JHU-2545 preferentially shields salivary glands and kidneys during PSMA-targeted imaging.

Purpose: Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause dose-limiting xerostomia and potential for nephrotoxicity.

Beyond Average: α-Particle Distribution and Dose Heterogeneity in Bone Metastatic Prostate Cancer.

α-particle emitters are emerging as a potent modality for disseminated cancer therapy because of their high linear energy transfer and localized absorbed dose profile. Despite great interest and pharmaceutical development, there is scant information on the distribution of these agents at the scale of the α-particle pathlength. We sought to determine the distribution of clinically approved [Ra]RaCl in bone metastatic castration-resistant prostate cancer at this resolution, for the first time to our knowledge, to inform activity distribution and dose at the near-cell scale.

A Projection-Domain Low-Count Quantitative SPECT Method for -Particle-Emitting Radiopharmaceutical Therapy.

Single-photon emission-computed tomography (SPECT) provides a mechanism to estimate regional isotope uptake in lesions and at-risk organs after administration of -particle-emitting radiopharmaceutical therapies (-RPTs). However, this estimation task is challenging due to the complex emission spectra, the very low number of detected counts (~20 times lower than in conventional SPECT), the impact of stray-radiation-related noise at these low counts, and the multiple image-degrading processes in SPECT. The conventional reconstruction-based quantification methods are observed to be erroneous for -RPT SPECT.

Cure of Disseminated Human Lymphoma with [Ac]Ac-Ofatumumab in a Preclinical Model.

Immunotherapies that target the CD20 protein expressed on most non-Hodgkin lymphoma cells have improved clinical outcomes, but relapse is common. We prepared Ac-labeled anti-CD20 ofatumumab and evaluated its in vitro characteristics and therapeutic efficacy in a murine model of disseminated human lymphoma. Ac was chelated by DOTA-ofatumumab, and radiochemical yield, purity, immunoreactivity, stability, and chelate number were determined.

Engineering a modular Ti/Sc generator: eluate evaluation in preclinical models and estimation of human radiation dosimetry.

Background: Sc/Sc is an attractive theranostic pair for targeted in vivo positron emission tomographic (PET) imaging and beta-particle treatment of cancer. The Ti/Sc generator allows daily onsite production of this diagnostic isotope, which may provide an attractive alternative for PET facilities that lack in-house irradiation capabilities. Early animal and patient studies have demonstrated the utility of Sc.

Quantitative In Vivo Imaging of the Androgen Receptor Axis Reveals Degree of Prostate Cancer Radiotherapy Response.

Unlabelled: Noninvasive biomarkers for androgen receptor (AR) pathway activation are urgently needed to better monitor patient response to prostate cancer therapies. AR is a critical driver and mediator of resistance of prostate cancer but currently available noninvasive prostate cancer biomarkers to monitor AR activity are discordant with downstream AR pathway activity. External beam radiotherapy (EBRT) remains a common treatment for all stages of prostate cancer, and DNA damage induced by EBRT upregulates AR pathway activity to promote therapeutic resistance.

Cure of Disseminated Human Lymphoma with [Lu]Lu-Ofatumumab in a Preclinical Model.

Although immunotherapies that target CD20 on most non-Hodgkin lymphoma (NHL) cells have improved patient outcomes, current therapies are inadequate because many cases are, or become, refractory or undergo relapse. Here, we labelled the third-generation human anti-CD20 antibody ofatumumab with Lu, determined the in vitro characteristics of [Lu]Lu-ofatumumab, estimated human dosimetry, and assayed tumor targeting and therapeutic efficacy in a murine model of disseminated NHL. CHX-A″-diethylenetriaminepentaacetic acid-[Lu]Lu-ofatumumab was prepared.

Radiochemical Quality Control Methods for Radium-223 and Thorium-227 Radiotherapies.

The majority of radiopharmaceuticals for use in disease detection and targeted treatment undergo a single radioactive transition (decay) to reach a stable ground state. Complex emitters, which produce a series of daughter radionuclides, are emerging as novel radiopharmaceuticals. The need for validation of chemical and radiopurity with such agents using common quality control instrumentation is an area of active investigation.

[F]-Labeled PARP-1 PET imaging of PSMA targeted alpha particle radiotherapy response.

The growing interest and clinical translation of alpha particle (α) therapies brings with it new challenges to assess target cell engagement and to monitor therapeutic effect. Noninvasive imaging has great potential to guide α-treatment and to harness the potential of these agents in the complex environment of disseminated disease. Poly(ADP) ribose polymerase 1 (PARP-1) is among the most abundantly expressed DNA repair enzymes with key roles in multiple repair pathways-such as those induced by irradiation.

Radiopharmaceutical Quality Control Considerations for Accelerator-Produced Actinium Therapies.

Alpha-particle-emitting radiotherapies are of great interest for the treatment of disseminated cancer. Actinium-225 (Ac) produces four α-particles through its decay and is among the most attractive radionuclides for use in targeted radiotherapy applications. However, supply issues for this isotope have limited availability and increased cost for research and translation.

Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for U Targeted α-Therapy.

Uranium-230 is an α-emitting radionuclide with favorable properties for use in targeted α-therapy (TAT), a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To successfully implement this radionuclide for TAT, a bifunctional chelator that can stably bind uranium in vivo is required. To address this need, we investigated the acyclic ligands Hdedpa, HCHXdedpa, Hhox, and HCHXhox as uranium chelators.

Practical considerations for quantitative clinical SPECT/CT imaging of alpha particle emitting radioisotopes.

Alpha particle emitting radiopharmaceuticals are generating considerable interest for the treatment of disseminated metastatic disease. Molecular imaging of the distribution of these agents is critical to safely and effectively maximize the clinical potential of this emerging drug class. The present studies aim to investigate the feasibility and limitations of quantitative SPECT for Ra, Ac and Th.

Towards the stable chelation of radium for biomedical applications with an 18-membered macrocyclic ligand.

Targeted alpha therapy is an emerging strategy for the treatment of disseminated cancer. [Ra]RaCl is the only clinically approved alpha particle-emitting drug, and it is used to treat castrate-resistant prostate cancer bone metastases, to which [Ra]Ra localizes. To specifically direct [Ra]Ra to non-osseous disease sites, chelation and conjugation to a cancer-targeting moiety is necessary.

Improved Radium-223 Therapy with Combination Epithelial Sodium Channel Blockade.

Radium-223 dichloride ([Ra]RaCl2) is the first approved alpha particle-emitting therapy and is indicated for treatment of bone metastatic castrate resistant prostate cancer. Approximately half of the dose is absorbed into the gastrointestinal (GI) tract within minutes of administration, limiting disease-site uptake and contributing to toxicity. Here, we investigate the role of enteric ion channels and their modulation for improved therapeutic efficacy and reduced side effects.

Prostate Cancer Theranostics - An Overview.

Metastatic prostate cancer is incurable, and novel methods to detect the disease earlier and to direct definitive treatment are needed. Molecularly specific tools to localize diagnostic and cytotoxic radionuclide payloads to cancer cells and the surrounding microenvironment are recognized as a critical component of new approaches to combat this disease. The implementation of theranostic approaches to characterize and personalize patient management is beginning to be realized for prostate cancer patients.

Preclinical Single Photon Emission Computed Tomography of Alpha Particle-Emitting Radium-223.

Dose optimization and pharmacokinetic evaluation of α-particle emitting radium-223 dichloride (RaCl) by planar γ-camera or single photon emission computed tomography (SPECT) imaging are hampered by the low photon abundance and injected activities. In this study, we demonstrate SPECT of Ra using phantoms and small animal models. Line phantoms and mice bearing Ra were imaged using a dedicated small animal SPECT by detecting the low-energy photon emissions from Ra.

PSMA expression in the Hi-Myc model; extended utility of a representative model of prostate adenocarcinoma for biological insight and as a drug discovery tool.

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is highly overexpressed in primary and metastatic prostate cancer (PCa). This has led to the development of radiopharmaceuticals for targeted imaging and therapy under current clinical evaluation. Despite this progress, the exact biological role of the protein in prostate cancer development and progression has not been fully elucidated.

Harnessing Androgen Receptor Pathway Activation for Targeted Alpha Particle Radioimmunotherapy of Breast Cancer.

Purpose: The impact of androgen receptor (AR) activity in breast cancer biology is unclear. We characterized and tested a novel therapy to an AR-governed target in breast cancer. We evaluated the expression of prototypical AR gene products human kallikrein 2 (hK2) and PSA in breast cancer models.

The impact of age on radium-223 distribution and an evaluation of molecular imaging surrogates.

Introduction: Radium-223 dichloride is the first alpha-particle emitting therapeutic agent approved by FDA and EMA for bone metastatic castration-resistant prostate cancer. We studied its age-dependent biodistribution in mice, and compared it with [Tc]Tc-MDP and [F]NaF aiming to identify a potential imaging surrogate to predict [Ra]RaCl whole-body localization.

Methods: Male C57Bl/6 mice dosed with [Ra]RaCl were sacrificed at different time points to explore [Ra]RaCl whole-body distribution.

Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer.

Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa.

Listening to membrane potential: photoacoustic voltage-sensitive dye recording.

Voltage-sensitive dyes (VSDs) are designed to monitor membrane potential by detecting fluorescence changes in response to neuronal or muscle electrical activity. However, fluorescence imaging is limited by depth of penetration and high scattering losses, which leads to low sensitivity in vivo systems for external detection. By contrast, photoacoustic (PA) imaging, an emerging modality, is capable of deep tissue, noninvasive imaging by combining near-infrared light excitation and ultrasound detection.

Internalization of secreted antigen-targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis.

Targeting the androgen receptor (AR) pathway prolongs survival in patients with prostate cancer, but resistance rapidly develops. Understanding this resistance is confounded by a lack of noninvasive means to assess AR activity in vivo. We report intracellular accumulation of a secreted antigen-targeted antibody (SATA) that can be used to characterize disease, guide therapy, and monitor response.

A Radium-223 microgenerator from cyclotron-produced trace Actinium-227.

The alpha particle emitter Radium-223 dichloride (RaCl) has recently been approved for treatment of late-stage bone metastatic prostate cancer. There is considerable interest in studying this new agent outside of the clinical setting, however the supply of Ra is limited and expensive. We have engineered a Ra microgenerator using traces of Ac previously generated from cyclotron-produced Ac.

In vivo radiometric analysis of glucose uptake and distribution in mouse bone.

Bone formation and remodeling occurs throughout life and requires the sustained activity of osteoblasts and osteoclasts, particularly during periods of rapid bone growth. Despite increasing evidence linking bone cell activity to global energy homeostasis, little is known about the relative energy requirements or substrate utilization of bone cells. In these studies, we measured the uptake and distribution of glucose in the skeleton in vivo using positron-emitting (18)F-fluorodeoxyglucose ([(18)F]-FDG) and non-invasive, high-resolution positron emission tomography/computed tomography (PET/CT) imaging and ex vivo autoradiography.