Synthesis of no-carrier-added [188, 189, 191Pt]cisplatin from a cyclotron produced 188, 189, 191PtCl42\u2212 complex

Honoka Obata,Katsuyuki Minegishi,Kotaro Nagatsu,Ming-Rong Zhang,Mikako Ogawa

doi:10.1038/s41598-021-87576-2

Abstract

We developed a novel method for production of no-carrier-added (n.c.a.) [188, 189, 191Pt]PtIICl42− from an Ir target material, and then synthesized n.c.a. [*Pt]cis-[PtIICl2(NH3)2] ([*Pt]cisplatin) from [*Pt]PtIICl42−. [*Pt]PtIICl42− was prepared as a synthetic precursor of n.c.a. *Pt complex by a combination of resin extraction and anion-exchange chromatography after the selective reduction of IrIVCl62− with ascorbic acid. The ligand-substitution reaction of Cl with NH3 was promoted by treating n.c.a. [*Pt]PtIICl42− with excess NH3 and heating the reaction mixture, and n.c.a. [*Pt]cisplatin was successfully produced without employing precipitation routes. After this treatment, [*Pt]cisplatin was isolated through preparative HPLC with a radiochemical purity of 99 + % at the end of synthesis (EOS).

Highlights

Targeted radionuclide therapy (TRT) is a type of radiation therapy in which malignant tissues are internally irradiated with radiopharmaceuticals emitting with β–ray, α-ray, or Auger electron (Auger e-). β–rays are the most commonly used in the clinic
In many radiopharmaceuticals developed to date, Auger-emitting radionuclides of 123,125I and 111In were labeled to DNA-targeting molecules, e.g., a nucleic acid derivative such as deoxyuridine (UdR)[3,17], a nuclear localization signal (NLS)[12,18], or a DNA-binding m olecule[19,20,21], to ensure their transport to DNA
The degree of therapeutic efficacy was reported in previous studies using carrier-added radio-cisplatin with low specific activity (~ MBq/mg)[28,29], it was doubtful whether the fundamental potential of Auger e- itself could be detected without being masked by the chemotherapeutic effects of non-radioactive cisplatin carriers

Summary

Introduction

Targeted radionuclide therapy (TRT) is a type of radiation therapy in which malignant tissues are internally irradiated with radiopharmaceuticals emitting with β–ray, α-ray, or Auger electron (Auger e-). β–rays are the most commonly used in the clinic. Because radio-Pt–labeled cisplatin acts as both an anticancer agent that can target and chemically damage DNA and an Auger e- emitter, it is expected to provide a superior therapeutic effect as an in vivo radio-chemotherapy agent. Contrary to these expectations, the production method of no-carrier-added (n.c.a.) radio-Pt remains to be established at a practical level. To reveal the therapeutic potential of Auger e-, the DNA-damaging effect of radio-cisplatin needs to be investigated using n.c.a. radio-Pt. Available radio-Pt is commonly produced by a reactor via the natPt(n,x)[191,193] m, 195mPt reaction, resulting in carrier-added radio-Pt derived from a non-radioactive Pt target material. In the experiments for this study, we used mixed 188,189, 191Pt (81.7 ± 0.4% of 189Pt, 17.6 ± 0.6% of 191Pt, and 0.7 ± 0.2% of 188Pt at the end of bombardment [EOB]), described as *Pt in the following, because 188,189Pt is co-produced along with 191Pt from a natural Ir target

Methods

Results

Conclusion