lead-radioisotopes and Neoplasms

Receptor-targeted image-guided Radionuclide Therapy (TRT) is increasingly recognized as a promising approach to cancer treatment. In particular, the potential for clinical translation of receptor-targeted alpha-particle therapy is receiving considerable attention as an approach that can improve outcomes for cancer patients. Higher Linear-energy Transfer (LET) of alpha-particles (compared to beta particles) for this purpose results in an increased incidence of double-strand DNA breaks and improved-localized cancer-cell damage. Recent clinical studies provide compelling evidence that alpha-TRT has the potential to deliver a significantly more potent anti-cancer effect compared with beta-TRT. Generator-produced 212Pb (which decays to alpha emitters 212Bi and 212Po) is a particularly promising radionuclide for receptor-targeted alpha-particle therapy. A second attractive feature that distinguishes 212Pb alpha-TRT from other available radionuclides is the possibility to employ elementallymatched isotope 203Pb as an imaging surrogate in place of the therapeutic radionuclide. As direct non-invasive measurement of alpha-particle emissions cannot be conducted using current medical scanner technology, the imaging surrogate allows for a pharmacologically-inactive determination of the pharmacokinetics and biodistribution of TRT candidate ligands in advance of treatment. Thus, elementally-matched 203Pb labeled radiopharmaceuticals can be used to identify patients who may benefit from 212Pb alpha-TRT and apply appropriate dosimetry and treatment planning in advance of the therapy. In this review, we provide a brief history on the use of these isotopes for cancer therapy; describe the decay and chemical characteristics of 203/212Pb for their use in cancer theranostics and methodologies applied for production and purification of these isotopes for radiopharmaceutical production. In addition, a medical physics and dosimetry perspective is provided that highlights the potential of 212Pb for alpha-TRT and the expected safety for 203Pb surrogate imaging. Recent and current preclinical and clinical studies are presented. The sum of the findings herein and observations presented provide evidence that the 203Pb/212Pb theranostic pair has a promising future for use in radiopharmaceutical theranostic therapies for cancer.

Topics: Bismuth; Humans; Lead Radioisotopes; Neoplasms; Precision Medicine; Radioisotopes; Radiopharmaceuticals; Tissue Distribution

Lead-compound optimization is an iterative process in the cancer drug development pipeline, in which small molecule inhibitors or biological compounds that are selected for their ability to bind specific targets are synthesised, tested and optimised. This process can be accelerated significantly using molecular imaging with nuclear medicine techniques, which aim to monitor the biodistribution and pharmacokinetics of radiolabelled versions of compounds. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can be used to quantify fourdimensional (temporal and spatial) clinically relevant information, to demonstrate tumor uptake of, and monitor the response to treatment with lead-compounds. This review discusses the pre-clinical and clinical value of the information provided by nuclear medicine imaging compared to the histological analysis of biopsied tissue samples. Also, the role of nuclear medicine imaging is discussed with regard to the assessment of the treatment response, radiotracer biodistribution, tumor accumulation, toxicity, and pharmacokinetic parameters, with mention of microdosing studies, pre-targeting strategies, and pharmacokinetic modelling.

Topics: Animals; Antineoplastic Agents; Humans; Lead Radioisotopes; Molecular Imaging; Neoplasms; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon

The use of targeted radionuclide therapy for cancer is on the rise. While beta-particle-emitting radionuclides have been extensively explored for targeted radionuclide therapy, alpha-particle-emitting radionuclides are emerging as effective alternatives. In this context, fundamental understanding of the interactions and dosimetry of these emitted particles with cells in the tumor microenvironment is critical to ascertaining the potential of alpha-particle-emitting radionuclides. One important parameter that can be used to assess these metrics is the S-value. In this study, we characterized several alpha-particle-emitting radionuclides (and their associated radionuclide progeny) regarding S-values in the cellular and tumor-metastasis environments. The Particle and Heavy Ion Transport code System (PHITS) was used to obtain S-values via Monte Carlo simulation for cell and tumor metastasis resulting from interactions with the alpha-particle-emitting radionuclides, lead-212 (

Topics: Actinium; Alpha Particles; Beta Particles; Bismuth; Dose-Response Relationship, Radiation; Humans; Lead Radioisotopes; Lutetium; Neoplasm Metastasis; Neoplasms; Radioisotopes; Yttrium Radioisotopes

A method for preparation of Pb-212 and Pb-203 labeled chelator-modified peptide-based radiopharmaceuticals for cancer imaging and radionuclide therapy has been developed and adapted for automated clinical production. Pre-concentration and isolation of radioactive Pb2+ from interfering metals in dilute hydrochloric acid was optimized using a commercially-available Pb-specific chromatography resin packed in disposable plastic columns. The pre-concentrated radioactive Pb2+ is eluted in NaOAc buffer directly to the reaction vessel containing chelator-modified peptides. Radiolabeling was found to proceed efficiently at 85°C (45min; pH 5.5). The specific activity of radiolabeled conjugates was optimized by separation of radiolabeled conjugates from unlabeled peptide via HPLC. Preservation of bioactivity was confirmed by in vivo biodistribution of Pb-203 and Pb-212 labeled peptides in melanoma-tumor-bearing mice. The approach has been found to be robustly adaptable to automation and a cassette-based fluid-handling system (Modular Lab Pharm Tracer) has been customized for clinical radiopharmaceutical production. Our findings demonstrate that the Pb-203/Pb-212 combination is a promising elementally-matched radionuclide pair for image-guided radionuclide therapy for melanoma, neuroendocrine tumors, and potentially other cancers.

Topics: Animals; Chromatography, High Pressure Liquid; Heterocyclic Compounds, 1-Ring; Humans; Lead Radioisotopes; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasms; Peptides; Radiopharmaceuticals; Radiotherapy, Image-Guided; Theranostic Nanomedicine; Tissue Distribution

(212)Pb is a clinically relevant therapeutic alpha emitter isotope. A surrogate, (203)Pb, if prepared with sufficiently high specific activity could be used to estimate (212)Pb in vivo absorbed doses. An improved production procedure of (203)Pb with a simple, new separation method and high specific radioactivity for imaging is reported. We determined the in-vivo biodistribution of (203)Pb in mice by SPECT/CT. This highlights application possibilities of (203)Pb for further in vivo and clinical uses (radiolabeled (212)Pb-peptide co-injection, dosimetry calculation).

Topics: Animals; Humans; Lead Radioisotopes; Male; Mice; Mice, Inbred C57BL; Neoplasms; Radiation Dosage; Radiometry; Radiotherapy; Single Photon Emission Computed Tomography Computed Tomography; Tissue Distribution

Radio-resistant hypoxic tumor cells are significant contributors to the locoregional recurrences and distant metastases that mark failure of radiotherapy. Due to restricted tissue oxygenation, chronically hypoxic tumor cells frequently become necrotic and thus there is often an association between chronically hypoxic and necrotic tumor regions. This simulation study is the first in a series to determine the feasibility of hypoxic cell killing after first targeting adjacent areas of necrosis with either an α- or β-emitting radioimmunoconjugate.

Topics: Absorption, Radiation; Computer Simulation; Humans; Lead Radioisotopes; Models, Statistical; Monte Carlo Method; Necrosis; Neoplasms; Radioimmunotherapy; Radiometry; Radiopharmaceuticals; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted

Targeted α-particle therapy offers the potential for more specific tumor cell killing with less damage to surrounding normal tissue than β-emitters because of the combination of short path length (50-80 μm) with the high linear energy transfer (100 keV μm(-1)) of this emission. These physical properties offer the real possibility of targeted (pre-targeted) α-therapy suitable for the elimination of minimal residual or micrometastatic disease. Targeted and pre-targeted radioimmunotherapy (RIT) using α-emitters such as (212)Bi (T(1/2) = 1.01 h) and (212)Pb (T(1/2) = 10.6 h) has demonstrated significant utility in both in vitro and in vivo model systems. (212)Pb, a promising α-particle emitting source, is the longer-lived parent nuclide of (212)Bi, and serves as an in vivo generator of (212)Bi. The radionuclide has been successfully used in RIT and pre-targeted RIT and demonstrated an enhanced therapeutic efficacy in combination with chemotherapeutics, such as gemcitabine and paclitaxel. The following perspective addresses the modes of radionuclide production, radiolabelling and chelation chemistry, as well as the application of (212)Pb to targeted and pre-targeted radiation therapy.

Topics: Alpha Particles; Coordination Complexes; Drug Evaluation, Preclinical; Heterocyclic Compounds, 1-Ring; Humans; Lead; Lead Radioisotopes; Linear Energy Transfer; Neoplasms; Radioimmunotherapy; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon

A two-compartment 212Pb generator has been constructed and characterized physically and chemically. It is based on transport by airflow of gaseous 220Rn emanating from thin layers of [228Th]barium stearate. 220Rn is collected in a glass bubbler by extraction into an organic solvent and solidified at temperatures below -72 degrees C. Tracer studies show that the decay product 212Pb can be recovered with approximately 70% yield. It is suggested that this generator design could accommodate therapeutic levels of 212Pb/228Th.

Topics: Equipment Design; Humans; Lead Radioisotopes; Neoplasms; Radiopharmaceuticals; Radon; Thorium

Topics: Animals; Bone and Bones; Lead Radioisotopes; Neoplasms; Radioactive Fallout; Radioactivity