br Lutetium Lu half life d is a therapeutic beta
Lutetium-177 (177Lu, half-life 6.6 d) is a therapeutic beta-emitter (Emax of 498.3 keV) radionuclide, useful for producing cytotoxicity in malignant tumors (particle range of 2 mm in tissue), but also a gamma-emitter (E = 208 keV), which makes its use for SPECT (single photon emission computed tomography) imaging possible (Hernandez-Jimenez
et al., 2018). Recent clinical studies have shown that the therapeutic application of diﬀerent prostate-specific membrane antigen (PSMA) inhibitors labeled with 177Lu produce a decrease of more than fifty percent in the prostate antigen (PSA) levels, as well as a significant survival increase (> 28 months) in seventy percent of patients with metastatic PCa (Baum et al., 2016; Rahbar et al., 2017). However, bone metastases appear to respond less to treatment with 177Lu- labeled PSMA inhibitors than visceral or lymph nodal disease (Emmett et al., 2017).
Alpha particles have also been proposed as an exceptional option for molecular targeted radiotherapy due to its destructive power towards malignant cells, since the deposition of DNA-damaging Cortistatin-14 TFA is at least 100 times greater than that of beta particles (Sgouros and Hobbs,
∗ Corresponding author. Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Carretera México-Toluca S/N. La Marquesa, Ocoyoacac, Estado de México, C.P. 52750, Mexico.
∗∗ Corresponding author. Departamento de Ciencias Ambientales, Instituto Nacional de Investigaciones Nucleares, Carretera México-Toluca S/N. La Marquesa, Ocoyoacac, Estado de México, C.P. 52750, Mexico.
E-mail addresses: [email protected] (E. Azorín-Vega), [email protected] (E. Rojas-Calderón).
2014). Radium-223 (223Ra, half-life 11.43 d) is an alpha-emitter (Emax of 5.7 MeV) radionuclide approved for human use and now employed in clinical practice for the treatment of prostate cancer bone lesions, producing an average survival of 3.6 months in patients (Nilsson et al., 2007).
Although targeted α-therapy with 225Ac-labeled PSMA inhibitors is still under investigation, it has a significant potential in benefitting advanced-stage prostate cancer patients, mainly due to the energy re-leased by the four alpha particles generated during the radionuclide chain decay (Kratochwil et al., 2018; Morgenstern et al., 2018).
It is important to highlight that the 177Lu-PSMA inhibitor (iPSMA) (Hernandez-Jimenez et al., 2018) and 225Ac-PSMA inhibitors are target-specific radiopharmaceuticals which are recognized by the PSMA pro-tein overexpressed in the prostate cancer cells, while 223RaCl2 is cal-cium mimetic that targets locations with high calcium turnover, such as bone. Therefore, 177Lu-iPSMA and 225Ac-iPSMA are mainly located at the prostate cancer cell membrane and 223RaCl2 is distributed in bone (62% trabecular and 38% cortical) with an increased uptake in lytic lesions induced by the invasion of malignant cells into the osseous tissue (ICRP (1995)).
This research aimed to assess and compare the radiation absorbed dose produced by 177Lu-iPSMA, 225Ac-iPSMA and 223RaCl2 to prostate cancer cell nuclei in osseous metastases by using an experimental in-vitro cell biokinetic study and Monte Carlo simulation (MCNPX code) in a simplified model of bone.
2. Experimental methods
The PSMA inhibitor (iPSMA) peptide (1,4,7,10-tetra-azacyclododecane N,N', N'´,N'´´-tetraacetic acid-hydrazinonicotinyl-Lys (Nal)-Urea-Glu derivative, MW 1038 g/mol) was synthesized by Ontores Biotechnology Co., Ltd (Zhejiang, China), with a purity > 98%, as analyzed by reversed phase HPLC (RP-HPLC) and mass spec-troscopy. Lutetium (177Lu) chloride was obtained from ITG Germany (EndolucinBeta 40 GBq/mL; in sterile 0.04 M HCl solution, non-carrier-added). All the other reagents were purchased from Sigma-Aldrich Chemical Co. and were used as received.
Lutetium-177-labeled iPSMA (177Lu-iPSMA) was prepared from a multidose lyophilized formulation under aseptic conditions in a GMP-certified facility according to the method described by Luna-Gutierrez et al. (2017). For the radiochemical synthesis, the 177LuCl3 vial (40 GBq/mL) was vented with a needle and 1.0–1.5 mL of the 1 M acetate buﬀer (pH 5.0) was added. The total volume was withdrawn using a sterile syringe and was afterwards employed for the reconstitution of the iPSMA lyophilized kit. The reconstituted vial was heated in a dry bath at 95 °C for 30 min. After cooling to room temperature, the vial was vented with a needle, and the volume was taken up to 10 mL with 0.9% saline solution (Pisa, Mexico) using a sterile syringe.
2.3. Radiochemical purity evaluation
Radiochemical purity was assessed by radio-HPLC with a Shimadzu instrument equipped with a radioactivity detector (Gabi, Raytest, Germany) and a μ-Bondapak C18 column (5 μm; 3.9 × 300 mm). Analyses were performed under a linear gradient of 0.1% TFA/water (solvent A) and 0.1% TFA/acetonitrile (solvent B), flow of 1 mL/min,