A Near-Infrared Peptide Probe with Tumor-Specific Excretion-Retarded Effect for Image-Guided Surgery of Renal Cell Carcinoma

Abstract

Image-guided surgery plays a crucial role in realizing complete tumor removal, reducing postoperative recurrence and increasing patient survival. However, imaging of tumor lesion in the typical metabolic organs, e.g., kidney and liver, still has great challenges due to the intrinsic nonspecific accumulation of imaging probes in those organs. Herein, we report an in situ self-assembled near-infrared (NIR) peptide probe with tumor-specific excretion-retarded (TER) effect in tumor lesions, enabling high-performance imaging of human renal cell carcinoma (RCC) and achieving complete tumor removal, ultimately reducing postoperative recurrence. The NIR peptide probe first specifically recognizes αvβ3 integrin overexpressed in renal cancer cells, then is cleaved by MMP-2/9, which is up-regulated in the tumor microenvironment. The probe residue spontaneously self-assembles into nanofibers that exhibit an excretion-retarded effect in the kidney, which contributes to a high signal-to-noise (S/N) ratio in orthotopic RCC mice. Intriguingly, the TER effect also enables precisely identifying eye-invisible tiny lesions (<1 mm), which contributes to complete tumor removal and significantly reduces the postoperative recurrence compared with traditional surgery. Finally, the TER strategy is successfully employed in high-performance identification of human RCC in an ex vivo kidney perfusion model. Taken together, this NIR peptide probe based on the TER strategy is a promising method for detecting tumors in metabolic organs in diverse biomedical applications.

Peptide-Based Nanoassemblies in Gene Therapy and Diagnosis: Paving the Way for Clinical Application

“…Given appropriate conditions, a peptide comprising an RGD recognition motif for targeting integrins (which are highly expressed in renal cell carcinoma (RCC)), a cleavage site for matrix metalloproteinases (MMP)-2/9 (which are typically overexpressed in the tumor microenvironment), and an NIR moiety (Cy) for signaling, self-assembled to nanofibers in solution ( Figure 18) [188]. When injected into mice bearing orthotopic RCC xenografts, the RGD targeted the peptide monomers to the tumor where they were cleaved by MMP-2/9 and gradually self-assembled into nanofibers in situ.…”

“…(A) Modular molecular design of the NIR peptide and the self-assembly of the peptide after cleavage by MMP-2/9. (B) NIR fluorescence image of tumor-bearing human kidney tissue after ex vivo perfusion for 2 h. Adapted and modified from[188], with permission. Copyright: 2020 American Chemical Society.…”

Hyperfluorescence Imaging of Kidney Cancer Enabled by Renal Secretion Pathway Dependent Efflux Transport

“…Thenovel renal tubular secretion pathway of ICG-PEG45 made it possible to investigate whether the renal cell carcinoma, originating from the renal tubules,can be targeted by the molecules with strong interaction with proximal tubules.W ef irstly established orthotopic xenograft model of papillary RCC (pRCC), one type of RCC that is difficult to be targeted by both passive targeting agent (such as ICG) and active targeting agent (such as 111 In-DOTA-girentuximab-IRDye800CW, [14] 18 F-FB-mini-PEG-E[c(RGDyK)] [15] )due to its low expression of carbonic anhydrase IX (CAIX) or integrin. [16] Thepapillary RCC cell line (ACHN), transfected with luciferase-expression vector, were surgically implanted into subcapsular space of the left kidney of mice and the right kidney was kept normal for renal function (Figure 2a). When the RCC tumor developed to as ize that can be reliably detected in the left kidney by bioluminescent imaging,w e intravenously injected ICG-PEG45 into the mice and then conducted noninvasive in vivo fluorescence imaging.A s shown in Figure 2b and c, the fluorescence intensity observed from the contralateral right kidney initially (% within 1-5hours) was higher than that from left kidney with pRCC because ICG-PEG45 rapidly transported through the normally functionalized right kidney.A sI CG-PEG45 was gradually eliminated through the right normal kidney,t he fluorescence intensity observed from the left kidney with pRCC became higher than the contralateral one over time.…”

Biomaterials based on noncovalent interactions of small molecules

“…The dual targeting strategy, that is, the use of dual targeting motif (either ligands or enzymes), also applies in molecular imaging (Chen et al, 2019[ 9 ]; Hai et al, 2019[ 30 ]; An et al, 2020[ 3 ]). As reported by Zheng et al (2016[ 118 ]), a precursor ( 14 ) is able to differentiate the extra- and intracellular environment based on the dual targeting motifs that react with both extracellular ALP and intracellular glutathione (GSH), generating different orders of assemblies ( 15 and 16 ) (Figure 5C (Fig.…”