CXCR‐4 Targeted, Short Wave Infrared (SWIR) Emitting Nanoprobes for Enhanced Deep Tissue Imaging and Micrometastatic Cancer Lesion Detection

Abstract

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.

Nanoparticles for imaging and treatment of metastatic breast cancer

“…These NPs can target subtissue microlesions in a lung metastatic model of breast cancer. [28] Bone-binding molecules have been used to target bone metastasis. The bisphosphonates such as alendronate and zoledronate have high affinity towards the hydroxyapatite and thus have been conjugated on NPs [29, 30] NPs modified with bisphosphonates showed enhanced bond binding in vitro and in vivo, and high bone marrow uptake in bone metastasis of breast cancer cells (MDA-MB-231) in mice.…”

“…These NPs are able to detect subtissue microlesions. [28] Using a similar NIR second window (NIR-II) fluorescent imaging (808 nm laser excitation and 900–1100 nm emission), the single-walled carbon nanotubes are able to visualize both the primary tumor and the sentinel lymph node metastasis in mice. [33] Considering much more tissue depth in human than in small animals, the translation of NIR imaging into clinical practice may be limited to surgery guidance but not body-scale imaging.…”

Optical windows for head tissues in near‐infrared and short‐wave infrared regions: Approaching transcranial light applications

“…Over the last decades, the optical tissue transparency window in NIR‐I has been employed for noninvasive optical bioimaging of small animals in biomedical research , advancing the development of imaging guided phototherapy and drug delivery . Quite recently, in addition to the conventional NIR‐I window, two or more optical windows have been identified, namely NIR‐II (~1000‐1350 nm) and NIR‐III or short‐wave IR (SWIR) (~1550‐1870 nm) .…”

Surface-Modified Shortwave-Infrared-Emitting Nanophotonic Reporters for Gene-Therapy Applications

“…15,17,20,21 We show that the surface charge of RENPs are tunable by modification with PEI coating (RENPs@PEI). PEI, a polycation typically used as a gene-delivery nanosystem, 23–25 was used to improve solubility of RENPs.…”

“…We have previously shown that RENPs can be rendered biologically safe by encapsulation in albumin nanocomposites 15 and can be targeted for the detection of micrometastatic lesions in multiple organs. 20,21 However, the lack of cationic charge on the surface of the albumin nanocomposites renders them unsuitable for the loading of genetic cargo. In the present study, by the surface modification of RENPs using PEI, we have developed a biologically well-tolerated formulation capable of detecting micrometastatic lesions with excellent signal-to-noise ratios and of carrying genetic cargo on its surface.…”