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WIREs Nanomed Nanobiotechnol
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A path toward the clinical translation of nano‐based imaging contrast agents

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Abstract Recently, nanoparticles have evolved ubiquitously in therapeutic applications to treat a range of diseases. Despite their regular use as therapeutic agents in the clinic, we have yet to see much progress in their clinical translation as diagnostic imaging agents. Several clinical and preclinical studies support their use as imaging contrast agents, but their use in the clinical setting has been limited to off‐label imaging procedures (i.e., Feraheme). Since diagnostic imaging has been historically used as an exploratory tool to rule out disease or to screen patients for various cancers, nanoparticle toxicity remains a concern, especially when introducing exogenous contrast agents into a potentially healthy patient population, perhaps rationalizing why several nano‐based therapeutic agents have been clinically translated before nano‐based imaging agents. Another potential hindrance toward their clinical translation could be their market potential, as most therapeutic drugs have higher earning potential than small‐molecule imaging contrast agents. With these considerations in mind, perhaps a clinical path forward for nano‐based imaging contrast agents is to help guide/manage therapy. Several studies have demonstrated the ability of nanoparticles to produce more accurate imaging preoperatively, intraoperatively, and postoperatively. These applications illustrate a more reliable method of cancer detection and treatment that can prevent incomplete tumor resection and incorrect assessment of tumor progression following treatment. The aim of this review is to highlight the research that supports the use of nanoparticles in biomedical imaging applications and offer a new perspective to illustrate how nano‐based imaging agents have the potential to better inform therapeutic decisions. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Advantages of using nanoparticles. (a) Leaky vasculature of tumors allows for passive extravasation of nanoparticles into the tumor space. The nanoparticle's larger size allows for retention of imaging contrast unlike small molecule dyes which are quickly cleared. The larger size of nanoparticles causes them to remain in the tumor for a longer period of time than small molecules, enabling an extended window of time for imaging. (b) Active tumor targeting is enhanced with nanoparticles due to multiple binding events with receptors
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(a) After tumor‐bearing mice were treated with Abraxane, Ferumoxytol was used in T2‐weighted MR images to monitor tumor response. Hypointensity was observed when compared to untreated group, signaling high TAM activity (adapted with permission from Cao et al., 2018, ©2018, Biomaterials published by Elsevier Ltd.). (b) Two 89Zr‐labeled nanoparticles were injected into mouse models with breast cancer tumors. PET/CT images showed high accumulation in tumors, indicating tumor‐associated macrophage activity (adapted with permission from Perez‐Medina et al., 2015, ©2015, Journal of Nuclear Medicine). (c) Iron‐oxide nanoparticles targeting malignant endothelium cells were imaged with T2‐weighted MR for treated and untreated mice. No dark contrast was apparent for the treated group, confirming efficacy of VEGF121/rGel (adapted with permission from Zhang et al., 2012, ©2012, Biomaterials published by Elsevier Ltd.)
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(a) A triple‐modality approach incorporating MRI, photoacoustic imaging, and Raman imaging was used to guide the resection of glioblastoma tumors in mice. MRI was used for pre‐surgical preparation, photoacoustic imaging was used for the gross resection steps, and Raman imaging used to remove any remaining microscopic tumor deposits and to confirm accurate and complete resection of the tumor (adapted with permission from Kircher et al., 2012, ©2012, Nature Medicine). (b) A handheld near infrared (NIR) fluorescence spectroscopic device was used to image pancreatic tumors. The tumors were imaged in mouse models using hyaluronic acid nanoformulations encapsulating ICG, called NanoICG, and with ICG. The use of NanoICG expressed fluorescence signal intensity 2.2 times greater than that of ICG (adapted with permission from Qi et al., 2018, ©2018, Nanomedicine: Nanotechnolgy, Biology and Medicine published by Elsevier Ltd.). (c) Lanthanide‐based downconversion nanoparticles (DCNPs) were used as contrast agents in fluorescence imaging to guide the removal of metastatic ovarian cancer tumors. The optimal time for the removal of these tumors when signal reaches a relative steady‐state is between 20 and 28 h after injection of the nanoparticles (adapted with permission from Wang et al., 2018, ©2018, Nature Communications published by Springer Nature). (d) SERS nanoparticles were topically applied to breast cancer tumors. A Raman‐encoded molecular imaging (REMI) modality was used to accurately image and quantify multiple strains of biomarkers with high sensitivity and specificity in a process that takes under 15 min (adapted with permission from Y. W. Wang, Reder, et al., 2017, ©2017, Cancer Research)
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(a,b) On T1‐weighted MR images, gadolinium and Ferumoxytol both enhanced the melanoma metastatic lesion (yellow arrows) in the brain. (c,d) In another patient's MR images, gadolinium enhanced the benign meningioma (yellow arrows) in the brain while Ferumoxytol did not. Both Ferumoxytol and gadolinium enhanced the glioblastoma lesion (black arrow). This indicates that Ferumoxytol may be better than gadolinium at differentiating between healthy and diseased tissue (adapted with permission from Toth et al., 2017, ©2017, Kidney International published by Elsevier, Inc)
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Nanoparticle type and delivery considerations for reduced toxicity and accelerated clinical translation. (a) Various administration routes are available to deliver nanoparticles more effectively. The ability of nanoparticles to degrade in the body will likely determine the most suitable delivery method. (b) Since systemic toxicity and prolonged retention are major concerns with nanoparticles, biodegradable nanoparticles are more favorable for intravenous administration. (c) Non‐biodegradable nanoparticles can still be useful for clinical applications when delivered topically to local areas of interest
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