High Sensitivity

Abstract

Background The use of antiangiogenic therapy in conjunction with traditional chemotherapy is becoming increasingly in cancer management, but the optimal benefit of these targeted pharmaceuticals has been limited to a subset of the population treated. Improved imaging probes that permit sensitive detection and high-resolution characterization of tumor angiogenesis could improve patient risk-benefit stratification. Objectives The overarching objective of these experiments was to develop a dual modality αvβ3-targeted nanoparticle molecular imaging agent that affords sensitive nuclear detection in conjunction with high-resolution MR characterization of tumor angiogenesis. Materials and Methods In part 1, New Zealand white rabbits (n = 21) bearing 14d Vx2 tumor received either αvβ3-targeted 99mTc nanoparticles at doses of 11, 22, or 44 MBq/kg, nontargeted 99mTc nanoparticles at 22 MBq/kg, or αvβ3-targeted 99mTc nanoparticles (22 MBq/kg) competitively inhibited with unlabeled αvβ3-nanoparticles. All animals were imaged dynamically over 2 hours with a planar camera using a pinhole collimator. In part 2, the effectiveness of αvβ3-targeted 99mTc nanoparticles in the Vx2 rabbit model was demonstrated using clinical SPECT-CT imaging techniques. Next, MR functionality was incorporated into αvβ3-targeted 99mTc nanoparticles by inclusion of lipophilic gadolinium chelates into the outer phospholipid layer, and the concept of high sensitivity – high-resolution detection and characterization of tumor angiogenesis was shown using sequential SPECT-CT and MR molecular imaging with 3D neovascular mapping. Results αvβ3-Targeted 99mTc nanoparticles at 22 MBq/kg produced the highest tumor-to-muscle contrast ratio (8.56 ± 0.13, TMR) versus the 11MBq/kg (7.32 ± 0.12) and 44 MBq/kg (6.55 ± 0.07) doses, (P < 0.05). TMR of nontargeted particles at 22.2 MBq/kg (5.48 ± 0.09) was less (P < 0.05) than the equivalent dosage of αvβ3-targeted 99mTc nanoparticles. Competitively inhibition of 99mTc αvβ3-integrin-targeted nanoparticles at 22.2 MBq/kg reduced (P < 0.05) TMR (5.31 ± 0.06) to the nontargeted control contrast level. Multislice CT imaging could not distinguish the presence of Vx2 tumor implanted in the popliteal fossa from lymph nodes in the same fossa or in the contralateral leg. However, the use of 99mTc αvβ3-nanoparticles with SPECT-CT produced a clear neovasculature signal from the tumor that was absent in the nonimplanted hind leg. Using αvβ3-targeted 99mTc-gadolinium nanoparticles, the sensitive detection of the Vx2 tumor was extended to allow MR molecular imaging and 3D mapping of angiogenesis in the small tumor, revealing an asymmetrically distributed, patchy neovasculature along the periphery of the cancer. Conclusion Dual modality molecular imaging with αvβ3-targeted 99mTc-gadolinium nanoparticles can afford highly sensitive and specific localization of tumor angiogenesis, which can be further characterized with high-resolution MR neovascular mapping, which may predict responsiveness to antiangiogenic therapy.

Tumor Uptake of Hollow Gold Nanospheres After Intravenous and Intra-arterial Injection: PET/CT Study in a Rabbit VX2 Liver Cancer Model

“…In a rabbit subcutaneous VX2 tumor model, Lijowski et al [38] found that systemically administered α v β 3 -targeted 99m Tc-gadolinium nanoparticles (270 nm in diameter) produced a higher tumor-to-muscle uptake ratio than nontargeted nanoparticles. Interestingly, we did not observe any differential uptake between PEG-HAuNS and RGD-PEG-HAuNS at any time point after IV injection, possibly because of preferential uptake of the nanoparticles in the liver’s reticuloendothelial system.…”

Molecular imaging for cancer diagnosis and surgery

“…The aforementioned PET imaging with 18F-fluorodeoxyglucose ( 18 F-FDG) depicts the metabolic discrepancies between malignant and healthy cells by indicating increased glucose uptake by cancer cells. An example for a more cancer specific approach which however is also not limited to a certain type of malignancy is designing probes which attach to certain integrins which are highly expressed on tumor vascular endothelial cells, while being almost undetectable on normal blood vessels, making them a potential target for imaging during early cancer diagnosis [16-18]. Similarly, probes developed in our collaborative laboratories are targeted at extracellular matrix enzymes, specifically matrix metalloproteinases (MMPs) 2 and 9 which are expressed by a range of tumor cell lines [19-24].…”

Targeted nanotechnology for cancer imaging

“…T1-based α v β 3 -targeted 99m Tc-Gd nanoparticles have been reported for SPECT-MR imaging of tumor angiogenesis. The high contrast sensitivity of SPECT enabled detection of small lesions, while the vascular-targeted MR component facilitated 3D characterization of neovasculature [149]. 111 In-perfluorocarbon nanoparticles have also been investigated as a multimodal PET-MR agent [133].…”