Realizing the promise of precision medicine in cancer therapy depends on identifying and tracking of cancerous growths in order to maximize treatment options and improve patient outcomes. However, this goal of early detection remains unfulfilled by current clinical imaging techniques that fail to detect diseased lesions, due to their small size and sub-organ localization. With proper probes, optical imaging techniques can overcome this limitation by identifying the molecular phenotype of tumors at both macroscopic and microscopic scales. In this study, we propose the first use of nanophotonic short wave infrared technology to molecularly phenotype small sub-surface lesions for more sensitive detection and improved patient outcomes. To this end, we designed human serum albumin encapsulated rare-earth (RE) nanoparticles (ReANCs)[1, 2] with ligands for targeted lesion imaging. AMD3100, an antagonist to CXCR4 (a chemokine receptor involved in cell motility and a classic marker of cancer metastasis) was adsorbed onto ReANCs to form functionalized ReANCs (fReANCs). Functionalized nanoparticles were able to discriminate and preferentially accumulate in receptor positive lesions when injected intraperitoneally in a subcutaneous tumor model. Additionally, fReANCs, administered intravenously, were able to target sub-tissue tumor micro-lesions, at a maximum depth of 10.5 mm, in a lung metastatic model of breast cancer. Internal lesions identified with fReANCs were 2.25 times smaller than those detected with unfunctionalized ReANCs (p < .01) with the smallest tumor being 18.9 mm3. Thus, we present an integrated nanoprobe detection platform that allows target-specific identification of sub-tissue cancerous lesions.

Metastatic cancer is the leading cause of almost 90% of cancer-related deaths. Early detection of metastatic lesions in breast cancer would lead to judicious therapeutic choices in the management of the disease. Current clinical imaging techniques are unable to detect micro-metastases due to limited resolution. Optical imaging technologies are challenged by high tissue scattering and absorption of visible light, limiting resolution of deeper tissue lesions. While optical imaging modalities have the potential for real-time in vivo monitoring, poor penetration through biological mediums limits their application to subcutaneous lesions. Our approach utilizes rare earth (RE) nanoprobes that absorb near infrared (NIR) radiation and emit in the shortwave infrared (SWIR) spectrum (1000-3000 nm), allowing for greater depth of detection. In this study, we demonstrate the ability of CXCR4-targeting Rare Earth Albumin NanoComposites (ReANCs) to preferentially accumulate in receptor positive tumor lesions and image lesion dynamics in an in vivo MDA-MB-231 derived lung metastatic model. ReANCs or AMD3100 (small molecule inhibitor of CXCR4) functionalized ReANCs (fReANCs) were injected via the tail vein once a week and SWIR imaging was performed up to 48 hours post injection. Tumor burden in the lungs was assessed by MRI and compared to the SWIR signal from the nanoprobes. Longitudinal in vivo imaging confirmed improved accumulation of functionalized nanoprobes in tumor lesions compared to control ReANCs. This improved accumulation at early lesion stages allowed for earlier and more sensitive detection of internal tumors. We also observed control ReANCs cleared faster through the liver as evidenced by increased SWIR signal in the liver of these animals. In addition to the targeted imaging effect of fReANCs, we were able to demonstrate the ability of ReANCs to image micro-metastatic lesions in long bones and spine of animals prior to their detection via conventional imaging techniques such as MRI and CT. This was confirmed by ex-vivo SWIR imaging of the skeleton and micro-CT of the long bones. This advancement is exciting due to the paucity of imaging modalities capable of detecting micro-metastasis of breast cancer to bone. Histological analysis was performed to validate the presence of micro-lesions in the bones. Furthermore, immunohistochemical analysis of bone sections using markers over-expressed by MDA-MB-231 cells, namely Vimentin and pan-Cytokeratin confirmed the presence of tumors in the regions of interest.. Findings from this study support the promise of the “new window” imaging platform and suggest future clinical translatability for nanomedicine. Given the multifunctional nature of ANCs as drug delivery vehicles, our imaging probes can also be adapted for pre-clinical pharmacogenomic screening, an emerging component of precision medicine. Citation Format: Margot Zevon, Vidya Ganapathy, Harini Kantamneni, Marco Mingozzi, Paul Kim, Derek Adler, Mark Pierce, Richard Riman, Charles Roth, Prabhas Moghe. Early detection and longitudinal imaging of breast cancer metastatic microlesions using short-wave infrared light emitting rare-earth nanoprobes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1482. doi:10.1158/1538-7445.AM2015-1482

We report the design, calibration, and testing of a pre-clinical small animal imaging platform for use with short-wave infrared (SWIR) emitting contrast agents. Unlike materials emitting at visible or near-infrared wavelengths, SWIRemitting agents require detection systems with sensitivity in the 1-2 μm wavelength region, beyond the range of commercially available small animal imagers. We used a collimated 980 nm laser beam to excite rare-earth-doped NaYF 4 :Er,Yb nanocomposites, as an example of a SWIR emitting material under development for biomedical imaging applications. This beam was raster scanned across the animal, with fluorescence in the 1550 nm wavelength region detected by an InGaAs area camera. Background adjustment and intensity non-uniformity corrections were applied in software. The final SWIR fluorescence image was overlaid onto a standard white-light image for registration of contrast agent uptake with respect to anatomical features.

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