In hepatic ⁹⁰Y radioembolization, pretreatment ^99mTc-macroaggregated albumin (^99mTc-MAA) nuclear imaging is used for lung shunt analysis, evaluation of extrahepatic deposition, and sometimes for treatment planning, using a partition model. A high level of agreement between pretreatment ^99mTc-MAA distribution and final ⁹⁰Y-microsphere distribution is assumed. The aim of this study was to investigate the value of pretreatment ^99mTc-MAA SPECT to predict intrahepatic posttreatment ⁹⁰Y-microsphere distribution. Methods: Volumes of interest (VOIs) were delineated on pretreatment contrast-enhanced CT or MR images according to Couinaud liver segmentation. All VOIs were registered to the ^99mTc-MAA SPECT and ⁹⁰Y SPECT images. The ^99mTc-MAA SPECT and ⁹⁰Y SPECT activity counts were normalized to the total administered activity of ⁹⁰Y. For each VOI, this practice resulted in a predictive amount of ⁹⁰Y (MBq/cm³) based on ^99mTc-MAA SPECT in comparison with an actual amount of ⁹⁰Y based on ⁹⁰Y SPECT. Bland–Altman analysis was used to investigate the agreement of the activity distribution between ^99mTc-MAA SPECT and ⁹⁰Y SPECT. Results: A total of 39 procedures (225 VOIs) in 31 patients were included for analysis. The overall mean difference between pretreatment and posttreatment distribution of activity concentration for all segments was −0.022 MBq/cm³ with 95% limits of agreement of −0.581 to 0.537 MBq/cm³ (−28.9 to 26.7 Gy absorbed dose). A difference of >10%, >20%, and >30% of the mean activity per milliliter was found in, respectively, 153 (68%), 97 (43%), and 72 (32%) of the 225 segments. In every ^99mTc-MAA procedure, at least 1 segment showed an under- or overestimation of >10%. The position of the catheter tip during administrations, as well as the tumor load of the liver segments, significantly influenced the disagreement. Conclusion: In current clinical practice, ^99mTc-MAA distribution does not accurately predict final ⁹⁰Y activity distribution. Awareness of the importance of catheter positioning and adherence to specific recommendations may lead to optimization of individualized treatment planning based on pretreatment imaging.

After yttrium-90 (⁹⁰Y) microsphere radioembolization (RE), evaluation of extrahepatic activity and liver dosimetry is typically performed on ⁹⁰Y Bremsstrahlung SPECT images. Since these images demonstrate a low quantitative accuracy, ⁹⁰Y PET has been suggested as an alternative. The aim of this study is to quantitatively compare SPECT and state-of-the-art PET on the ability to detect small accumulations of ⁹⁰Y and on the accuracy of liver dosimetry. SPECT/CT and PET/CT phantom data were acquired using several acquisition and reconstruction protocols, including resolution recovery and Time-Of-Flight (TOF) PET. Image contrast and noise were compared using a torso-shaped phantom containing six hot spheres of various sizes. The ability to detect extra- and intrahepatic accumulations of activity was tested by quantitative evaluation of the visibility and unique detectability of the phantom hot spheres. Image-based dose estimates of the phantom were compared to the true dose. For clinical illustration, the SPECT and PET-based estimated liver dose distributions of five RE patients were compared. At equal noise level, PET showed higher contrast recovery coefficients than SPECT. The highest contrast recovery coefficients were obtained with TOF PET reconstruction including resolution recovery. All six spheres were consistently visible on SPECT and PET images, but PET was able to uniquely detect smaller spheres than SPECT. TOF PET-based estimates of the dose in the phantom spheres were more accurate than SPECT-based dose estimates, with underestimations ranging from 45% (10-mm sphere) to 11% (37-mm sphere) for PET, and 75% to 58% for SPECT, respectively. The differences between TOF PET and SPECT dose-estimates were supported by the patient data. In this study we quantitatively demonstrated that the image quality of state-of-the-art PET is superior over Bremsstrahlung SPECT for the assessment of the ⁹⁰Y microsphere distribution after radioembolization.

Although the first nanomedicine was clinically approved more than two decades ago, nanoparticles’ (NP) in vivo behavior is complex and the immune system’s role in their application remains elusive. At present, only passive-targeting nanoformulations have been clinically approved, while more complicated active-targeting strategies typically fail to advance from the early clinical phase stage. This absence of clinical translation is, amongst others, due to the very limited understanding for in vivo targeting mechanisms. Dynamic in vivo phenomena such as NPs’ real-time targeting kinetics and phagocytes’ contribution to active NP targeting remain largely unexplored. To better understand in vivo targeting, monitoring NP accumulation and distribution at complementary levels of spatial and temporal resolution is imperative. Here, we integrate in vivo positron emission tomography / computed tomography (PET/CT) imaging with intravital microscopy (IVM) and flow cytometric analyses to study αvβ3-integrin-targeted cyclic arginine-glycine-aspartate (cRGD) decorated liposomes and oil-in-water nanoemulsions in tumor mouse models. We observed that ligand-mediated accumulation in cancerous lesions is multifaceted and identified “NP hitchhiking” with phagocytes to contribute considerably to this intricate process. We anticipate that this understanding can facilitate rational improvement of nanomedicine applications and that immune cell-NP interactions can be harnessed to develop clinically viable nanomedicine-based immunotherapies.

Background: Intra-arterial radioembolization with yttrium-90 microspheres ( ⁹⁰Y-RE) is an increasingly used therapy for patients with unresectable liver malignancies. Over the last decade, radioactive holmium-166 poly(L-lactic acid) microspheres ( ¹⁶⁶Ho-PLLA-MS) have been developed as a possible alternative to ⁹⁰Y-RE. Next to high-energy beta-radiation, ¹⁶⁶Ho also emits gamma-radiation, which allows for imaging by gamma scintigraphy. In addition, Ho is a highly paramagnetic element and can therefore be visualized by MRI. These imaging modalities are useful for assessment of the biodistribution, and allow dosimetry through quantitative analysis of the scintigraphic and MR images. Previous studies have demonstrated the safety of ¹⁶⁶Ho-PLLA-MS radioembolization ( ¹⁶⁶Ho-RE) in animals. The aim of this phase I trial is to assess the safety and toxicity profile of ¹⁶⁶Ho-RE in patients with liver metastases. Methods: The HEPAR study (Holmium Embolization Particles for Arterial Radiotherapy) is a non-randomized, open label, safety study. We aim to include 15 to 24 patients with liver metastases of any origin, who have chemotherapy-refractory disease and who are not amenable to surgical resection. Prior to treatment, in addition to the standard technetium-99m labelled macroaggregated albumin ( ^99mTc-MAA) dose, a low radioactive safety dose of 60-mg ¹⁶⁶Ho-PLLA-MS will be administered. Patients are treated in 4 cohorts of 3-6 patients, according to a standard dose escalation protocol (20 Gy, 40 Gy, 60 Gy, and 80 Gy, respectively). The primary objective will be to establish the maximum tolerated radiation dose of ¹⁶⁶Ho-PLLA-MS. Secondary objectives are to assess tumour response, biodistribution, performance status, quality of life, and to compare the ¹⁶⁶Ho-PLLA-MS safety dose and the ^99mTc-MAA dose distributions with respect to the ability to accurately predict microsphere distribution. Discussion: This will be the first clinical study on ¹⁶⁶Ho-RE. Based on preclinical studies, it is expected that ¹⁶⁶Ho-RE has a safety and toxicity profile comparable to that of ⁹⁰Y-RE. The biochemical and radionuclide characteristics of ¹⁶⁶Ho-PLLA-MS that enable accurate dosimetry calculations and biodistribution assessment may however improve the overall safety of the procedure. Trial registration: ClinicalTrials.gov NCT01031784