Targeted design of a recombinant tracer for SPECT renal imaging

Abstract

Rationale: A robust radiopharmaceutical has high uptake in the target and low retention in non-target tissues. However, traditional tracers for renal imaging that chemically chelate 99m Tc are excreted through the renal route with transient resident time in the kidney. Following a rational design approach, we constructed a protein-based radiotracer, designated PBT-Fc, to sequentially bind tubular neonatal Fc-receptor and subsequently proximal tubular basement membrane for its targeted sequestration in kidney parenchyma. In this process, the tracer participates in physiologic glomerular filtration and tubular reabsorption while escaping lysosomal catabolism and urinary clearance. Methods: To specifically target renal receptors in navigating the urinary passage in the kidney, we produced a recombinant fusion protein with two separate functional parts: a polybasic PBT segment derived from human Vascular Endothelial Growth Factor and Fc segment of IgG1. The chimeric fusion of PBT-Fc was labeled with radionuclide 99m Tc and tested in rodent models of kidney diseases. Planar scintigraphy and single-photon emission computerized tomography (SPECT) were performed to evaluate renal-specificity of the tracer. Results: When injected in mouse and rat, following a brief 10 - 15 min dynamic redistribution phase in circulation, ~ 95% of the [ 99m Tc]-PBT-Fc signal was concentrated in the kidney and lasted for hours without urinary loss or surrounding tissue activities. Long-lasting tracer signals in the kidney cortex in conjunction with SPECT greatly augmented the image quality in detecting pathological lesions in a variety of disease models, including ischemic acute kidney injury, drug-induced renal toxicity, and chronic kidney disease from renin-angiotensin system (RAS) overactivation. Conclusion: Exclusive renal retention of the recombinant radiotracer greatly facilitated static-phase signal acquisition by SPECT and achieved submillimeter spatial resolution of kidney alternations in glomerular and tubular disease models.

Hydrogel and nanoparticle carriers for kidney disease therapy: trends and recent advancements

“…Nuclear imaging computed tomography (CT) techniques, such as single photon emission computed tomography (SPECT) and positron emission tomography (PET), can provide higher sensitivity due to lower detection limits with unrestricted depth of tissue penetration. CT scanning can facilitate the non-invasive imaging of NPs within the kidney in tandem with split renal function and clearance measurements [228]. However, widespread use of whole-body PET scanners is limited to specialist clinical institutions due to high installation and maintenance costs.…”

Emerging early diagnostic methods for acute kidney injury

“…Imaging diagnosis includes ultrasound, computed tomography etc. can assess kidney morphology and provide insights into the function, perfusion, and possible etiology for AKI 19 , 20 . However, these methods have disadvantages such as low resolution, radiation damage, and the potential risk of increased nephrotoxicity caused by contrast agents, and is not suitable for the diagnosis of early AKI.…”

In vivo assessment of hypertensive nephrosclerosis using ultrasound localization microscopy

“…Currently, in clinical practice, non‐invasive evaluation of renal perfusion is mainly carried out by renal dynamic imaging based on single photon emission‐computed tomography (SPECT) 15 . However, this method has poor spatial resolution and cannot observe the dynamic changes of renal cortex and medulla perfusion, respectively 16 . Other approaches of medical imaging such as contrast‐enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are incompetent in the diagnosis of CKD, because they have toxic side effects on renal function due to the nature of the contrast agent, and their resolution is not high enough to display the arterioles in the kidney 17 …”

“…15 However, this method has poor spatial resolution and cannot observe the dynamic changes of renal cortex and medulla perfusion, respectively. 16 Other approaches of medical imaging such as contrastenhanced computed tomography (CT) and magnetic resonance imaging (MRI) are incompetent in the diagnosis of CKD, because they have toxic side effects on renal function due to the nature of the contrast agent, and their resolution is not high enough to display the arterioles in the kidney. 17 Ultrasound imaging has become a preferred method for evaluating renal diseases because it is non-invasive, real-time, convenient, and suitable for multiple followups.…”