Radiometal-Labeled Photoactivatable Pt(IV) Anticancer Complex for Theranostic Phototherapy.

A novel photoactivatable Pt(IV) diazido anticancer agent, Pt-succ-DFO, bearing a pendant deferoxamine (DFO) siderophore for radiometal chelation, has been synthesized for the study of its in vivo behavior with radionuclide imaging. Pt-succ-DFO complexation of Fe(III) and Ga(III) ions yielded new heterobimetallic complexes that maintain the photoactivation properties and photocytotoxicity of the parent Pt complex in human cancer cell lines. Radiolabeled Pt-succ-DFO-68Ga (t1/2 = 68 min, positron emitter) was readily prepared under mild conditions and was stable in the dark upon incubation with human serum. PET imaging of Pt-succ-DFO-68Ga in healthy mice revealed a promising biodistribution profile with rapid renal excretion and limited organ accumulation, implying that little off-target uptake is expected for this class of agents. Overall, this research provides the first in vivo imaging study of the whole-body distribution of a photoactivatable Pt(IV) azido anticancer complex and illustrates the potential of radionuclide imaging as a tool for the preclinical development of novel light-activated agents.

Targeted Auger electron-emitter therapy: Radiochemical approaches for thallium-201 radiopharmaceuticals.

INTRODUCTION: Thallium-201 is a radionuclide that has previously been used clinically for myocardial perfusion scintigraphy. Although in this role it has now been largely replaced by technetium-99 m radiopharmaceuticals, thallium-201 remains attractive in the context of molecular radionuclide therapy for cancer micrometastases or single circulating tumour cells. This is due to its Auger electron (AE) emissions, which are amongst the highest in total energy and number per decay for AE-emitters. Currently, chemical platforms to achieve this potential through developing thallium-201-labelled targeted radiopharmaceuticals are not available. Here, we describe convenient methods to oxidise [201Tl]Tl(I) to chelatable [201Tl]Tl(III) and identify challenges in stable chelation of thallium to support future synthesis of effective [201Tl]-labelled radiopharmaceuticals. METHODS: A plasmid pBR322 assay was carried out to determine the DNA damaging properties of [201Tl]Tl(III). A range of oxidising agents (ozone, oxygen, hydrogen peroxide, chloramine-T, iodogen, iodobeads, trichloroisocyanuric acid) and conditions (acidity, temperature) were assessed using thin layer chromatography. Chelators EDTA, DTPA and DOTA were investigated for their [201Tl]Tl(III) radiolabelling efficacy and complex stability. RESULTS: Isolated plasmid studies demonstrated that [201Tl]Tl(III) can induce single and double-stranded DNA breaks. Iodo-beads, iodogen and trichloroisocyanuric acid enabled more than 95% conversion from [201Tl]Tl(I) to [201Tl]Tl(III) under conditions compatible with future biomolecule radiolabelling (mild pH, room temperature and post-oxidation removal of oxidising agent). Although chelation of [201Tl]Tl(III) was possible with EDTA, DTPA and DOTA, only radiolabeled DOTA showed good stability in serum. CONCLUSIONS: Decay of [201Tl]Tl(III) in proximity to DNA causes DNA damage. Iodobeads provide a simple, mild method to convert thallium-201 from a 1+ to 3+ oxidation state and [201Tl]Tl(III) can be chelated by DOTA with moderate stability. Of the well-established chelators evaluated, DOTA is most promising for future molecular radionuclide therapy using thallium-201; nevertheless, a new generation of chelating agents offering resistance to reduction and dissociation of [201Tl]Tl(III) complexes is required.

Re-assessing gallium-67 as a therapeutic radionuclide.

INTRODUCTION: Despite its desirable half-life and low energy Auger electrons that travel further than for other radionuclides, 67Ga has been neglected as a therapeutic radionuclide. Here, 67Ga is compared with Auger electron emitter 111In as a potential therapeutic radionuclide. METHODS: Plasmid pBR322 studies allowed direct comparison between 67Ga and 111In (1MBq) in causing DNA damage, including the effect of chelators (EDTA and DTPA) and the effects of a free radical scavenger (DMSO). The cytotoxicity of internalized (by means of delivery in the form of oxine complexes) and non-internalized 67Ga and 111In was measured in DU145 prostate cancer cells after a one-hour incubation using cell viability (trypan blue) and clonogenic studies. MDA-MB-231 and HCC1954 cells were also used. RESULTS: Plasmid DNA damage was caused by 67Ga and was comparable to that caused by 111In; it was reduced in the presence of EDTA, DTPA and DMSO. The A50 values (internalized activity of oxine complexes per cell required to kill 50% of cells) as determined by trypan blue staining was 1.0Bq/cell for both 67Ga and 111In; the A50 values determined by clonogenic assay were 0.7Bq/cell and 0.3Bq/cell for 111In and 67Ga respectively. At the concentrations required to achieve these uptake levels, non-internalized 67Ga and 111In caused no cellular toxicity. Qualitatively similar results were found for MDA-MB-231 and HCC1954 cells. CONCLUSION: 67Ga causes as much damage as 111In to plasmid DNA in solution and shows similar toxicity as 111In at equivalent internalized activity per cell. 67Ga therefore deserves further evaluation for radionuclide therapy. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: The data presented here is at the basic level of science. If future in vivo and clinical studies are successful, 67Ga could become a useful radionuclide with little healthy tissue toxicity in the arsenal of weapons for treating cancer.

Synthesis, Characterization, and Application of Core-Shell Co0.16Fe2.84O4@NaYF4(Yb, Er) and Fe3O4@NaYF4(Yb, Tm) Nanoparticle as Trimodal (MRI, PET/SPECT, and Optical) Imaging Agents.

Multimodal nanoparticulate materials are described, offering magnetic, radionuclide, and fluorescent imaging capabilities to exploit the complementary advantages of magnetic resonance imaging (MRI), positron emission tomography/single-photon emission commuted tomography (PET/SPECT), and optical imaging. They comprise Fe3O4@NaYF4 core/shell nanoparticles (NPs) with different cation dopants in the shell or core, including Co0.16Fe2.84O4@NaYF4(Yb, Er) and Fe3O4@NaYF4(Yb, Tm). These NPs are stabilized by bisphosphonate polyethylene glycol conjugates (BP-PEG), and then show a high transverse relaxivity (r2) up to 326 mM(-1) s(-1) at 3T, a high affinity to [(18)F]-fluoride or radiometal-bisphosphonate conjugates (e.g., (64)Cu and (99m)Tc), and fluorescent emissions from 500 to 800 nm under excitation at 980 nm. The biodistribution of intravenously administered particles determined by PET/MR imaging suggests that negatively charged Co0.16Fe2.84O4@NaYF4(Yb, Er)-BP-PEG (10K) NPs cleared from the blood pool more slowly than positively charged NPs Fe3O4@NaYF4(Yb, Tm)-BP-PEG (2K). Preliminary results in sentinel lymph node imaging in mice indicate the advantages of multimodal imaging.