Functionalized TiO2 nanoparticles labelled with 225Ac for targeted alpha radionuclide therapy

Abstract

The 225Ac radioisotope exhibits very attractive nuclear properties for application in radionuclide therapy. Unfortunately, the major challenge for radioconjugates labelled with 225Ac is that traditional chelating moieties are unable to sequester the radioactive daughters in the bioconjugate which is critical to minimize toxicity to healthy, non-targeted tissues. In the present work, we propose to apply TiO2 nanoparticles (NPs) as carrier for 225Ac and its decay products. The surface of TiO2 nanoparticles with 25 nm diameter was modified with Substance P (5-11), a peptide fragment which targets NK1 receptors on the glioma cells, through the silan-PEG-NHS linker. Nanoparticles functionalized with Substance P (5-11) were synthesized with high yield in a two-step procedure, and the products were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and thermogravimetric analysis (TGA). The obtained results show that one TiO2-bioconjugate nanoparticle contains in average 80 peptide molecules on its surface. The synthesized TiO2-PEG-SP(5-11) conjugates were labelled with 225Ac by ion-exchange reaction on hydroxyl (OH) functional groups on the TiO2 surface. The labelled bioconjugates almost quantitatively retain 225Ac in phosphate-buffered saline (PBS), physiological salt and cerebrospinal fluid (CSF) for up to 10 days. The leaching of 221Fr, a first decay daughter of 225Ac, in an amount of 30% was observed only in CSF after 10 days. The synthesized 225Ac-TiO2-PEG-SP(5-11) has shown high cytotoxic effect in vitro in T98G glioma cells; therefore, it is a promising new radioconjugate for targeted radionuclide therapy of brain tumours.

Trastuzumab Conjugated Superparamagnetic Iron Oxide Nanoparticles Labeled with 225Ac as a Perspective Tool for Combined α-Radioimmunotherapy and Magnetic Hyperthermia of HER2-Positive Breast Cancer

“…In human serum, the fraction of 225 Ac released from 225 Ac@Fe3O4 was still less than 2%, but the retention of 221 Fr and 213 Bi decreased to 70% after 10 days. Our results are comparable or slightly better, especially in the case of released daughter radionuclides, as observed previously on 225 Ac-labeled titanium oxide [40] nanoparticles and Fe3O4 NPs labeled with 223 Ra [28]. The obtained results can be interpreted on the basis of recoil energy in the 225 Ac → 221 Fr decay reaction and subsequent α decays [41].…”

“…Synthesized nanoparticles were tested for the determination of leaching of the mother radionuclide 225 Ac and its decay daughters as described earlier [40]. Briefly, a portion of radiolabeled nanoparticles was placed in a dialysis tube (D-Tube Dializer Midi with 3.5 kDa cut-off membrane, Novagen) and was dialyzed against 20 mL of 0.9% NaCl or 1 mM PBS for up to 10 days at room temperature.…”

A Proof-of-Concept Study on the Therapeutic Potential of Au Nanoparticles Radiolabeled with the Alpha-Emitter Actinium-225

“…During the past decade, an increasing number of studies have been reported on tumor treatment with radiolabeled NPs, most of which have been performed with NPs radiolabeled with the β-emitting isotope Lutetium-177 ( 177 Lu, half-life: t 1/2 = 6.7 d) [12,[19][20][21][22][23][24]. Regarding 225 Ac, only a few studies have examined NPs radiolabeled with this radionuclide for tumor treatment [25][26][27]. The present work was designed to investigate a gold nanoparticle radiolabeled with an α-emitter as an injectable radiopharmaceutical form of BRT for local radiation treatment of cancer.…”

Study of223Ra uptake mechanism on hydroxyapatite and titanium dioxide nanoparticles as a function of pH

“…There are some studies dedicated to labelling of TiO 2 with 48 V or 125 I for in vivo toxicological studies 22,23 and with 225 Ac for targeted alpha radionuclide therapy. 24 This article is focused on the study of 223 Ra sorption on nHAp and nTiO 2 . The published data on radium sorption using chosen nanoparticles are quite limited and available papers are focused mainly on 226 Ra behavior in uranium mill tailings and the articles studied only iron compounds as a goethite or ferrihydrite, or environmental minerals.…”