Tumor-Specific Binding of Radiolabeled PEGylated GIRLRG Peptide: A Novel Agent for Targeting Cancers

Abstract

Cancer-specific targeting sparing normal tissues would significantly enhance cancer therapy outcomes and reduce cancer-related mortality. One approach is to target receptors or molecules that are specifically expressed on cancer cells. Peptides as cancer-specific targeting agents offer advantages such as ease of synthesis, low antigenicity, and enhanced diffusion into tissues. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum stress chaperone that regulates the unfolded protein response and is overexpressed in various cancers. In this study, we evaluated GIRLRG peptide that specifically targets GRP78 for cancer-specific binding (in vitro) and noninvasive tumor imaging (in vivo). Methods: GIRLRG peptide was modeled into the GRP78 ATPase domain using computational modeling. Surface plasmon resonance studies were performed to determine the affinity of GIRLRG peptide to GRP78 protein. GIRLRG was conjugated with PEG to prolong its circulation in mice. Tumor binding efficacy of PEG-GIRLRG peptide was evaluated in nude mice bearing heterotopic cervical (HT3), esophageal (OE33), pancreatic (BXPC3), lung (A549), and glioma (D54) tumors. Nano-SPECT/CT imaging of the mice was performed 48 and 72 h after injection with 111 In-labeled PEG-GIRLRG or PEG-control peptide. Post-SPECT biodistribution studies were performed 96 h after injection of the radiolabeled peptides. Results: Using molecular modeling and surface plasmon resonance, we identified that GIRLRG was binding with an affinity constant of 2.16 · 10 −3 M in the ATPase domain of GRP78. GIRLRG peptide specifically bound to cervical, lung, esophageal, and glioma cells. SPECT imaging revealed that 111 In-PEG-GIRLRG specifically bound to cervical, esophageal, pancreatic, lung, and brain tumors. Post-SPECT biodistribution data also validated the SPECT imaging results. Conclusion: GIRLRG peptide specifically binds to the ATPase domain of GRP78. Radiolabeled PEG-GIRLRG could be used to target various cancers. Further studies would be required to translate PEG-GIRLRG peptide into the clinic.

Impact of time-of-flight PET on quantification accuracy and lesion detection in simultaneous 18F-choline PET/MRI for prostate cancer

“…Our data demonstrate that TOF PET/MRI reconstruction results in higher SUV max measurements in physiological osseous structures as well as in lesions within the prostate, bones, and lymph nodes compared to non-TOF PET reconstructions. This is in concordance to preliminary data shown in an abstract by Mollard et al who also found higher SUV max in TOF reconstructions compared to non-TOF reconstructions in lesions in prostate patients with 18 F-choline [ 55 ] and is consistent with the findings of a simulation study of Mehranian et al [ 21 ].…”

Recent advances in the bioanalytical methods of polyethylene glycols and PEGylated pharmaceuticals

“…Since the intrinsic labeling does not alter the structure of the molecule and possesses fast identical physicochemical property to analytes, it can represent the pharmacokinetic behavior of the analytes precisely. Radiolabeling is commonly used in the studies of the in vivo absorption, distribution, metabolism, and excretion (ADME) processes of PEG [62,78,79], PEGylated small molecules [80], PEGylated peptides [81–83], PEGylated proteins [84–86], and PEGylated nanoparticles [10,87–93], which will be discussed in the following parts respectively.…”

PEGylated peptide to TIP1 is a novel targeting agent that binds specifically to various cancers in vivo

“…For all in vivo studies, DTPA-PEG-control and DTPA-PEG-HVGGSSV peptide were labeled with 111 Indium. The labeling efficiency was optimized by trying different temperatures, buffers, and pH as described earlier [26]. The best yield was obtained by carrying out all reactions under absolute metal-free condition.…”