, and third in terms of mortality. Despite significant advances in the treatment of HCC, its prognosis remains bleak. Transarterial radioembolization with radiolabeled microspheres and Lipiodol has demonstrated significant effectiveness. Here we present a new, simple radiolabeling of Lipiodol with Yttrium-90, for the potential treatment of HCC. Keywords: hepatocellular carcinoma; hinokitiol; lipiodol; radionuclide therapy; yttrium-90 Citation: Bouvry, C.; Ardisson, V.; Noiret, N.; Garin, E.; Lepareur, N. 1. Introduction Labeling of Hinokitiol with 90Y for Liver tumors, either primary or metastatic, are a leading cause of death throughout Potential Radionuclide Therapy of the world. Primary liver cancers rank third in cancer-related deaths, behind lung and Hepatocellular Carcinoma. Processes colorectal cancers [1,2], the latter being the major cause for metastatic liver cancers [3]. 2021, 9, 940. https://doi.org/ In 2020, primary liver cancers accounted for circa 906,000 new cases and 830,000 deaths 10.3390/pr9060940 worldwide. Primary liver cancers include essentially hepatocellular carcinoma (HCC) (representing approximately 75% of the cases) and intrahepatic cholangiocarcinoma [4,5]. Academic Editor: Bonglee Kim Most HCC cases arise in Asia and sub-Saharan Africa, with China alone accounting for half the number of cases and deaths [6,7]. Incidence and mortality rates of liver cancer seem to Received: 31 March 2021 be decreasing in high-risk countries, but incidence is increasing in India, Oceania, Europe Accepted: 24 May 2021 Published: 26 May 2021 and the Americas [8,9]. HCC is an aggressive disease with a grim prognosis. Median survival from the time of diagnosis is often only 6 to 20 months. Patients frequently present Publisher’s Note: MDPI stays neutral with advanced disease or suffer from chronic liver disease, which restricts their treatment with regard to jurisdictional claims in options [10,11]. Notably, few patients are eligible for a curative treatment. In this context, published maps and institutional affil- loco-regional therapies are commonly used and have demonstrated some effectiveness in iations. the management of HCC [12]. In particular, based on the fact that HCC has a vascular sup- ply mostly dependent on the hepatic artery, while healthy liver parenchyma is essentially irrigated through the portal vein, intra-arterially delivered treatments represent a treatment method of choice for intermediate stage HCCs [13]. Transarterial radioembolization (TARE) is an emerging strategy to treat liver malignancies. It consists of the delivery of a radioactive Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. material to the tumor through its feeding artery. Different agents and materials have been 90 This article is an open access article investigated and labeled with different therapeutic radioisotopes [14,15]. Currently, Y- 166 distributed under the terms and and Ho-labeled microspheres are commercially available for the treatment of primary conditions of the Creative Commons and secondary liver cancers. Attribution (CC BY) license (https:// Another potentially interesting TARE agent is Lipiodol, an oily mixture of iodinated creativecommons.org/licenses/by/ esters of fatty acids derived from poppy seeds. Due to its adequate physico-chemical prop- 4.0/). erties and prolonged retention time in the tumor, while quickly washed out from the liver, Processes 2021, 9, 940. https://doi.org/10.3390/pr9060940 https://www.mdpi.com/journal/processes Processes 2021, 9, x FOR PEER REVIEW 2 of 14 properties and prolonged retention time in the tumor, while quickly washed out from the liver, it is the vehicle of choice for chemotherapeutic agents in transarterial chemoemboli- Processes 2021, 9, 940 zation (TACE) and has been used for the delivery of radionuclides in TARE2 [15 of 14–17]. No- tably, our team has successfully developed a 188Re-labeling of Lipiodol (188Re-SSS/Lip- iodol), currently being investigated in clinical trials [18,19]. Yttrium-90 is another beta- emittit is theing vehicle nuclide of choice of interest for chemotherapeutic for radionuclide agents therapy. in transarterial It is a pure chemoembolization β- emitter, with a high- energy(TACE) emission and has been of 2.28 used MeV, for the enabling delivery a ofmaximum radionuclides tissue in penetration TARE [15–17 of]. Notably,12 mm. It has a halfour- teamlife of has 64 successfully h, longer than developed the 17 h a of188 188Re-labelingRe. The absence of Lipiodol of gamma (188Re-SSS/Lipiodol), emission is beneficial incurrently terms beingof radioprotection investigated in constraints clinical trials [20]. [18, 19Besides]. Yttrium-90 its already is another mentioned beta-emitting use in micro- β- spheresnuclide offor interest radioembolization, for radionuclide it has therapy. been Itused is a purein peptideemitter, receptor with radionuclide a high-energy therapy emission of 2.28 MeV, enabling a maximum tissue penetration of 12 mm. It has a half-life (PRRT) and radioimmunotherapy (RIT) of various tumor types [21]. 90Y-labeling of Lip- of 64 h, longer than the 17 h of 188Re. The absence of gamma emission is beneficial in terms 131 iodolof radioprotection has also been constraints described [20 [22]. Besides–25]. With its already the exception mentioned of useI-radiolabeling, in microspheres Lipiodol labelingfor radioembolization, is reached through it has been solubilization used in peptide of a lipophilic receptor radionuclide chelate into therapy the oily (PRRT) medium. One suchand radioimmunotherapy chelate that attracted (RIT) attention of various was tumor 8-hydroxyquinol types [21]. 90ine,Y-labeling or oxine. of Lipiodol It is known has to form lipidalso been-soluble described complexes, [22–25 ].suitable With the for exception imaging of or131 therapy,I-radiolabeling, depending Lipiodol on labelingthe radiometal chosenis reached [26 through–28]. Though solubilization the poor of solubility a lipophilic of chelate the oxine into- thebased oily complexes medium. One because such of their highchelate lipophilicity that attracted may attention be a drawback was 8-hydroxyquinoline, [29], this property or oxine. is of Itinterest is known for tothe form labeling of Lipiodol.lipid-soluble It has complexes, thus been suitable investigated for imaging with or therapeutic therapy, depending radionuclides, on the such radiometal as Yttrium-90 chosen [26–28]. Though the poor solubility of the oxine-based complexes because of their [23] and radiolanthanides [30,31]. However, the procedure to label Lipiodol is not straight- high lipophilicity may be a drawback [29], this property is of interest for the labeling of forward,Lipiodol. Itsince has thusdirect been extrac investigatedtion into withLipiodol therapeutic led to radionuclides,poor yields. An such intermediate as Yttrium- extrac- tion90 [23 of] the and oxine radiolanthanides complex into [30 dichloromethane,31]. However, the was procedure thus needed. to label Moreover, Lipiodol is in not vivo stud- iesstraightforward, showed instability since direct of the extraction radiotracer into Lipiodolwith increasing led to poor bone yields. uptake An intermediate over time. To date, oxineextraction radiocomplexe of the oxine complexs have been into dichloromethane mainly used to was label thus blood needed. cells Moreover, for imagingin vivo of inflam- mationstudies showedand infection instability [32,33]. of the (111 radiotracerIn)-oxine-labeled with increasing white blood bone uptakecells remain over time. the gold To stand- arddate, for oxine infection radiocomplexes imaging. have been mainly used to label blood cells for imaging of 111 inflammationOther lipid and- infectionsoluble [complexes32,33]. ( In)-oxine-labeled have nonetheless white been blood investigated cells remain theto goldlabel blood standard for infection imaging. cells, such as tropolone derivatives, with good results [34,35]. Tropolone, or 2-Hydroxy- Other lipid-soluble complexes have nonetheless been investigated to label blood 2,4,6cells,- suchcycloheptatrien as tropolone-1 derivatives,-one, readily with forms good lipid results-soluble [34,35]. complexes Tropolone, orwith 2-Hydroxy- di- or trivalent 111 57 59 64 metals2,4,6-cycloheptatrien-1-one, [36]. Besides In, tropolone readily forms has been lipid-soluble used to complexescomplex withCo [37], di- orFe trivalent [36], Cu [38], 67/68metalsGa [[39,40],36]. Besides 89Zr111 [41]In, and tropolone 99mTc has[42] been. Using used an to complexanalogy57 betweenCo [37], 59 oxineFe [36 and],