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Endothelial targeting of polymeric nanoparticles stably labeled with the PET imaging radioisotope iodine-124.

ABSTRACT: Targeting of therapeutics or imaging agents to the endothelium has the potential to improve specificity and effectiveness of treatment for many diseases. One strategy to achieve this goal is the use of nanoparticles (NPs) targeted to the endothelium by ligands of protein determinants present on this tissue, including cell adhesion molecules, peptidases, and cell receptors. However, detachment of the radiolabel probes from NPs poses a significant problem. In this study, we devised polymeric NPs directly labeled with radioiodine isotopes including the positron emission tomography (PET) isotope (124)I, and characterized their targeting to specific endothelial determinants. This approach provided sizable, targetable probes for specific detection of endothelial surface determinants non-invasively in live animals. Direct conjugation of radiolabel to NPs allowed for stable longitudinal tracking of tissue distribution without label detachment even in an aggressive proteolytic environment. Further, this approach permits tracking of NP pharmacokinetics in real-time and non-invasive imaging of the lung in mice using micro-PET imaging. The use of this strategy will considerably improve investigation of NP interactions with target cells and PET imaging in small animals, which ultimately can aid in the optimization of targeted drug delivery.

SUBMITTER: Simone EA

PROVIDER: S-EPMC3356447 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Endothelial targeting of polymeric nanoparticles stably labeled with the PET imaging radioisotope iodine-124.

Simone Eric A EA Zern Blaine J BJ Chacko Ann-Marie AM Mikitsh John L JL Blankemeyer Eric R ER Muro Silvia S Stan Radu V RV Muzykantov Vladimir R VR

Biomaterials 20120504 21

Targeting of therapeutics or imaging agents to the endothelium has the potential to improve specificity and effectiveness of treatment for many diseases. One strategy to achieve this goal is the use of nanoparticles (NPs) targeted to the endothelium by ligands of protein determinants present on this tissue, including cell adhesion molecules, peptidases, and cell receptors. However, detachment of the radiolabel probes from NPs poses a significant problem. In this study, we devised polymeric NPs d ...[more]

PMID: 22560201

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Project description:The radioiodine isotope pair 124I/131I is used in a theranostic approach for patient-specific treatment of differentiated thyroid cancer. Lesion detectability is notably higher for 124I PET (positron emission tomography) than for 131I gamma camera imaging but can be limited for small and low uptake lesions. The recently introduced silicon-photomultiplier-based (SiPM-based) PET/CT (computed tomography) systems outperform previous-generation systems in detector sensitivity, coincidence time resolution, and spatial resolution. Hence, SiPM-based PET/CT shows an improved detectability, particularly for small lesions. In this study, we compare the size-dependant minimum detectable 124I activity (MDA) between the SiPM-based Biograph Vision and the previous-generation Biograph mCT PET/CT systems and we attempt to predict the response to 131I radioiodine therapy of lesions additionally identified on the SiPM-based system. A tumour phantom mimicking challenging conditions (derived from published patient data) was used; i.e., 6 small spheres (diameter of 3.7-9.7 mm), 9 low activity concentrations (0.25-25 kBq/mL), and a very low signal-to-background ratio (20:1). List-mode emission data (single-bed position) were divided into frames of 4, 8, 16, and 30 min. Images were reconstructed with ordinary Poisson ordered-subsets expectation maximization (OSEM), additional time-of-flight (OSEM-TOF) or TOF and point spread function modelling (OSEM-TOF+PSF). The signal-to-noise ratio and the MDA were determined. Absorbed dose estimations were performed to assess possible treatment response to high-activity 131I radioiodine therapy. The signal-to-noise ratio and the MDA were improved from the mCT to the Vision, from OSEM to OSEM-TOF and from OSEM-TOF to OSEM-TOF+PSF reconstructed images, and from shorter to longer emission times. The overall mean MDA ratio of the Vision to the mCT was 0.52 ± 0.18. The absorbed dose estimations indicate that lesions ≥ 6.5 mm with expected response to radioiodine therapy would be detectable on both systems at 4-min emission time. Additional smaller lesions of therapeutic relevance could be detected when using a SiPM-based PET system at clinically reasonable emission times. This study demonstrates that additional lesions with predicted response to 131I radioiodine therapy can be detected. Further clinical evaluation is warranted to evaluate if negative 124I PET scans on a SiPM-based system can be sufficient to preclude patients from blind radioiodine therapy.

Project description:PurposeSigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of iodine-124-labeled IPAG ([124I]IPAG) to image S1R-overexpressing tumors.Procedures[124I]IPAG was synthesized from a tributyltin precursor dissolved in ethanol using chloramine-T as oxidant. Purity was analyzed using HPLC. In vitro and in vivo studies were performed using the breast cancer cell line MCF-7. Competitive inhibition studies were performed using haloperidol and cold IPAG. Tumors were established in athymic nude mice by injecting 107 cells subcutaneously. Mice were imaged on micro-positron emission tomography (PET) at 4, 24, 48, 72, and 144 h post i.v. injection. Biodistribution studies were performed at same time points. In vivo tracer dilution studies were performed using excess of IPAG and haloperidol. The efficacy of [124I]IPAG to image tumors was evaluated in LNCaP tumor-bearing mice as well.Results[124I]IPAG was synthesized in quantitative yield and in vitro studies indicated that [124I]IPAG binding was specific to S1R. PET imaging studies in MCF7 tumor-bearing mice reveal that [124I]IPAG accumulates in tumor and is preferentially retained while clearing from non-target organs. The tumor to background increases with time, and tumors could be clearly visualized starting from 24 h post administration. Similar results were obtained in mice bearing LNCaP tumors. In vivo tracer dilution studies showed that the uptake of [124I]IPAG could be competitively inhibited by excess of IPAG and haloperidol.Conclusions[124I]IPAG was synthesized successfully in high yields, and in vitro and in vivo studies demonstrate specificity of [124I]IPAG. [124I]IPAG shows specific accumulation in tumors with increasing tumor to background ratio at later time points and therefore has high potential for imaging S1R-overexpressing cancers.

Dataset Information

Endothelial targeting of polymeric nanoparticles stably labeled with the PET imaging radioisotope iodine-124.

Publications

Endothelial targeting of polymeric nanoparticles stably labeled with the PET imaging radioisotope iodine-124.

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