Targeted Radionuclide Therapy Research Articles

Immune-Checkpoint Blockade Enhances 225Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (RNT) may increase tumor immunogenicity. We aimed at exploiting this effect by combining RNT with immunotherapy in a mouse model of prostate cancer (PC). Methods: C57BL/6-mice bearing syngeneic RM1-PGLS tumors were treated with 225Ac-PSMA617, an anti-PD-1 antibody, or both. Therapeutic efficacy was assessed by tumor volume measurements (CT), time to progression (TTP), and survival. Results: PSMA RNT or anti-PD-1 alone tended to prolong TTP (isotype control, 25 d; anti-PD-1, 33.5 d [P = 0.0153]; RNT, 30 d [P = 0.1038]) and survival (control, 28 d; anti-PD-1, 37 d [P = 0.0098]; RNT, 32 d [P = 0.1018]). Combining PSMA RNT and anti-PD-1 significantly improved disease control compared with either monotherapy. TTP was extended to 47.5 d (P ≤ 0.0199 vs. monotherapies), and survival to 51.5 d (P ≤ 0.0251 vs. monotherapies). Conclusion: PSMA RNT and PD-1 blockade synergistically improve therapeutic outcomes in our PC model, supporting the evaluation of RNT and immunotherapy combinations for PC patients.

Cellular S values in spindle-shaped cells: a dosimetry study on more realistic cell geometries using Geant4-DNA Monte Carlo simulation toolkit

Cellular dosimetry plays a crucial role in radiobiology and evaluation of the relative merits of radiopharmaceuticals used for targeted radionuclide therapy. The present study aims to investigate the effects of various cell geometries on dosimetric characteristics of several Auger emitters distributed in different subcellular compartments using Monte Carlo simulation. The Geant4-DNA extension of the Geant4 Monte Carlo simulation toolkit was employed to calculate the mean absorbed dose per unit cumulated activity (S value) for different subcellular distributions of several Auger electron-emitting theranostic radionuclides including 99mTc, 111In, 123I, 125I, and 201Tl. The simulations were carried out in various single-cell models of liquid water including spherical, ellipsoidal, spherical spindle, and ellipsoidal spindle cell models. The latter two models which are generalized from the first two models were inspired by the morphologies of spindle-shaped (fusiform) cells, and were developed to provide more realistic modeling of this common geometry observed in many healthy and cancerous cells. Evaluation of the S values calculated for the examined cell models reveals that the differences are small (less than 9%) for the cell ← cell, cell ← cell surface, and nucleus ← nucleus source-target combinations. However, moderate discrepancies are seen (up to 28%) when the nucleus is considered as the target, as well as the radioactivity is either internalized into the cytoplasm or bound to the cell membrane. The findings of the present work suggest that the assumption of spherical cell geometry may provide reasonably accurate estimates of the cellular/nuclear dose for the considered Auger emitters, even for spindle-shaped cells. Of course, this approximation should be used with caution for the nucleus ← cytoplasm and nucleus ← cell surface configurations, since the S-value sensitivity to the cell geometry is somewhat significant in these cases.

Phase I trial of docetaxel plus lutetium-177-labeled anti–prostate‐specific membrane antigen monoclonal antibody J591 (177Lu‐J591) for metastatic castration‐resistant prostate cancer

BackgroundDocetaxel remains a standard of care for metatsatic castration resistant porstate cancer (mCRPC) and has radiosensitizing properties. The dose limiting toxicity (DLT) of radioimmunotherapy is myelosuppression; dose fractionation of 177Lu-J591 allows similar administered doses with less toxicity. This study (NCT00916123) was designed to determine the safety, DLT, and maximum tolerated dose of fractionated 177Lu-J591 administered concurrently with standard docetaxel. MethodsMen with progressive mCRPC received docetaxel 75 mg/m2 every 3 weeks with escalating 2 fractionated doses of 177Lu-J591 (1.48 GBq/m2 up to max of 2.96 GBq/m2) with cycle 3. Cycle 4 of docetaxel was planned 6 weeks after cycle 3 to allow for recovery from 177Lu-J591-associated hematologic toxicity. DLT was defined as delay in docetaxel >3 weeks, prolonged myelosuppression or need for >2 platelet transfusions, febrile neutropenia, or grade ≥3 nonhematological toxicity following 177Lu-J591. PSA was assessed prior to each cycle and serial computed tomography (CT) and bone scan were performed. ResultsFifteen men with progressive mCRPC received dose-escalated targeted radionuclide therapy in 4 cohorts up to the highest planned dose (2.96 GBq/m2). No DLT was seen at any dose level. Grade 4 neutropenia without fever occurred in 8 (53.5%) and thromboytopenia in 2 (13.3%), with 2 receiving prophylactic platelet transfusion. No grade ≥3 nonhematological toxicity was observed. 11 (73.3%) had >50% PSA decline, with 78.6% having favorable circulating tumor cell counts after 177Lu-J591. All patients had targeting of known sites of disease by planar 177Lu-J591 imaging. ConclusionThe combination of 177Lu-J591 delivered as a single fractionated cycle with docetaxel/prednisone is feasible in patients with mCRPC. Without preselection for prostate-specific membrane antigen, accurate targeting of known sites of disease and a strong preliminary efficacy signal was observed.

Theoretical Prediction of the Preferred Production Routes of 225Ac from Proton Induced Reactions on 232Th

Alpha emitting radionuclides have potential for the therapy of cancers because of their high linear energy transfer, and short range biologic effectiveness. Alpha emitter 225Ac(T1/2 = 10.0 days) is a potent nuclide for targeted radionuclide therapy. 225Ac excitation functions via 232Th (p,7np)225Th→225Ac, 232Th (p,6n2p)225Ac, 232Th (p,4nα)225Ac, 232Th (p,5n3p)225Th→ 225Ac, and 232Th (p,3nαp)225Ra→225Ac reactions were calculated by Empire 3.2 code up to 200MeV and compared with existing data. No single nuclear level density with a pre-equilibrium model produce results which agree with the existing experimental data all through the energy range. However, a hybrid of the different nuclear level densities with the Hybrid Monte Carlo Simulation (HMS) and the exciton PCROSS pre-equilibrium models at different energy range provide results which are in good agreement with the existing experimental data. Hence the preferred production route for the direct and indirect production of 225Ac has also been suggested.

64Cu-labeled melanin nanoparticles for PET/CT and radionuclide therapy of tumor

Melanin is a group of natural pigments found in living organism. It can be used for positron emission tomography (PET) imaging due to its inherent chelating ability to radioactive cupric ion. This study was to prepare 64Cu-labeled PEGylated melanin nanoparticles (64Cu-PEG-MNPs), and to further take advantage of the enhanced permeability and retention (EPR) effect of radiolabeled nanoparticles to realize the integration of tumor diagnosis and treatment. We successfully synthesized PEG-MNPs. Saline and serum stability experiments demonstrated good stability. PET/CT showed high tumor aggregation. Moreover, 64Cu-PEG-MNPs resulted in a therapeutic effect on the A431 tumor-bearing mice in the treatment group. The pathological results further confirmed that the therapeutic doses of 64Cu-PEG-MNPs cause pathological changes of tumor tissues while showing minimal toxicity to normal tissues. Our data successfully demonstrate the good imaging performance of 64Cu-PEG-MNPs on A431 tumors and further proved its therapeutic effect, highlighting a great potential in targeted radionuclide therapy.

A Perspective in TRT and TAT —Clinical Topics and Current Status—

Targeted radionuclide therapy（TRT）は一部のがんに対し有効な治療の選択肢の一つとして確立している。2000年代まではβ線による治療のみが臨床で確立した治療であったが，2010年代に入り223Raによるα線治療が臨床に登場し，α線の応用を含めた最先端のTRTやtargeted alpha therapy（TAT）の臨床応用に期待が高まっている。オージェ電子による治療は研究段階であり臨床治療は未だ確立していない。最近の臨床TRTでのトピックスや現状をレビューする。

Influence of Several Compounds and Drugs on the Renal Uptake of Radiolabeled Affibody Molecules.

Affibody molecules are the most studied class of engineered scaffold proteins (ESPs) in radionuclide molecular imaging. Attempts to use affibody molecules directly labelled with radiometals for targeted radionuclide therapy were hampered by the high uptake and retention of radioactivity in kidneys. Several promising strategies have been implemented to circumvent this problem. Here, we investigated whether a pharmacological approach targeting different components of the reabsorption system could be used to lower the uptake of [99mTc]Tc-ZHER:2395 affibody molecule in kidneys. Pre-injection of probenecid, furosemide, mannitol or colchicine had no influence on activity uptake in kidneys compared to the control group. Mice pre-injected with maleate and fructose had 33% and 51% reduction in the kidney-associated activity, respectively, compared to the control group. Autoradiography images showed that the accumulation of activity after [99mTc]Tc-ZHER2:2395 injection was in the renal cortex and that both maleate and fructose could significantly reduce it. Results from this study demonstrate that pharmacological intervention with maleate and fructose was effective in reducing the kidney uptake of affibody molecules. A presumable mechanism is the disruption of ATP-mediated cellular uptake and endocytosis processes of affibody molecules by tubular cells.

The Nationwide Survey on Avoidance of Targeted Radionuclide Therapy in Patients with Limited Activities of Daily Living and Those Undergoing Hemodialysis

Targeted radionuclide therapy with high-dose radioisotopes should be performed in isolation rooms. Patients can be released only after radioactivity remaining in their bodies becomes less than the limits determined by the release criteria in order to secure public protection. Patients are asked to stay in isolation rooms for a few days. Physicians often face difficulties to carry out therapy in patients with limited activities of daily living and those undergoing hemodialysis, and have to avoid therapy in such cases. The Japanese Society of Nuclear Medicine conducted a nationwide survey in order to find out the actual situation. The survey results should reflect future improvement of therapeutic environment in collaborating with related societies and administrative bodies.

Targeted Radionuclide Therapy of Painful Bone Metastases: Past Developments, Current Status, Recent Advances and Future Directions

Bone pain arising from secondary skeletal malignancy constitutes one of the most common types of chronic pain among patients with cancer which can lead to rapid deterioration of the quality of life. Radionuclide therapy using bone-seeking radiopharmaceuticals based on the concept of localization of the agent at bone metastases sites to deliver focal cytotoxic levels of radiation emerged as an effective treatment modality for the palliation of symptomatic bone metastases. Bone-seeking radiopharmaceuticals not only provide palliative benefit but also improve clinical outcomes in terms of overall and progression-free survival. There is a steadily expanding list of therapeutic radionuclides which are used or can potentially be used in either ionic form or in combination with carrier molecules for the management of bone metastases. This article offers a narrative review of the armamentarium of bone-targeting radiopharmaceuticals based on currently approved investigational and potentially useful radionuclides and examines their efficacy for the treatment of painful skeletal metastases. In addition, the article also highlights the processes, opportunities, and challenges involved in the development of bone-seeking radiopharmaceuticals. Radium-223 is the first agent in this class to show an overall survival advantage in Castration-Resistant Prostate Cancer (CRPC) patients with bone metastases. This review summarizes recent advances, current clinical practice using radiopharmaceuticals for bone pain palliation, and the expected future prospects in this field.

Immune checkpoint inhibitors reverse tolerogenic mechanisms induced by melanoma targeted radionuclide therapy.

In line with the ongoing phase I trial (NCT03784625) dedicated to melanoma targeted radionuclide therapy (TRT), we explore the interplay between immune system and the melanin ligand [131I]ICF01012 alone or combined with immunotherapy (immune checkpoint inhibitors, ICI) in preclinical models. Here we demonstrate that [131I]ICF01012 induces immunogenic cell death, characterized by a significant increase in cell surface-exposed annexin A1 and calreticulin. Additionally, [131I]ICF01012 increases survival in immunocompetent mice, compared to immunocompromised (29 vs. 24days, p = 0.0374). Flow cytometry and RT-qPCR analyses highlight that [131I]ICF01012 induces adaptive and innate immune cell recruitment in the tumor microenvironment. [131I]ICF01012 combination with ICIs (anti-CTLA-4, anti-PD-1, anti-PD-L1) has shown that tolerance is a main immune escape mechanism, whereas exhaustion is not present after TRT. Furthermore, [131I]ICF01012 and ICI combination has systematically resulted in a prolonged survival (p < 0.0001) compared to TRT alone. Specifically, [131I]ICF01012 + anti-CTLA-4 combination significantly increases survival compared to anti-CTLA-4 alone (41 vs. 26days; p = 0.0011), without toxicity. This work represents the first global characterization of TRT-induced modifications of the antitumor immune response, demonstrating that tolerance is a main immune escape mechanism and that combining TRT and ICI is promising.

Targeted alpha therapy: a critical review of translational dosimetry research with emphasis on actinium-225.

This review provides a general overview of the current achievements and challenges in translational dosimetry for targeted alpha therapy (TAT). The concept of targeted radionuclide therapy (TRNT) is described with an overview of its clinical applicability and the added value of TAT is discussed. For TAT, we focused on actinium-225 (225Ac) as an example for alpha particle emitting radionuclides and their features, such as limited range within tissue and high linear energy transfer, which make alpha particle emissions more effective in targeted killing of tumour cells compared to beta radiation. Starting with the state-of-the-art dosimetry for TRNT and TAT, we then describe the challenges that still need to be met in order to move to a personalized dosimetry approach for TAT. Specifically for 225Ac, we discuss the recoiled daughter effect which may provoke significant damage to healthy tissue or organs and should be considered. Next, a broad overview is given of the pre-clinical research on 225Ac-TAT with an extensive description of tools which are only available in a pre-clinical setting and their added value. In addition, we review the preclinical biodistribution and dosimetry studies that have been performed on TAT-agents and more specifically of 225Ac and its multiple progeny, and describe their potential role to better characterize the pharmacokinetic (PK) profile of TAT-agents and to optimize the use of theranostic approaches for dosimetry. Finally, we discuss the support pre-clinical studies may provide in understanding dose-effect relationships, linking radiation dose quantities to biological endpoints and even moving away from macro- to microdosimetry. As such, the translation of pre-clinical findings may provide valuable information and new approaches for improved clinical dosimetry, thus paving the way to personalized TAT.

Theoretical investigation for optimizing the production of 223Ra in research reactors for treatment of bone metastases

223Ra is one of the most promising $$\alpha$$ -particle emitters for targeted radionuclide therapy. In this work, the possibility of producing 223Ra by neutron irradiation of 226Ra in Dhruva Reactor at Bhabha Atomic Research Centre, India has been studied. A Bateman equation solver has been developed and used to calculate the activity yield of 227Ac for various combinations of irradiation and cooling periods. Based on this analysis, optimum time of irradiation and cooling have been estimated for maximizing the activity of 227Ac while keeping the activity from other unwanted nuclides as small as reasonably possible.

SUN-LB26 Radioligand Theranostics of Endocrine-Related Cancers; A New, Revolutionary Approach

The successful clinical development of octreotide targeting somatostatin receptors (SSRs) revolutionized treatment of Neuro Endocrine Tumors (NETs)and pituitary adenomas. Recently, clinical applications of peptide bioconjugates including octreotide have taken a giant leap forward into a new diagnostic and therapeutic arena of additional endocrine-related cancers including prostate, breast, and small cell lung cancers. Molecularly targeted radionuclide therapy (RT) opens new horizons for otherwise resistant or widely dispersed malignancies and has far-reaching implications as a personalized therapeutic approach. Cancer-type specific, radiolabeled diagnostic imaging agents have been developed to select patients who then receive precise radioligand therapy targeting the identified cancer cells. This RT using alpha or beta radiation is cytotoxic to targeted cancer cells, while nearby healthy cells are unharmed—minimizing side effects and improving patient quality of life. Thus, theranostics represent a groundbreaking approach to bring radionuclide endocrine cancer therapy to patients via a multidisciplinary team consisting of endocrinologists, surgeons, oncologists and nuclear medicine physicians. In recognition of this exploding new field, the US FDA approved 68Ga-DOTATOC and -DOTATATE for use in PET/CT and 177Lu-DOTATATE for the treatment of SSR-positive NETs. Clinical trials with new theranostic compounds are ongoing for prostate cancer (PSMA), breast cancer (bombesin receptor), and small cell lung cancer (cytokine receptor CXCR4). Exciting future developments will undoubtedly involve development of radionuclide agents targeting additional cell surface receptors, enzymatic pathways, and clonal variations as well as combinations of alpha- and beta-emitters. Health care facilities worldwideare in the process of adding RT to their armamentarium for cancer patients; this requires a multidisciplinary team approach to optimize access to and delivery of care. To advance the science and enable translation of theranostics worldwide, the Gordon Research Conferences (GRC) organization [www.grc.org] has selected the authors to organize a 5-day inaugural meeting on Radionuclide Theranostics for the Management of Cancer in June 2020 [https://www.grc.org/radionuclide-theranostics-for-the-management-of-cancer-conference/2020/]that brings together cancer biologists, radiation physicists, receptor pharmacologists, nuclear medicine physicians, and industry representatives to 1) Identify new molecular targets and targeting vectors for specific malignancies; 2) Explore development of novel radionuclides and molecularly targeted radiopharmaceuticals; and 3) Optimize therapeutic benefits based on an understanding of radionuclide risks to normal tissues. This presentation will review the key topics discussed during this GRC meeting2496 characters (without spaces): limit 2500.

A multicentric IT platform for storage and sharing of imaging-based radiation dosimetric data.

The MEDIRAD project is about the effects of low radiation dose in the context of medical procedures. The goal of the work is to develop an informatics service that will provide the researchers of the MEDIRAD project with a platform to share acquired images, along with the associated dosimetric data pertaining to the radiation resulting from the procedure. The authors designed a system architecture to manage image data and dosimetric data in an integrated way. DICOM and non-DICOM data are stored in separated repositories, and the link between the two is provided through a semantic database, i.e., a database whose information schema in aligned with an ontology. The system currently supports CT, PET, SPECT, and NM images as well as dose reports. Currently, two workflows for non-DICOM data generated from dosimetric calculations have been taken into account, one concerning Monte Carlo-based calculation of organ doses in Chest CT, and the other estimation of doses in nontarget organs in 131I targeted radionuclide therapy of the thyroid. The system is currently deployed, thus providing access to image and related dosimetric data to all MEDIRAD users. The software was designed in such a way that it can be reused to support similar needs in other projects.

Development of a Chimeric Antigen-Binding Fragment Directed Against Human Galectin-3 and Validation as an Immuno-Positron Emission Tomography Tracer for the Sensitive In Vivo Imaging of Thyroid Cancer.

Background: The lack of facile methods for the specific characterization of malignant thyroid nodules makes the diagnosis of thyroid cancer (TC) challenging. Due to its restricted expression in such nodules, the cell-associated lectin galectin-3 (Gal3) has emerged as a marker for TC with growing interest for in vivo imaging as well as targeted radionuclide therapy. To accelerate translation into clinical application, we have developed a cognate chimeric human antigen-binding fragment (Fab) derived from the rat anti-Gal3 monoclonal antibody M3/38. Methods: The variable immunoglobulin (Ig) light and heavy chain sequences were cloned from the hybridoma cell line, and the corresponding Fab carrying human IgG1/κ constant genes was functionally produced in the periplasm of Escherichia coli and purified to homogeneity. To moderately prolong its plasma half-life and, thus, increase tumor uptake, the recombinant Fab was fused with a long disordered amino acid chain comprising in total 200 Pro, Ala, and Ser residues (PASylation). This novel tracer was subjected to in vitro characterization and in vivo validation by using two thyroid cancer orthotopic murine models. To this end, the αGal3-Fab-PAS200 was conjugated with deferoxamine (Dfo), labeled with 89Zr under mild conditions and tested for binding on TC cell lines. Athymic nude mice were inoculated either with FRO82-1 or with CAL62 tumor cells into the left thyroid lobe. After intravenous injection with ∼3.0 MBq of 89Zr-Dfo-PAS200-Fab, these mice were subjected to positron emission tomography (PET)/computed tomography imaging followed by quantification of tumor accumulation and immunohistochemical analysis. Results: The αGal3-Fab-PAS200 revealed high affinity toward the recombinant Gal3 antigen, with a dissociation constant ≤1 nM as measured via enzyme-linked immunosorbent assay, surface plasmon resonance spectroscopy, and radioactive cell binding assay. The in vivo Gal3-targeting by the 89Zr(IV)-labeled protein tracer, as investigated by immuno-PET, demonstrated highly selective and fast accumulation in orthotopically implanted tumors, with strong contrast images achieved 24 hours postinjection, and no uptake in the tumor-free thyroid lobe, as also confirmed by biodistribution studies. Conclusions: The chimeric αGal3 89Zr-Dfo-PAS200-Fab tracer exhibits selective accumulation in the tumor-bearing thyroid lobe of xenograft mice. Thus, this novel radioactive probe offers potential to change TC management, in addition to current diagnostic procedures, and to reduce unnecessary thyroidectomies.

The Effect of Nucleus Size on the Cell Dose in Targeted Radionuclide Therapy - A Monte Carlo Study.

Background:Nowadays, the use of radiopharmaceuticals in medicine is unavoidable. Depending on the distribution of the radiopharmaceutical in the cells, the nucleus absorbed dose changes by the variations in their geometry size. Therefore, this study aims to investigate the S-value by the variation of nucleus size using Geant4 toolkit.Methods:Two spherical cells with a variety of nucleus size have been considered as the cancerous cell. Monoenergetic electrons ranging from 5 to 300 keV are distributed uniformly. The S-value for four target-source components (including Nucleus←Cytoplasm, Nucleus←Cell surface, Nucleus←Nucleus, and Nucleus←Nucleus surface) is computed and plotted. Then, the obtained data are compared with analytical Medical Internal Radiation Dose (MIRD) data.Results:In Nucleus←Cytoplasm compartment for electrons below 10 keV, obtained S-values show a slight decrease for the nucleus in the radii of around half of the cell radius and then S-values increase with the increase in the nucleus radii. In the S-value of Nucleus←Cell surface, for all electron energy levels, a slight decrease observed with the increase of nucleus radii. For Nucleus←Nucleus and Nucleus←Nucleus surface cases, with an increase in the size of the cell nucleus, a sharp reduction in the S-values is detected.Conclusion:It can be concluded that for the beta emitters with low-energy radiation (<40 keV), the S-value is heavily dependent on the nucleus size which may affect the treatment of small tumors. While for the beta emitters with higher-energy radiation (>100 keV), the size of the nucleus is not very noticeable in the induced S-value.

Enhancing the therapeutic effects of in vitro targeted radionuclide therapy of 3D multicellular tumor spheroids using the novel stapled MDM2/X-p53 antagonist PM2

BackgroundPrecision therapeutics continuously make advances in cancer therapy, and a field of growing interest is the combination of targeted radionuclide therapy (TRNT) with potential radiosensitizing agents. This study evaluated whether the effects of in vitro TRNT, using the 177Lu-labeled anti-CD44v6 antibody AbN44v6, were potentiated by the novel stapled MDM2/X-p53 antagonist PM2.Materials and methodsTwo wt p53 cell lines, HCT116 (colorectal carcinoma) and UM-SCC-74B (head and neck squamous cell carcinoma), expressing different levels of the target antigen, CD44v6, were used. Antigen-specific binding of 177Lu-AbN44v6 was initially verified in a 2D cell assay, after which the potential effects of unlabeled AbN44v6 on downstream phosphorylation of Erk1/2 were evaluated by western blotting. Further, the therapeutic effects of unlabeled AbN44v6, 177Lu-AbN44v6, PM2, or a combination (labeled/unlabeled AbN44v6 +/− PM2) were assessed in 3D multicellular tumor spheroid assays.ResultsRadiolabeled antibody bound specifically to CD44v6 on both cell lines. Unlabeled AbN44v6 binding did not induce downstream phosphorylation of Erk1/2 at any of the concentrations tested, and repeated treatments with the unlabeled antibody did not result in any spheroid growth inhibition. 177Lu-AbN44v6 impaired spheroid growth in a dose-dependent and antigen-dependent manner. A single modality treatment with 20 μM of PM2 significantly impaired spheroid growth in both spheroid models. Furthermore, the combination of TRNT and PM2-based therapy proved significantly more potent than either monotherapy. In HCT116 spheroids, this resulted in a two- and threefold spheroid growth rate decrease for the combination of PM2 and 100 kBq 177Lu-AbN44v6 compared to monotherapies 14-day post treatment. In UM-SCC-74B spheroids, the combination therapy resulted in a reduction in spheroid size compared to the initial spheroid size 10-day post treatment.ConclusionTRNT using 177Lu-AbN44v6 proved efficient in stalling spheroid growth in a dose-dependent and antigen-dependent manner, and PM2 treatment demonstrated a growth inhibitory effect as a monotherapy. Moreover, by combining TRNT with PM2-based therapy, therapeutic effects of TRNT were potentiated in a 3D multicellular tumor spheroid model. This proof-of-concept study exemplifies the strength and possibility of combining TRNT targeting CD44v6 with PM2-based therapy.

Preparation and in vivo evaluation of red blood cell membrane coated porous silicon nanoparticles implanted with 155Tb

IntroductionPorous silicon (PSi) nanoparticles are capable of delivering therapeutic payloads providing targeted delivery and sustained release of the payloads. In this work we describe the development and proof-of-concept in vivo evaluation of thermally hydrocarbonized porous silicon (PSi) nanoparticles that are implanted with radioactive 155Tb atoms and coated with red blood cell (RBC) membrane (155Tb-THCPSi). The developed nanocomposites can be utilized as an intravenous delivery platform for theranostic radionuclides. MethodsTHCPSi thin films were implanted with 155Dy ions that decay to 155Tb at the ISOLDE radioactive ion-beam (RIB) facility at CERN. The films were processed to nanoparticles by ball-milling and sonication, and subsequently coated with either a solid lipid and RBC membrane or solely with RBC membrane. The nanocomposites were evaluated in vitro for stability and in vivo for circulation half-life and ex vivo for biodistribution in Balb/c mice. ResultsNanoporous THCPSi films were successfully implanted with 155Tb and processed to coated nanoparticles. The in vitro stability of the particles in plasma and buffer solutions was not significantly different between the particle types, and therefore the RBC membrane coated particles with less laborious processing method were chosen for the biological evaluation. The RBC membrane coating enhanced significantly the blood half-life compared to bare THCPSi particles. In the ex vivo biodistribution study a pronounced accumulation to the spleen was found, with lower uptake in the liver and a minor uptake in the lung, gall bladder and bone marrow. ConclusionsWe have demonstrated, using 155Tb RIB-implanted PSi nanoparticles coated with mouse RBC membranes, the feasibility of using such a theranostic nanosystem for the delivery of RIB based radionuclides with prolonged circulation time. Advances in knowledge and implications for patient careFor the first time, the RIB implantation technique has been utilized to produce PSi nanoparticle with a surface modified for better persistence in circulation. When optimized, these particles could be used in targeted radionuclide therapy with a combination of chemotherapeutic payload within the PSi structure.

Targeted Radionuclide Therapy of Prostate Cancer-From Basic Research to Clinical Perspectives.

Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related deaths in Western civilization. Although localized prostate cancer can be treated effectively in different ways, almost all patients progress to the incurable metastatic castration-resistant prostate cancer. Due to the significant mortality and morbidity rate associated with the progression of this disease, there is an urgent need for new and targeted treatments. In this review, we summarize the recent advances in research on identification of prostate tissue-specific antigens for targeted therapy, generation of highly specific and selective molecules targeting these antigens, availability of therapeutic radionuclides for widespread medical applications, and recent achievements in the development of new-generation small-molecule inhibitors and antibody-based strategies for targeted prostate cancer therapy with alpha-, beta-, and Auger electron-emitting radionuclides.

A Conversation with John Sunderland, Johannes Czernin, and Thomas Hope.

477 Background: Prostate specific-membrane antigen (PSMA) targeted radionuclide therapy (TRT) has emerged as a promising treatment for prostate cancer (PCa) patients1,2. However, xerostomia has been identified as a dose-limiting side-effect for PSMA-TRT3,4. Xerostomia results from salivary gland irradiation due to PSMA mediated accumulation of PSMA-TRT and can cause severe symptoms which affect patients qualify of life5,6,7. Even though PSMA has been studied extensively for developing imaging and therapy agents, little is known about why it is physiologically expressed in the salivary glands and its role in the salivary function, including whether PSMA-targeted agent is excreted in the saliva8. Information on the excretion of these agents via saliva can help design better strategies to prevent dose-limiting toxicity of PSMA-TRT. Thus, with an intent to learn more about the fate of PSMA targeted agents, data from patients administered with the PSMA targeted PET agent [18F]DCFPyL were prospectively collected, and radioactivity in saliva were measured over-time. METHOD: Five patients with prostate cancer were enrolled in a prospective prostate cancer PET imaging clinical trial using [18F]DCFPyL. Patients were intravenously administered with 6.20-6.59 mCi of [18F]DCFPyL. Saliva samples were collected at baseline (prior to administration of [18F]DCFPyL) and 15, 30, 60, and 120 min post-injection of [18F]DCFPyL. Radioactivity in saliva was measured using the gamma counter and the percentage injected dose/gram (%ID/g) of saliva was calculated. PET images were obtained 2 h after administration of the radioactive agent. Images were reconstructed and SUV was drawn to determine radioactivity in the salivary glands. All the studies were conducted following the IRB protocol. Results: Five enrolled prostate cancer patients were intravenously injected with an average of 6.48 mCi of [18F]DCFPyL. The amount of radioactivity in the saliva, increased over 120 min, with the max radioactivity (2.04E-03-2.70E-03 %ID/g of saliva) in the saliva for each patient recorded at this time-point. At 15 min and 30 min, the radioactivity (% ID/g of saliva) in the saliva ranged between 3.95E-05 to 9.98E-05 and 3.33E-04 to 6.12E-04 respectively. Compared to 60 min, at 120 min, an average of 169.2 % increase in radioactivity was observed in the saliva. SUV of the salivary gland of these five patients were typical of images obtained with [18F]DCFPyL, and the radioactivity in the saliva could be qualitatively visualized in the gravity-dependent pocket of the oral cavity. CONCLUSION: The results indicate that after administration of [18F]DCFPyL the amount of radioactivity in the saliva increased over 120 min in all the patients (5/5). Moreover, radioactivity in the saliva was also observed on the PET images. This finding helps expand our knowledge about the fate of PSMA-targeted agents in the salivary glands and may help researchers design more-effective strategies to prevent xerostomia. However, it will be interesting to identify if the radioactivity in the saliva is contributed by intact [18F]DCPyL or its metabolite. We intend to characterize the radioactive content in the saliva in the future studies.