Prostate Cancer: Detection of Lymph Node Metastases Outside the Routine Surgical Area with Ferumoxtran-10–enhanced MR Imaging

171

143

With noncommunicable diseases (NCDs) now constituting the majority of global mortality, there is a growing need for low-cost, noninvasive methods to diagnose and treat this class of diseases, especially in resource-limited settings. Molecular biomarkers combined with low-cost point-of-care assays constitute a potential solution for diagnosing NCDs, but the dearth of naturally occurring, predictive markers limits this approach. Here, we describe the design of exogenous agents that serve as synthetic biomarkers for NCDs by producing urinary signals that can be quantified by a companion paper test. These synthetic biomarkers are composed of nanoparticles conjugated to ligand-encoded reporters via protease-sensitive peptide substrates. Upon delivery, the nanoparticles passively target diseased sites, such as solid tumors or blood clots, where up-regulated proteases cleave the peptide substrates and release reporters that are cleared into urine. The reporters are engineered for detection by sandwich immunoassays, and we demonstrate their quantification directly from unmodified urine; furthermore, capture antibody specificity allows the probes to be multiplexed in vivo and quantified simultaneously by ELISA or paper lateral flow assay (LFA). We tailor synthetic biomarkers specific to colorectal cancer, a representative solid tumor, and thrombosis, a common cardiovascular disorder, and demonstrate urinary detection of these diseases in mouse models by paper diagnostic. Together, the LFA and injectable synthetic biomarkers, which could be tailored for multiple diseases, form a generalized diagnostic platform for NCDs that can be applied in almost any setting without expensive equipment or trained medical personnel.protease nanosensor | urine biomarker | image-free diagnostic | engineered disease reporter | global health

Section: Discussionmentioning

confidence: 99%

Point-of-care diagnostics for noncommunicable diseases using synthetic urinary biomarkers and paper microfluidics

Warren

Kwong

Wood

et al. 2014

171

143

“…However, iron oxide-containing contrast media are in clinical use (39,40), and both we and others (41) are developing micrometer-sized biodegradable particles. Smaller iron oxide particles, such as superparamagnetic particles of iron oxide (SPIO) and ultrasmall SPIO (USPIO), cannot be used for this application owing, in part, to their long half-life (42), which precludes rapid molecular imaging of target-specific binding because of high background levels.…”

Section: Discussionmentioning

confidence: 99%

Molecular MRI enables early and sensitive detection of brain metastases

Serres

Soto

Hamilton

et al. 2012

129

Metastasis to the brain is a leading cause of cancer mortality. The current diagnostic method of gadolinium-enhanced MRI is sensitive only to larger tumors, when therapeutic options are limited. Earlier detection of brain metastases is critical for improved treatment. We have developed a targeted MRI contrast agent based on microparticles of iron oxide that enables imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Our objectives here were to determine whether VCAM-1 is up-regulated on vessels associated with brain metastases, and if so, whether VCAM-1-targeted MRI enables early detection of these tumors. Early up-regulation of cerebrovascular VCAM-1 expression was evident on tumor-associated vessels in two separate murine models of brain metastasis. Metastases were detectable in vivo using VCAM-1-targeted MRI 5 d after induction (<1,000 cells). At clinical imaging resolutions, this finding is likely to translate to detection at tumor volumes two to three orders of magnitude smaller (0.3-3 × 10 5 cells) than those volumes detectable clinically (10 7 -10 8 cells). VCAM-1 expression detected by MRI increased significantly (P < 0.0001) with tumor progression, and tumors showed no gadolinium enhancement. Importantly, expression of VCAM-1 was shown in human brain tissue containing both established metastases and micrometastases. Translation of this approach to the clinic could increase therapeutic options and change clinical management in a substantial number of cancer patients.

“…By contrast, signal curves broadened and increased in magnitude when the administered dose of NPs (N, Fig. 3D) was increased from 2.5 μM (∼0.5 mg/kg) to 20 μM (∼4 mg/kg)-a range of concentrations for iron oxide nanomaterials that are well-tolerated in humans (30,31). Intuitively, larger substrate reservoirs are created at higher NP doses, consequently prolonging and extending peak signal intensities.…”

Section: Significancementioning

confidence: 98%

Mathematical framework for activity-based cancer biomarkers

Kwong

Dudani

Carrodeguas

et al. 2015

Advances in nanomedicine are providing sophisticated functions to precisely control the behavior of nanoscale drugs and diagnostics. Strategies that coopt protease activity as molecular triggers are increasingly important in nanoparticle design, yet the pharmacokinetics of these systems are challenging to understand without a quantitative framework to reveal nonintuitive associations. We describe a multicompartment mathematical model to predict strategies for ultrasensitive detection of cancer using synthetic biomarkers, a class of activity-based probes that amplify cancerderived signals into urine as a noninvasive diagnostic. Using a model formulation made of a PEG core conjugated with protease-cleavable peptides, we explore a vast design space and identify guidelines for increasing sensitivity that depend on critical parameters such as enzyme kinetics, dosage, and probe stability. According to this model, synthetic biomarkers that circulate in stealth but then activate at sites of disease have the theoretical capacity to discriminate tumors as small as 5 mm in diameter-a threshold sensitivity that is otherwise challenging for medical imaging and blood biomarkers to achieve. This model may be adapted to describe the behavior of additional activity-based approaches to allow cross-platform comparisons, and to predict allometric scaling across species.compartmental modeling | activity-based probes | cancer diagnostics | urine biomarkers | nanomedicine T he clinical management of cancer is increasingly dependent on the discovery of new biomarkers and the development of ultrasensitive technologies to detect them at a stage when therapeutic interventions may be effective (1, 2). However, despite their growing importance, biomarkers lack predictive power to impact patient outcomes during the earliest stages of disease. The challenges are multifaceted: Biomarkers are shed from tumors at rates that vary by four orders in magnitude (3), are significantly diluted in blood, and circulate for short periods. Recent mathematical studies showed that tumors may remain undetectable with blood biomarkers for an entire decade following tumorigenesis, reaching 1-2.5 cm in diameter (4, 5). To increase sensitivity, major research areas include the development of ultrasensitive in vitro diagnostic platforms (6-11), as well as methods to increase biomarker production by solid tumors (12, 13). These approaches are designed to measure the quantity, or abundance, of a disease biomarker.In contrast to abundance-based methods, activity-based probes are a class of agents that are administered in prodiagnostic form but produce strong diagnostic signals after enzymatic activation (14, 15). These approaches rely on disease-associated enzymes as catalysts to produce a detection signal, of which proteases are particularly potent because the cleavage of peptide bonds is irreversible, and a single protease can cleave many substrates to amplify signals. However, activity-based probes operate within a narrow time window and are activated by offtarget...