Hybrid PET-optical imaging using targeted probes

Abstract

Fusion imaging of radionuclide-based molecular (PET) and structural data [x-ray computed tomography (CT)] has been firmly established. Here we show that optical measurements [fluorescence-mediated tomography (FMT)] show exquisite congruence to radionuclide measurements and that information can be seamlessly integrated and visualized. Using biocompatible nanoparticles as a generic platform (containing a 18 F isotope and a far red fluorochrome), we show good correlations between FMT and PET in probe concentration (r 2 > 0.99) and spatial signal distribution (r 2 > 0.85). Using a mouse model of cancer and different imaging probes to measure tumoral proteases, macrophage content and integrin expression simultaneously, we demonstrate the distinct tumoral locations of probes in multiple channels in vivo. The findings also suggest that FMT can serve as a surrogate modality for the screening and development of radionuclide-based imaging agents.fluorescence-mediated tomography | molecular imaging | multimodal image fusion | computed tomography T oday, clinical imaging is used largely to provide anatomic, physiological, and metabolic information, but it generally cannot provide information about the underlying molecular aberrations of disease. Molecular imaging probes have the potential to provide such information by interrogating specific targets, such as cell surface receptors, enzymes, and structural proteins. By detecting specific molecular markers, imaging probes could vastly improve the early detection and staging of disease, and thus promote tailoring of targeted therapies for individual patients. There is also considerable interest in identifying and validating surrogate imaging biomarkers as indicators of drug efficacy in clinical trials and medical practice (1).Increasingly, particular attention has been paid to the development of combined PET-optical molecular imaging agents for translational applications, because these two modalities can provide complementary molecular information. A combined approach would be invaluable for purposes such as whole-body imaging (with, e.g., PET) and subsequent surgical intervention (with, e.g., an intraoperative optical imaging system). Moreover, because preclinical studies can use optical modalities, a combined approach would significantly reduce the hurdles commonly encountered with nuclear imaging and thus accelerate throughput and the development of PET imaging agents. For instance, this strategy would obviate some of the need for expensive equipment, controlled facilities, and a local cyclotron for supplying the radionuclide, and also would reduce the costs associated with handling radioactivity. Furthermore, by targeting the agent toward a surrogate biomarker, its specific localization within the tissue could be visualized via fluorescence; thus, this technique could provide a better understanding of underlying pathophysiology of disease.A unique platform for the combined development of targeted multifunctional imaging agents is provided by biocompatible nanoparticles (2-...

Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma

“…Its applications include real-time, intraoperative detection and imaging of nodal metastases, differential tumor burden, and lymphatic drainage patterns in melanoma. Although several investigators have synthesized radiolabeled fluorescent particle probes (25,30,40), our multimodal agent has been radiolabeled with the long-lived positron-emitter iodine-124, and, thus, we believe it can provide unique longer-term pharmacokinetic clearance and targeting information over the course of days. The complementary nature of this platform, coupled with its small size (~7-nm i.d.…”

“…Bifunctional PEGs, MALdPEG12-NHS ester (Quanta Biodesigns Ltd.), were derivatized with silanes, specifically 3-aminopropyl triethoxysilane (Gelest), for attachment to the silica surface and for peptide coupling via reactions between the sulfhydryl groups and maleimide moieties of the derivatized PEGs. In addition, methoxy-capped PEG chains were added to the particle surface using functional organosilicon compounds (Si compounds), specifically (MeO)3Si-PEG (Gelest), according to modified protocols (40). Briefly, (MeO)3Si-PEG was added, at approximately 3 molar excess, to particles in a water/alcohol basic mixture (~1:5 v/v), and the mixture was stirred overnight at room temperature.…”

Noninvasive Optical Imaging of Nanomedicine Biodistribution

“…Extending several pioneering efforts with regard to the combination of FMT with microcomputed tomography (μCT) for molecular imaging purposes, [31][32][33] using HPMA-based and NIRF-labeled polymeric nanocarriers known to accumulate in tumors both effectively and selectively by means of EPR, 10,12,34,35 we here show that hybrid CT-FMT imaging can be employed to non-invasively assess the accumulation of nanomedicine formulations in tissues other than superficial / subcutaneous tumors. To this end, the biodistribution and tumor accumulation of 5-10 nm-sized Dy750-labeled polymeric carrier materials was visualized and quantified using 3D FMT, and the data sets obtained were fused with 3D anatomical μCT data sets in which several different physiologically relevant organs were pre-segmented.…”

Radiolabeled Nanoparticles for In Vivo Tumor PET Imaging

“…12 The nanoparticle had a cross-linked iron oxide core with a dextran surface with a blood half-life of about 6 h and excretion of less than 5% at 24 h (Figure 4(A)). A specially designed imaging cassette was used for PET/CT/optical imaging (Figure 4(B)).…”