Effects of Recombinant α-Microglobulin on Early Proteomic Response in Risk Organs after Exposure to Lu-Octreotate.

Recombinant α-microglobulin (A1M) is proposed as a protector during Lu-octreotate treatment of neuroendocrine tumors, which is currently limited by bone marrow and renal toxicity. Co-administration of Lu-octreotate and A1M could result in a more effective treatment by protecting healthy tissue, but the radioprotective action of A1M is not fully understood. The aim of this study was to examine the proteomic response of kidneys and bone marrow early after Lu-octreotate and/or A1M administration.

Hematological and renal toxicity in mice after three cycles of high activity [Lu]Lu-PSMA-617 with or without human α-microglobulin.

Radioligand therapy with [Lu]Lu-PSMA-617 can be used to prolong life and reduce tumor burden in terminally ill castration resistant prostate cancer patients. Still, accumulation in healthy tissue limits the activity that can be administered. Therefore, fractionated therapy is used to lower toxicity.

Tumor Control Probability and Small-Scale Monte Carlo Dosimetry: Effects of Heterogenous Intratumoral Activity Distribution in Radiopharmaceutical Therapy.

In radiopharmaceutical therapy, intratumoral uptake of radioactivity usually leads to heterogeneous absorbed dose distribution. The likelihood of treatment success can be estimated with the tumor control probability (TCP), which requires accurate dosimetry, estimating the absorbed dose rate per unit activity to individual tumor cells. Xenograft cryosections of the prostate cancer cell line LNCaP treated with [Lu]Lu-PSMA-617 were evaluated with digital autoradiography and stained with hematoxylin and eosin.

Recombinant α-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a Lu-DOTATATE Mouse Radiation Model.

Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although Lu-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients.

Small-scale dosimetry for alpha particle Am source cell irradiation and estimation of γ-H2AX foci distribution in prostate cancer cell line PC3.

Background: The development of new targeted alpha therapies motivates improving alpha particle dosimetry. For alpha particles, microscopic targets must be considered to estimate dosimetric quantities that can predict the biological response. As double-strand breaks (DSB) on DNA are the main cause of cell death by ionizing radiation, cell nuclei are relevant volumes necessary to consider as targets.

Hematological Toxicity in Mice after High Activity Injections of Lu-PSMA-617.

Prostate cancer (PC) is one of the most common malignancies affecting men, with poor prognosis after progression to metastatic castration-resistant prostate cancer (mCRPC). Radioligand therapy (RLT) targeting the overexpressed PSMA on PC cells, with, e.g.

Humanization, Radiolabeling and Biodistribution Studies of an IgG-Type Antibody Targeting Uncomplexed PSA for Theranostic Applications.

Metastatic castration-resistant prostate cancer is today incurable. Conventional imaging methods have limited detection, affecting their ability to give an accurate outcome prognosis, and current therapies for metastatic prostate cancer are insufficient. This inevitably leads to patients relapsing with castration-resistant prostate cancer.

Kidney Protection with the Radical Scavenger α-Microglobulin (A1M) during Peptide Receptor Radionuclide and Radioligand Therapy.

α-Microglobulin (A1M) is an antioxidant found in all vertebrates, including humans. It has enzymatic reductase activity and can scavenge radicals and bind free heme groups. Infused recombinant A1M accumulates in the kidneys and has therefore been successful in protecting kidney injuries in different animal models.

A Conjugation Strategy to Modulate Antigen Binding and FcRn Interaction Leads to Improved Tumor Targeting and Radioimmunotherapy Efficacy with an Antibody Targeting Prostate-Specific Antigen.

Background: The humanized monoclonal antibody (mAb) hu5A10 specifically targets and internalizes prostate cancer cells by binding to prostate specific antigen (PSA). Preclinical evaluations have shown that hu5A10 is an excellent vehicle for prostate cancer (PCa) radiotheranostics. We studied the impact of different chelates and conjugation ratios on hu5A10's target affinity, neonatal fc-receptor interaction on in vivo targeting efficacy, and possible enhanced therapeutic efficacy.

Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α-Microglobulin (A1M), Including Kidney Damage Assessment Using Tc-MAG3 Imaging.

Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger α-microglobulin (A1M) together with 177-Lutetium (Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity.

PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates.

Purpose: Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA ().

Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy.

Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; ). In multiple rodent models, Actinium-225-labeled hu11B6-IgG ([Ac]hu11B6-IgG) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [Ac]hu11B6 treatment.

Quantitative γ-H2AX immunofluorescence method for DNA double-strand break analysis in testis and liver after intravenous administration of InCl.

Background: It is well known that a severe cell injury after exposure to ionizing radiation is the induction of DNA double-strand breaks (DSBs). After exposure, an early response to DSBs is the phosphorylation of the histone H2AX molecule regions adjacent to the DSBs, referred to as γ-H2AX foci. The γ-H2AX assay after external exposure is a good tool for investigating the link between the absorbed dose and biological effect.

Preclinical efficacy of hK2 targeted [Lu]hu11B6 for prostate cancer theranostics.

Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease.

Preserving Preclinical PET Quality During Intratherapeutic Imaging in Radionuclide Therapy with Rose Metal Shielding Reducing Photon Flux.

Performing PET imaging during ongoing radionuclide therapy can be a promising method to follow tumor response in vivo. However, the high therapeutic activity can interfere with the PET camera performance and degrade both image quality and quantitative capabilities. As a solution, low-energy photon emissions from the therapeutic radionuclide can be highly attenuated, still allowing sufficient detection of annihilation photons in coincidence.

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.

Simultaneous Preclinical Positron Emission Tomography-Magnetic Resonance Imaging Study of Lymphatic Drainage of Chelator-Free Cu-Labeled Nanoparticles.

Background: Hybrid positron emission tomography (PET)-magnetic resonance imaging (MRI) systems have been taken in use as new clinical diagnostic tools including detection and therapy planning of cancer. To reduce the amount of contrast agents injected in patients while fully benefitting both modalities, dual-modality probes are required.

Material And Methods: This study was first aimed at developing a hybrid PET-MRI probe by labeling superparamagnetic iron oxide nanoparticles (SPIONs) with Cu using a fast and chelator-free conjugation method, and second, to demonstrate the ability of the agent to target sentinel lymph nodes (SLNs) in vivo using simultaneous PET-MRI imaging.

Protection of Kidney Function with Human Antioxidation Protein α-Microglobulin in a Mouse Lu-DOTATATE Radiation Therapy Model.

Aims: Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage.

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.

Combined Magnetomotive ultrasound, PET/CT, and MR imaging of Ga-labelled superparamagnetic iron oxide nanoparticles in rat sentinel lymph nodes in vivo.

Current methods for intra-surgical guidance to localize metastases at cancer surgery are based on radioactive tracers that cause logistical challenges. We propose the use of a novel ultrasound-based method, magnetomotive ultrasound (MMUS) imaging that employ a nanoparticle-based contrast agent that also may be used for pre-operative PET/MRI imaging. Since MMUS is radiation free, this eliminates the dependence between pre- and intra-operative imaging and the radiation exposure for the surgical staff.

Size-dependent lymphatic uptake of nanoscale-tailored particles as tumor mass increases.

Aim: To investigate the size-dependent lymphatic uptake of nanoparticles in mice with rapidly growing syngeneic tumors.

Materials & Methods: Mice were inoculated subcutaneously with EL4 lymphoma cells and on day 5 or day 6 of tumor growth, injected peritumorally with either 29 nm or 58 nm of ultra-small superparamagnetic iron oxide nanoparticles. Twenty-four hours later the animals were imaged using MRI.

High resolution digital autoradiographic and dosimetric analysis of heterogeneous radioactivity distribution in xenografted prostate tumors.

Purpose: The first main aim of this study was to illustrate the absorbed dose rate distribution from Lu in sections of xenografted prostate cancer (PCa) tumors using high resolution digital autoradiography (DAR) and compare it with hypothetical identical radioactivity distributions of Y or 7 MeV alpha-particles. Three dosimetry models based on either dose point kernels or Monte Carlo simulations were used and evaluated. The second and overlapping aim, was to perform DAR imaging and dosimetric analysis of the distribution of radioactivity, and hence the absorbed dose rate, in tumor sections at an early time point after injection during radioimmunotherapy using Lu-h11B6, directed against the human kallikrein 2 antigen.

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.

Counting Rate Characteristics and Image Distortion in Preclinical PET Imaging During Radiopharmaceutical Therapy.

Unlabelled: PET may provide important information on the response during radiopharmaceutical therapy (RPT). Emission of radiation from the RPT radionuclide may disturb coincidence detection and impair image resolution. In this study, we tested the feasibility of performing intratherapeutic PET on 3 preclinical PET systems.

Radioimmunotherapy for Prostate Cancer--Current Status and Future Possibilities.

Prostate cancer (PCa) is one of the most common cancers in men and is the second leading cause of cancer-related deaths in the USA. In the United States, it is the second most frequently diagnosed cancer after skin cancer, and in Europe it is number one. According to the American Cancer Society, approximately 221,000 men in the United States would be diagnosed with PCa during 2015, and approximately 28,000 would die of the disease.