Therapeutic efficacy of an alpha-particle emitter labeled anti-GD2 humanized antibody against osteosarcoma-a proof of concept study.

PURPOSE: Current treatments for osteosarcoma (OS) have a poor prognosis, particularly for patients with metastasis and recurrence, underscoring an urgent need for new targeted therapies to improve survival. Targeted alpha-particle therapy selectively delivers cytotoxic payloads to tumors with radiolabeled molecules that recognize tumor-associated antigens. We have recently demonstrated the potential of an FDA approved, humanized anti-GD2 antibody, hu3F8, as a targeted delivery vector for radiopharmaceutical imaging of OS. The current study aims to advance this system for alpha-particle therapy of OS. METHODS: The hu3F8 antibody was radiolabeled with actinium-225, and the safety and therapeutic efficacy of the [225Ac]Ac-DOTA-hu3F8 were evaluated in both orthotopic murine xenografts of OS and spontaneously occurring OS in canines. RESULTS: Significant antitumor activity was proven in both cases, leading to improved overall survival. In the murine xenograft's case, tumor growth was delayed by 16-18 days compared to the untreated cohort as demonstrated by bioluminescence imaging. The results were further validated with magnetic resonance imaging at 33 days after treatment, and microcomputed tomography and planar microradiography post-mortem. Histological evaluations revealed radiation-induced renal toxicity, manifested as epithelial cell karyomegaly and suggestive polyploidy in the kidneys, suggesting rapid recovery of renal function after radiation damage. Treatment of the two canine patients delayed the progression of metastatic spread, with an overall survival time of 211 and 437 days and survival beyond documented metastasis of 111 and 84 days, respectively. CONCLUSION: This study highlights the potential of hu3F8-based alpha-particle therapy as a promising treatment strategy for OS.

Large-scale in vitro microdosimetry via live cell microscopy imaging: implications for radiosensitivity and RBE evaluations in alpha-emitter radiopharmaceutical therapy.

BACKGROUND: Alpha-emitter radiopharmaceutical therapy (αRPT) has shown promising outcomes in metastatic disease. However, the short range of the alpha particles necessitates dosimetry on a near-cellular spatial scale. Current knowledge on cellular dosimetry is primarily based on in vitro experiments using cell monolayers. The goal of such experiments is to establish cell sensitivity to absorbed dose (AD). However, AD cannot be measured directly and needs to be modeled. Current models, often idealize cells as spheroids in a regular grid (geometric model), simplify binding kinetics and ignore the stochastic nature of radioactive decay. It is unclear what the impact of such simplifications is, but oversimplification results in inaccurate and non-generalizable results, which hampers the rigorous study of the underlying radiobiology. METHODS: We systematically mapped out 3D cell geometries, clustering behavior, agent binding, internalization, and subcellular trafficking kinetics for a large cohort of live cells under representative experimental conditions using confocal microscopy. This allowed for realistic Monte Carlo-based (micro)dosimetry. Experimentally established surviving fractions of the HER2 + breast cancer cell line treated with a 212Pb-labelled anti-HER2 conjugate or external beam radiotherapy, anchored a rigorous statistical approach to cell sensitivity and relative biological effectiveness (RBE) estimation. All outcomes were compared to a reference geometric model, which allowed us to determine which aspects are crucial model components for the proper study of the underlying radiobiology. RESULTS: In total, 567 cells were measured up to 26 h post-incubation. Realistic cell clustering had a large (2x), and cell geometry a small (16.4% difference) impact on AD, compared to the geometric model. Microdosimetry revealed that more than half of the cells do not receive any dose for most of the tested conditions, greatly impacting cell sensitivity estimates. Including these stochastic effects in the model, resulted in significantly more accurate predictions of surviving fraction and RBE (permutation test; p < .01). CONCLUSIONS: This comprehensive integration of the biological and physical aspects resulted in a more accurate method of cell survival modelling in αRPT experiments. Specifically, including realistic stochastic radiation effects and cell clustering behavior is crucial to obtaining generalizable radiobiological parameters.

Anti-GD2 antibody for radiopharmaceutical imaging of osteosarcoma.

PURPOSE: Osteosarcoma (OS) is the most frequently diagnosed bone cancer in children with little improvement in overall survival in the past decades. The high surface expression of disialoganglioside GD2 on OS tumors and restricted expression in normal tissues makes it an ideal target for anti-OS radiopharmaceuticals. Since human and canine OS share many biological and molecular features, spontaneously occurring OS in canines has been an ideal model for testing new imaging and treatment modalities for human translation. In this study, we evaluated a humanized anti-GD2 antibody, hu3F8, as a potential delivery vector for targeted radiopharmaceutical imaging of human and canine OS. METHODS: The cross-reactivity of hu3F8 with human and canine OS cells and tumors was examined by immunohistochemistry and flow cytometry. The hu3F8 was radiolabeled with indium-111, and the biodistribution of [111In]In-hu3F8 was assessed in tumor xenograft-bearing mice. The targeting ability of [111In]In-hu3F8 to metastatic OS was tested in spontaneous OS canines. RESULTS: The hu3F8 cross reacts with human and canine OS cells and canine OS tumors with high binding affinity. Biodistribution studies revealed selective uptake of [111In]In-hu3F8 in tumor tissue. SPECT/CT imaging of spontaneous OS canines demonstrated avid uptake of [111In]In-hu3F8 in all metastatic lesions. Immunohistochemistry confirmed the extensive binding of radiolabeled hu3F8 within both osseous and soft lesions. CONCLUSION: This study demonstrates the feasibility of targeting GD2 on OS cells and spontaneous OS canine tumors using hu3F8-based radiopharmaceutical imaging. Its ability to deliver an imaging payload in a targeted manner supports the utility of hu3F8 for precision imaging of OS and potential future use in radiopharmaceutical therapy.

Methods of improving brain dose estimates for internally deposited radionuclides.

The US National Council on Radiation Protection and Measurements (NCRP) convened Scientific Committee 6-12 (SC 6-12) to examine methods for improving dose estimates for brain tissue for internally deposited radionuclides, with emphasis on alpha emitters. This Memorandum summarises the main findings of SC 6-12 described in the recently published NCRP Commentary No. 31, 'Development of Kinetic and Anatomical Models for Brain Dosimetry for Internally Deposited Radionuclides'. The Commentary examines the extent to which dose estimates for the brain could be improved through increased realism in the biokinetic and dosimetric models currently used in radiation protection and epidemiology. A limitation of most of the current element-specific systemic biokinetic models is the absence of brain as an explicitly identified source region with its unique rate(s) of exchange of the element with blood. The brain is usually included in a large source region calledOtherthat contains all tissues not considered major repositories for the element. In effect, all tissues inOtherare assigned a common set of exchange rates with blood. A limitation of current dosimetric models for internal emitters is that activity in the brain is treated as a well-mixed pool, although more sophisticated models allowing consideration of different activity concentrations in different regions of the brain have been proposed. Case studies for 18 internal emitters indicate that brain dose estimates using current dosimetric models may change substantially (by a factor of 5 or more), or may change only modestly, by addition of a sub-model of the brain in the biokinetic model, with transfer rates based on results of published biokinetic studies and autopsy data for the element of interest. As a starting place for improving brain dose estimates, development of biokinetic models with explicit sub-models of the brain (when sufficient biokinetic data are available) is underway for radionuclides frequently encountered in radiation epidemiology. A longer-term goal is development of coordinated biokinetic and dosimetric models that address the distribution of major radioelements among radiosensitive brain tissues.

Imaging and dosimetry for alpha-particle emitter radiopharmaceutical therapy: improving radiopharmaceutical therapy by looking into the black box.

Radiopharmaceutical therapy using α-particle emitting radionuclides (αRPT) is a novel treatment modality that delivers highly potent alpha-particles to cancer cells or their environment. We review the advantages and challenges of imaging and dosimetry in implementing αRPT for cancer patients.

Transport-driven engineering of liposomes for delivery of α-particle radiotherapy to solid tumors: effect on inhibition of tumor progression and onset delay of spontaneous metastases.

PURPOSE: Highly cytotoxic α-particle radiotherapy delivered by tumor-selective nanocarriers is evaluated on metastatic Triple Negative Breast Cancer (TNBC). On vascularized tumors, the limited penetration of nanocarriers (<50-80 µm) combined with the short range of α-particles (40-100 µm) may, however, result in only partial tumor irradiation, compromising efficacy. Utilizing the α-particle emitter Actinium-225 (225Ac), we studied how the therapeutic potential of a general delivery strategy using nanometer-sized engineered liposomes was affected by two key transport-driven properties: (1) the release from liposomes, when in the tumor interstitium, of the highly diffusing 225Ac-DOTA that improves the uniformity of tumor irradiation by α-particles and (2) the adhesion of liposomes on the tumors' ECM that increases liposomes' time-integrated concentrations within tumors and, therefore, the tumor-delivered radioactivities. METHODS: On an orthotopic MDA-MB-231 TNBC murine model forming spontaneous metastases, we evaluated the maximum tolerated dose (MTD), biodistributions, and control of tumor growth and/or spreading after administration of 225Ac-DOTA-encapsulating liposomes, with different combinations of the two transport-driven properties. RESULTS: At 83% of MTD, 225Ac-DOTA-encapsulating liposomes with both properties (1) eliminated formation of spontaneous metastases and (2) best inhibited the progression of orthotopic xenografts, compared to liposomes lacking one or both properties. These findings were primarily affected by the extent of uniformity of the intratumoral microdistributions of 225Ac followed by the overall tumor uptake of radioactivity. At the MTD, long-term toxicities were not detected 9.5 months post administration. CONCLUSION: Our findings demonstrate the potential of a general, transport-driven strategy enabling more uniform and prolonged solid tumor irradiation by α-particles without cell-specific targeting.

Process validation, current good manufacturing practice production, dosimetry, and toxicity studies of the carbonic anhydrase IX imaging agent [111 In]In-XYIMSR-01 for phase I regulatory approval.

[111 In]In-XYIMSR-01 is a promising single-photon emission computed tomography (SPECT) imaging agent for identification of tumors that overexpress carbonic anhydrase IX. To translate [111 In]In-XYIMSR-01 to phase I trials, we performed animal toxicity and dosimetry studies, determined the maximum dose for human use, and completed the chemistry, manufacturing, and controls component of a standard regulatory application. The production process, quality control testing, stability studies, and specifications for sterile drug product release were based on United States Pharmacopeia chapters <823> and <825>, FDA 21 CFR Part 212. Toxicity was evaluated by using nonradioactive [113/115 In]In-XYIMSR-01 according to 21 CFR Part 58 guidelines. Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM) was used to calculate the maximum single dose for human studies. Three process validation runs at starting radioactivities of ~800 MBq were completed with a minimum concentration of 407 MBq/ml and radiochemical purity of ≥99% at the end of synthesis. A single intravenous dose of 55 µg/ml of [113/115 In]In-XYIMSR-01 was well tolerated in male and female Sprague-Dawley rats. The calculated maximum single dose for human injection from dosimetry studies was 390.35 MBq of [111 In]In-XYIMSR-01. We have completed toxicity and dosimetry studies as well as validated a manufacturing process to test [111 In]In-XYIMSR-01 in a phase I clinical trial.

Targeted and Nontargeted α-Particle Therapies.

α-Particle irradiation of cancerous tissue is increasingly recognized as a potent therapeutic option. We briefly review the physics, radiobiology, and dosimetry of α-particle emitters, as well as the distinguishing features that make them unique for radiopharmaceutical therapy. We also review the emerging clinical role of α-particle therapy in managing cancer and recent studies on in vitro and preclinical α-particle therapy delivered by antibodies, other small molecules, and nanometer-sized particles. In addition to their unique radiopharmaceutical characteristics, the increased availability and improved radiochemistry of α-particle radionuclides have contributed to the growing recent interest in α-particle radiotherapy. Targeted therapy strategies have presented novel possibilities for the use of α-particles in the treatment of cancer. Clinical experience has already demonstrated the safe and effective use of α-particle emitters as potent tumor-selective drugs for the treatment of leukemia and metastatic disease.

Combined model-based and patient-specific dosimetry for 18F-DCFPyL, a PSMA-targeted PET agent.

PURPOSE: Prostate-specific membrane antigen (PSMA), a type-II integral membrane protein highly expressed in prostate cancer, has been extensively used as a target for imaging and therapy. Among the available PET radiotracers, the low molecular weight agents that bind to PSMA are proving particularly effective. We present the dosimetry results for 18F-DCFPyL in nine patients with metastatic prostate cancer. METHODS: Nine patients were imaged using sequential PET/CT scans at approximately 1, 12, 35 and 70 min, and a final PET/CT scan at approximately 120 min after intravenous administration of 321 ± 8 MBq (8.7 ± 0.2 mCi) of18F-DCFPyL. Time-integrated-activity coefficients were calculated and used as input in OLINDA/EXM software to obtain dose estimates for the majority of the major organs. The absorbed doses (AD) to the eye lens and lacrimal glands were calculated using Monte-Carlo models based on idealized anatomy combined with patient-specific volumes and activity from the PET/CT scans. Monte-Carlo based models were also developed for calculation of the dose to two major salivary glands (parotid and submandibular) using CT-based patient-specific gland volumes. RESULTS: The highest calculated mean AD per unit administered activity of 18F was found in the lacrimal glands, followed by the submandibular glands, kidneys, urinary bladder wall, and parotid glands. The S-values for the lacrimal glands to the eye lens (0.42 mGy/MBq h), the tear film to the eye lens (1.78 mGy/MBq h) and the lacrimal gland self-dose (574.10 mGy/MBq h) were calculated. Average S-values for the salivary glands were 3.58 mGy/MBq h for the parotid self-dose and 6.78 mGy/MBq h for the submandibular self-dose. The resultant mean effective dose of 18F-DCFPyL was 0.017 ± 0.002 mSv/MBq. CONCLUSIONS: 18F-DCFPyL dosimetry in nine patients was obtained using novel models for the lacrimal and salivary glands, two organs with potentially dose-limiting uptake for therapy and diagnosis which lacked pre-existing models.

[(18)F]Fluoroethyl Triazole Substituted PSMA Inhibitor Exhibiting Rapid Normal Organ Clearance.

Prostate-specific membrane antigen (PSMA) is overexpressed in the epithelium of prostate cancer and nonprostate solid tumor neovasculature. PSMA is increasingly utilized as a target for cancer imaging and therapy. Here, we report the synthesis and in vivo biodistribution of a low-molecular-weight PSMA-based imaging agent, 2-[3-(1-carboxy-5-{3-[1-(2-[(18)F]fluoroethyl)-1H-1,2,3-triazol-yl]propanamido}pentyl)ureido]pentanedioic acid ([(18)F]YC-88), containing an [(18)F]fluoroethyl triazole moiety. [(18)F]YC-88 was synthesized from 2-[(18)F]fluoroethyl azide and the corresponding alkyne precursor in two steps using either a one- or two-pot procedure. Biodistribution and positron emission tomography (PET) imaging were performed in immunocompromised mice using isogenic PSMA(+) PC3 PIP and PSMA(-) PC3 flu xenografts. YC-88 exhibited high affinity for PSMA as evidenced by a Ki value of 12.9 nM. The non-decay corrected radiochemical yields of [(18)F]YC-88 averaged 14 ± 1% (n = 5). Specific radioactivities ranged from 320 to 2,460 Ci/mmol (12-91 GBq/µmol) with an average of 940 Ci/mmol (35 GBq/µmol, n = 5). In an immunocompromised mouse model, [(18)F]YC-88 clearly delineated PSMA(+) PC3 PIP prostate tumor xenografts on imaging with PET. At 1 h postinjection, 47.58 ± 5.19% injected dose per gram of tissue (% ID/g) was evident within the PSMA(+) PC3 PIP tumor, with a ratio of 170:1 of uptake within PSMA(+) PC3 PIP to PSMA(-) PC3 flu tumor placed in the opposite flank. The tumor-to-kidney ratio at 2 h postinjection was 4:1. At or after 30 min postinjection, minimal nontarget tissue uptake of [(18)F]YC-88 was observed. Compared to [(18)F]DCFPyL, which is currently in clinical trials, the uptake of [(18)F]YC-88 within the kidney, liver, and spleen was significantly lower at all time-points studied. At 30 min and 1 h postinjection, salivary gland uptake of [(18)F]YC-88 was significantly less than that of [(18)F]DCFPyL. [(18)F]YC-88 is a new PSMA-targeted PET agent synthesized utilizing click chemistry that demonstrates high PSMA(+) tumor uptake in a xenograft model. Because of its low uptake in the kidney, rapid clearance from nontarget organs, and relatively simple one-pot, two-step radiosynthesis, [(18)F]YC-88 is a viable new PET radiotracer for imaging PSMA-expressing lesions.

Alpha and Beta Radiation for Theragnostics.

Targeted radionuclide therapy (TRT) has significantly evolved from its beginnings with iodine-131 to employing carrier molecules with beta emitting isotopes like lutetium-177. With the success of Lu-177-DOTATATE for neuroendocrine tumors and Lu-177-PSMA-617 for prostate cancer, several other beta emitting radioisotopes, such as Cu-67 and Tb-161, are being explored for TRT. The field has also expanded into targeted alpha therapy (TAT) with agents like radium-223 for bone metastases in prostate cancer, and several other alpha emitter radioisotopes with carrier molecules, such as Ac-225, and Pb-212 under clinical trials. Despite these advancements, the scope of TRT in treating diverse solid tumors and integration with other therapies like immunotherapy remains under investigation. The success of antibody-drug conjugates further complements treatments with TRT, though challenges in treatment optimization continue.

Girth-based administered activity for pediatric 99m Tc-DMSA SPECT.

BACKGROUND: Pediatric molecular imaging requires a balance between administering an activity that will yield sufficient diagnostic image quality while maintaining patient radiation exposure at acceptable levels. In current clinical practice, this balance is arrived at by the current North American Consensus Guidelines in which patient weight is used to recommend the administered activity (AA). PURPOSE: We have previously demonstrated that girth (waist circumference at the level of the kidneys) is better at equalizing image quality than patient weight for pediatric Tc-99m DMSA renal function imaging. However, the correlation between image quality (IQ), AA, and patient girth has not been rigorously and systematically developed. In this work, we generate a series of curves showing the tradeoff between AA and IQ as a function of patient girth, providing the data for standards bodies to develop the next generation of dosing guideline for pediatric DMSA SPECT. METHODS: An anthropomorphic phantom series that included variations in age (5, 10, and 15 years), gender (M, F), local body morphometry (5, 10, 50, 90, and 95th girth percentiles), and kidney size (±15% standard size), was used to generate realistic SPECT projections. A fixed and clinically challenging defect-to-organ volume percentage (0.49% of renal cortex value) was used to model a focal defect with zero uptake (i.e., full local loss of renal function). Task-based IQ assessment methods were used to rigorously measure IQ in terms of renal perfusion defect detectability. This assessment was performed at multiple count levels (corresponding to various AAs) for groups of patients that had similar girths and defect sizes. Receiver-operating characteristics (ROC) analysis was applied; the area under the ROC curve (AUC) was used as a figure-of-merit for task performance. Curves showing the tradeoff between AUC and AA were generated for these groups of phantoms. RESULTS: Overall, the girth-based dosing method suggested different amounts of AA compared to weight-based dosing for the phantoms that had a relatively large body weight but a small girth or phantoms with relatively small bodyweight but large girth. Reductions of AA to 62.9% compared to weight-based dosing guidelines can potentially be realized while maintaining a baseline (AUC = 0.80) IQ for certain 15-year-olds who have a relatively small girth and large defect size. Note that the task-based IQ results are heavily dependent on the simulated defect size for the defect detection task and the appropriate AUC value must be decided by the physicians for this diagnostic task. These results are based purely on simulation and are subject to future clinical validation. CONCLUSIONS: The study provides simulation-based IQ-AA data for a girth-based dosing method for pediatric renal SPECT, suggesting that patient waist circumference at the level of kidneys should be considered in selecting the AA needed to achieve an acceptable IQ. This data may be useful for standards bodies to develop girth-based dosing guidelines.

A persistent belief in radiopharmaceutical therapy.

Imaging and dosimetry physics are essential to the long-term success of radiopharmaceutical therapy (RPT), a cancer treatment modality that can deliver potent cytotoxic radiation to disseminated cancer cells. This is a review of my personal journey in this field.

Gel-forming therapeutic peptide exhibits sustained delivery and efficacy in a mouse model of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a particularly aggressive and invasive subtype of breast cancer that represents a major cause of death of women worldwide. Here we describe the efficacy of an integrin-binding antiangiogenic peptide in a variety of delivery methods and dosing conditions. This peptide, AXT201, demonstrated consistent anti-tumor efficacy when administered intraperitoneally, subcutaneously, and intratumorally, and retained this activity even when dosing frequency was reduced to once every two weeks. Finally, in vivo imaging and biodistribution studies of AXT201 showed a long-term persistence of at least 10 days at the site of injection and a stable detectable signal in the blood over 48 h, indicating a sustained release profile. Taken together, these findings indicate AXT201 exhibits favorable pharmacokinetic properties for a 20-mer peptide.

Cure of Micrometastatic B-Cell Lymphoma in a SCID Mouse Model Using 213Bi-Anti-CD20 Monoclonal Antibody.

We studied the feasibility of using the α-emitting 213Bi-anti-CD20 therapy with direct bioluminescent tracking of micrometastatic human B-cell lymphoma in a SCID mouse model. Methods: A highly lethal SCID mouse model of minimal-tumor-burden disseminated non-Hodgkin lymphoma (NHL) was established using human Raji lymphoma cells transfected to express the luciferase reporter. In vitro and in vivo radioimmunotherapy experiments were conducted. Single- and multiple-dose regimens were explored, and results with 213Bi-rituximab were compared with various controls, including no treatment, free 213Bi radiometal, unlabeled rituximab, and 213Bi-labeled anti-HER2/neu (non-CD20-specific antibody). 213Bi-rituximab was also compared in vivo with the low-energy ß-emitter 131I-tositumomab and the high-energy ß-emitter 90Y-rituximab. Results: In vitro studies showed dose-dependent target-specific killing of lymphoma cells with 213Bi-rituximab. Multiple in vivo studies showed significant and specific tumor growth delays with 213Bi-rituximab versus free 213Bi, 213Bi-labeled control antibody, or unlabeled rituximab. Redosing of 213Bi-rituximab was more effective than single dosing. With a single dose of therapy given 4 d after intravenous tumor inoculation, disease in all untreated controls, and in all mice in the 925-kBq 90Y-rituximab group, progressed. With 3,700 kBq of 213Bi-rituximab, 75% of the mice survived and all but 1 survivor was cured. With 2,035 kBq of 131I-tositumomab, 75% of the mice were tumor-free by bioluminescent imaging and 62.5% survived. Conclusion: Cure of micrometastatic NHL is achieved in most animals treated 4 d after intravenous tumor inoculation using either 213Bi-rituximab or 131I-tositumomab, in contrast to the lack of cures with unlabeled rituximab or 90Y-rituximab or if there was a high tumor burden before radioimmunotherapy. α-emitter-labeled anti-CD20 antibodies are promising therapeutics for NHL, although a longer-lived α-emitter may be of greater efficacy.

Early Normal Tissue Effects and Bone Marrow Relative Biological Effectiveness for an Actinium 225-Labeled HER2/neu-Targeting Antibody.

PURPOSE: In this study we determined the dose-independent relative biological effectiveness (RBE2) of bone marrow for an anti-HER2/neu antibody labeled with the alpha-particle emitter actinium 225 (225Ac). Hematologic toxicity is often a consequence of radiopharmaceutical therapy (RPT) administration, and dosimetric guidance to the bone marrow is required to limit toxicity. METHODS AND MATERIALS: Female neu/N transgenic mice (MMTV-neu) were intravenously injected with 0 to 16.65 kBq of the alpha-particle emitter labeled antibody, 225Ac-DOTA-7.16.4, and euthanized at 1 to 9 days after treatment. Complete blood counts were performed. Femurs and tibias were collected, and bone marrow was isolated from 1 femur and tibia and counted for radioactivity. Contralateral intact femurs were fixed, decalcified, and assessed by histology. Marrow cellularity was the biologic endpoint selected for RBE2 determination. For the reference radiation, both femurs of the mice were photon irradiated with 0 to 5 Gy using a small animal radiation research platform. RESULTS: Response as measured by cellularity for the alpha-particle emitter RPT (αRPT) RPT and the external beam radiation therapy were linear and linear quadratic, respectively, as a function of absorbed dose. The resulting dose-independent RBE2 for bone marrow was 6. CONCLUSIONS: As αRPT gains prominence, preclinical studies evaluating RBE in vivo will be important in relating to human experience with beta-particle emitter RPT. Such normal tissue RBE evaluations will help mitigate unexpected toxicity in αRPT.

Bone Marrow Relative Biological Effectiveness for a 212Pb-labeled Anti-HER2/neu Antibody.

PURPOSE: We have determined the in vivo relative biological effectiveness (RBE) of an alpha-particle-emitting radiopharmaceutical therapeutic agent (212Pb-labeled anti-HER2/neu antibody) for the bone marrow, a potentially dose-limiting normal tissue. METHODS AND MATERIALS: The RBE was measured in mice using femur marrow cellularity as the biological endpoint. External beam radiation therapy (EBRT), delivered by a small-animal radiation research platform was used as the reference radiation. Alpha-particle emissions were delivered by 212Bi after the decay of its parent nuclide 212Pb, which was conjugated onto an anti-HER2/neu antibody. The alpha-particle absorbed dose to the marrow after an intravenous administration (tail vein) of 122.1 to 921.3 kBq 212Pb-TCMC-7.16.4 was calculated. The mice were sacrificed at 0 to 7 days after treatment and the radioactivity from the femur bone marrow was measured. Changes in marrow cellularity were assessed by histopathology. RESULTS: The dose response for EBRT and 212Pb-anti-HER2/neu antibody were linear-quadratic and linear, respectively. On transforming the EBRT dose-response relationship into a linear relationship using the equivalent dose in 2-Gy fractions of external beam radiation formalism, we obtained an RBE (denoted RBE2) of 6.4, which is independent of cellularity and absorbed dose. CONCLUSIONS: Because hematologic toxicity is dose limiting in almost all antibody-based RPT, in vivo measurements of RBE are important in helping identify an initial administered activity in phase 1 escalation trials. Applying the RBE2 and assuming typical antibody clearance kinetics (biological half-life of 48 hours), using a modified blood-based dosimetry method, an average administered activity of approximately 185.5 MBq (5.0 mCi) per patient could be administered before hematologic toxicity is anticipated.

In vivo multicolor molecular MR imaging using diamagnetic chemical exchange saturation transfer liposomes.

A variety of (super)paramagnetic contrast agents are available for enhanced MR visualization of specific tissues, cells, or molecules. To develop alternative contrast agents without the presence of metal ions, liposomes were developed containing simple bioorganic and biodegradable compounds that produce diamagnetic chemical exchange saturation transfer MR contrast. This diamagnetic chemical exchange saturation transfer contrast is frequency-dependent, allowing the unique generation of "multicolor" images. The contrast can be turned on and off at will, and standard images do not show the presence of these agents. As an example, glycogen, L-arginine, and poly-L-lysine were encapsulated inside liposomes and injected intradermally into mice to image the lymphatic uptake of these liposomes. Using a frequency-dependent acquisition scheme, it is demonstrated that multicolor MRI can differentiate between different contrast particles in vivo following their homing to draining lymph nodes. Being nonmetallic and bioorganic, these diamagnetic chemical exchange saturation transfer liposomes form an attractive novel platform for multicolor imaging in vivo.

Three-dimensional radiobiological dosimetry of kidneys for treatment planning in peptide receptor radionuclide therapy.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) delivers high absorbed doses to kidneys and may lead to permanent nephropathy. Reliable dosimetry of kidneys is thus critical for safe and effective PRRT. The aim of this work was to assess the feasibility of planning PRRT based on 3D radiobiological dosimetry (3D-RD) in order to optimize both the amount of activity to administer and the fractionation scheme, while limiting the absorbed dose and the biological effective dose (BED) to the renal cortex. METHODS: Planar and SPECT data were available for a patient examined with (111)In-DTPA-octreotide at 0.5 (planar only), 4, 24, and 48 h post-injection. Absorbed dose and BED distributions were calculated for common therapeutic radionuclides, i.e., (111)In, (90)Y and (177)Lu, using the 3D-RD methodology. Dose-volume histograms were computed and mean absorbed doses to kidneys, renal cortices, and medullae were compared with results obtained using the MIRD schema (S-values) with the multiregion kidney dosimetry model. Two different treatment planning approaches based on (1) the fixed absorbed dose to the cortex and (2) the fixed BED to the cortex were then considered to optimize the activity to administer by varying the number of fractions. RESULTS: Mean absorbed doses calculated with 3D-RD were in good agreement with those obtained with S-value-based SPECT dosimetry for (90)Y and (177)Lu. Nevertheless, for (111)In, differences of 14% and 22% were found for the whole kidneys and the cortex, respectively. Moreover, the authors found that planar-based dosimetry systematically underestimates the absorbed dose in comparison with SPECT-based methods, up to 32%. Regarding the 3D-RD-based treatment planning using a fixed BED constraint to the renal cortex, the optimal number of fractions was found to be 3 or 4, depending on the radionuclide administered and the value of the fixed BED. Cumulative activities obtained using the proposed simulated treatment planning are compatible with real activities administered to patients in PRRT. CONCLUSIONS: The 3D-RD treatment planning approach based on the fixed BED was found to be the method of choice for clinical implementation in PRRT by providing realistic activity to administer and number of cycles. While dividing the activity in several cycles is important to reduce renal toxicity, the clinical outcome of fractionated PRRT should be investigated in the future.

I-124 PET/CT image-based dosimetry in patients with differentiated thyroid cancer treated with I-131: correlation of patient-specific lesional dosimetry to treatment response.

PURPOSE: The objective of this study is to evaluate the lesion absorbed dose (AD), biological effective dose (BED), and equivalent uniform dose (EUD) to clinical-response relationship in lesional dosimetry for 131I therapy. METHODS: Nineteen lesions in four patients with metastatic differentiated thyroid cancer (DTC) were evaluated. The patients underwent PET/CT imaging at 2 h, 24 h, 48 h, 72 h, and 96 h post administration of ~ 33-65 MBq (0.89-1.76 mCi) of 124I before undergoing 131I therapy. The 124I PET/CT images were used to perform dosimetry calculations for 131I therapy. Lesion dose-rate values were calculated using the time-activity data and integrated over the measured time points to obtain AD and BED. The Geant4 toolkit was used to run Monte Carlo on spheres the same size as the lesions to estimate EUD. The lesion AD, BED, and EUD values were correlated with response data (i.e. change in lesion size pre- and post-therapy): complete response (CR, i.e. disappearance of the lesion), partial response (PR, i.e. any decrease in lesion length), stable disease (SD, i.e., no change in length), and progressive disease (PD, i.e., any increase in length). RESULTS: The lesion responses were CR and PR (58%, 11/19 lesions), SD (21%, 4/19), and PD (21%, 4/19). For CR and PR lesions, the ADs, BEDs and EUDs were > 75 Gy for 82% (9/11) and < 75 Gy for 18% (2/11). The ADs and BEDs were < 75 Gy for SD and PD lesions. CONCLUSION: By performing retrospective dosimetry calculations for 131I therapy based on 124I PET/CT imaging, we evaluated the correlation of three dosimetric quantities to lesional response. When lesion AD, BED, and EUD values were > 75 Gy, 47% (9/19) of the lesions had a CR or PR. The AD, BED, and EUD values for SD and PD lesions were < 75 Gy. The data presented herein suggest that the greater the lesion AD, BED, and/or EUD, the higher the probability of a therapeutic response to 131I therapy.