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![Representative static [⁶⁸Ga]Ga-HX01 PET/CT MIP images of BxPC-3, MCF-7, NOZ, HCC827, SK-OV-3, HCT-8, HuH-7, and NUGC-4 subcutaneous tumor models; BxPC-3 and U87 orthotopic tumor models (or carcinoma in situ, CIS) at 1 h p.i. of [⁶⁸Ga]Ga-HX01 (5.55 MBq). Tumors were indicated by white arrows (A). Semi-quantitative analysis of [⁶⁸Ga]Ga-HX01 PET/CT images of above tumors (B). Quantification of [⁶⁸Ga]Ga-HX01 uptake of above tumors. T/M (C) and T/B (D) of [⁶⁸Ga]Ga-HX01 in above tumors. Immunohistochemistry assay of CD13, the integrin ανβ3, and CD31 in BxPC-3, NOZ, HCC827, HCT-8, HuH-7, and NUGC-4 subcutaneous tumor models; BxPC-3 and U87 orthotopic tumor models (200 ×) (E). Data were expressed as mean ± SD (n = 4)](publication/373488519/figure/fig4/AS:11431281207477226@1701226295022/Representative-static-GaGa-HX01-PET-CT-MIP-images-of-BxPC-3-MCF-7-NOZ-HCC827.png)
Representative static [⁶⁸Ga]Ga-HX01 PET/CT MIP images of BxPC-3, MCF-7, NOZ, HCC827, SK-OV-3, HCT-8, HuH-7, and NUGC-4 subcutaneous tumor models; BxPC-3 and U87 orthotopic tumor models (or carcinoma in situ, CIS) at 1 h p.i. of [⁶⁸Ga]Ga-HX01 (5.55 MBq). Tumors were indicated by white arrows (A). Semi-quantitative analysis of [⁶⁸Ga]Ga-HX01 PET/CT images of above tumors (B). Quantification of [⁶⁸Ga]Ga-HX01 uptake of above tumors. T/M (C) and T/B (D) of [⁶⁸Ga]Ga-HX01 in above tumors. Immunohistochemistry assay of CD13, the integrin ανβ3, and CD31 in BxPC-3, NOZ, HCC827, HCT-8, HuH-7, and NUGC-4 subcutaneous tumor models; BxPC-3 and U87 orthotopic tumor models (200 ×) (E). Data were expressed as mean ± SD (n = 4)
Source publication
![A 90-min dynamic [⁶⁸Ga]Ga-HX01 PET/CT image of the BxPC-3 xenograft...](publication/373488519/figure/fig2/AS:11431281207477224@1701226294475/A-90-min-dynamic-GaGa-HX01-PET-CT-image-of-the-BxPC-3-xenograft-model-A_Q320.jpg)
![Gradient doses of [⁶⁸Ga]Ga-HX01 static representative PET/CT image of...](publication/373488519/figure/fig3/AS:11431281207477225@1701226294782/Gradient-doses-of-GaGa-HX01-static-representative-PET-CT-image-of-the-BxPC-3_Q320.jpg)
![Representative static [⁶⁸Ga]Ga-HX01 PET/CT MIP images of BxPC-3, MCF-7,...](publication/373488519/figure/fig4/AS:11431281207477226@1701226295022/Representative-static-GaGa-HX01-PET-CT-MIP-images-of-BxPC-3-MCF-7-NOZ-HCC827_Q320.jpg)
![PET/CT images and semi-quantitative analysis of [⁶⁸Ga]Ga-HX01 and...](publication/373488519/figure/fig5/AS:11431281207458022@1701226295434/PET-CT-images-and-semi-quantitative-analysis-of-GaGa-HX01-and-FFDG-in-BxPC-3_Q320.jpg)
Purpose:
The integrin αvβ3 and aminopeptidase N (APN/CD13) play vital roles in the tumor angiogenesis process. They are highly expressed in a variety of tumor cells and proliferating endothelial cells during angiogenesis, which have been considered as highly promising targets for tumor imaging. Arginine-glycine-aspartic (RGD) and asparagine-glycin...
Citations
... In our previous work, we developed a heterodimeric tracer, [ 68 Ga]Ga-NOTA-RGD-NGR ([ 68 Ga]Ga-HX01), which targets both integrin α v β 3 and APN. This tracer has exhibited a significant diagnostic potential in several tumor models [5,12]. Following these promising results, [ 68 Ga]Ga-HX01 has been approved by the Center for Drug Evaluation of NMPA for phase I clinical trials. ...
... This study has several limitations. First, our focus was primarily on screening radiopharmaceuticals through in vivo imaging, without conducting cell studies to assess their target specificity, since the targeting ligands have already been reported in previous research [5,12]. Second, we utilized only one type of mouse xenograft model. ...
Purpose
The advancement of heterodimeric tracers, renowned for their high sensitivity, marks a significant trend in the development of radiotracers for cancer diagnosis. Our prior work on [⁶⁸Ga]Ga-HX01, a heterodimeric tracer targeting CD13 and integrin αvβ3, led to its approval for phase I clinical trials by the China National Medical Production Administration (NMPA). However, its fast clearance and limited tumor retention pose challenges for broader clinical application in cancer treatment. This study aims to develop a new radiopharmaceutical with increased tumor uptake and prolonged retention, rendering it a potential therapeutic candidate.
Methods
New albumin binder-conjugated compounds were synthesized based on the structure of HX01. In vitro and in vivo evaluation of these new compounds were performed after labelling with ⁶⁸Ga. Small-animal PET/CT imaging were conducted at different time points at 0.5–6 h post injection (p.i.) using BxPC-3 xenograft mice models. The one with the best imaging performance was further radiolabeled with ¹⁷⁷Lu for small-animal SPECT/CT and ex vivo biodistribution investigation.
Results
We have synthesized novel albumin binder-conjugated compounds, building upon the structure of HX01. When radiolabeled with ⁶⁸Ga, all compounds demonstrated improved pharmacokinetics (PK). Small-animal PET/CT studies revealed that these new albumin binder-conjugated compounds, particularly [⁶⁸Ga]Ga-L6, exhibited significantly enhanced tumor accumulation and retention compared with [⁶⁸Ga]Ga-L0 without an albumin binder. [⁶⁸Ga]Ga-L6 outperformed [⁶⁸Ga]Ga-L7, a compound developed using a previously reported albumin binder. Furthermore, [¹⁷⁷Lu]Lu-L6 demonstrated rapid clearance from normal tissues, high tumor uptake, and prolonged retention in small-animal SPECT/CT and biodistribution studies, positioning it as an ideal candidate for radiotherapeutic applications.
Conclusion
A new integrin αvβ3 and CD13 targeting compound was screened out. This compound bears a novel albumin binder and exhibits increased tumor uptake and prolonged tumor retention in BxPC-3 tumors and low background in normal organs, making it a perfect candidate for radiotherapy when radiolabeled with ¹⁷⁷Lu.
Graphical abstract
An albumin binder-conjugated heterodimeric radiopharmaceutical was developed and evaluated, which exhibited high tumor uptake and long residence time in BxPC-3 tumors, positioning it as an ideal candidate for radiotherapy.
... 111 An instance of this can be observed in the case of integrin αvβ3, which is absent in the vasculature of normal tissues but exhibits significant expression on endothelial cells during instances of pathological angiogenesis, such as vascular regeneration following ischemic tissues and the neovascularization of tumors. 112,113 Consequently, this integrin can serve as a viable target for delivering therapeutic agents. The Arg-Gly-Asp (RGD) peptide functions as a ligand that specifically binds to the integrin αvβ3 receptor with high affinity. ...
Ischemic stroke, being a prominent contributor to global disability and mortality, lacks an efficacious therapeutic approach in current clinical settings. Neural stem cells (NSCs) are a type of stem cell that are only found inside the nervous system. These cells can differentiate into various kinds of cells, potentially regenerating or restoring neural networks within areas of the brain that have been destroyed. This review begins by providing an introduction to the existing therapeutic approaches for ischemic stroke, followed by an examination of the promise and limits associated with the utilization of NSCs for the treatment of ischemic stroke. Subsequently, a comprehensive overview was conducted to synthesize the existing literature on the underlying processes of neural stem cell-derived small extracellular vesicles (NSC-sEVs) transplantation therapy in the context of ischemic stroke. These mechanisms encompass neuroprotection, inflammatory response suppression, and endogenous nerve and vascular regeneration facilitation. Nevertheless, the clinical translation of NSC-sEVs is hindered by challenges such as inadequate targeting efficacy and insufficient content loading. In light of these limitations, we have compiled an overview of the advancements in utilizing modified NSC-sEVs for treating ischemic stroke based on current methods of extracellular vesicle modification. In conclusion, examining NSC-sEVs-based therapeutic approaches is anticipated to be prominent in both fundamental and applied investigations about ischemic stroke.
