In vivo imaging of tumour angiogenesis in mice with the αvβ3 integrin-targeted tracer 99mTc-RAFT-RGD

Sancey, Lucie; Ardisson, Valérie; Riou, Laurent; Ahmadi, Mitra; Marti-Batlle, D.; Boturyn, Didier; Dumy, Pascal; Fagret, Daniel; Ghezzi, Cathérine; Vuillez, Jean‐Philippe

doi:10.1007/s00259-007-0497-z

Cited by 57 publications

(43 citation statements)

References 42 publications

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“…The development of multimeric RGD peptides to enhance specific uptake in integrin a v b 3 -expressing tumors through multidentate binding sites (36)(37)(38) was thought to reduce specific uptake in nontumor tissues. Despite the multimeric nature of 111 In-RGD 2 , uptake of the tracer was still visualized in these nontumor tissues, as seen in the biodistribution studies described here.…”

Section: Discussionmentioning

confidence: 99%

Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts

et al. 2014

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Arginine-glycine-aspartic acid (RGD)-based imaging tracers allow specific imaging of integrin a v b 3 , a protein overexpressed during angiogenesis, leading to the possibility that it might serve as a tool to stratify patients for antiangiogenic treatment. However, these tracers have generally been characterized in xenograft models in which integrin a v b 3 was constitutively expressed by the tumor cells themselves. In the studies presented here, the use of 111 In-RGD 2 as a tracer to image only integrin a v b 3 expression on blood vessels in the tumor was determined using tumor xenografts in which tumor cells were integrin a v b 3 -negative. Methods: DOTA-E-[c(RGDfK)] 2 was radiolabeled with 111 In ( 111 In-RGD 2 ), and biodistribution studies were performed in squamous cell carcinoma of the head and neck (HNSCC) xenograft mouse models to determine the optimal peptide dose to image angiogenesis. Next, biodistribution and imaging studies were performed at the optimal peptide dose in 3 HNSCC mouse models, FaDu, SCCNij3, and SCCNij202. Immunohistochemical analysis of tumor vascular and cell surface expression of integrin a v b 3 and correlation analysis of vascular integrin a v b 3 and autoradiography were completed. Results: All 3 HNSCC xenografts expressed integrin a v b 3 on the vessels only. The optimal peptide dose of 111 In-RGD 2 was 1 mg or less for specific integrin a v b 3 -mediated uptake of the tracer. SPECT/CT imaging showed clear uptake of the tracer in the periphery of the tumors, corresponding with wellvascularized areas of the tumor. Within the tumor, 111 In-RGD 2 autoradiography coincided with vascular integrin a v b 3 expression, as determined immunohistochemically. Integrin a v b 3 -mediated uptake was also detected in nontumor tissues, which, through immunohistochemical analysis, proved positive for integrin a v b 3 . Conclusion: 111 In-RGD 2 allows the visualization of integrin a v b 3 in xenograft models in which integrin a v b 3 is expressed only on the neovasculature, such as in the HNSCC tumors. Thus, 111 In-RGD 2 allows specific visualization of angiogenesis in tumor models lacking constitutive tumoral integrin a v b 3 expression but may be less useful for this purpose in many tumors in which tumor cells express integrin a v b 3 .

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Section: Discussionmentioning

confidence: 99%

Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts

et al. 2014

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“…TS/A-pc mice mammary carcinoma cells were cultured in RPMI 1640 supplemented with 1% glutamine, 10% FBS, 50 U/ml penicillin, and 50 g/ml streptomycin at 37°C in a humidified 95% air, 5% CO 2 atmosphere. These cells are integrin vb3 positive (Klepfish et al, 1993;Sancey et al, 2007).…”

Section: Cell Culturementioning

confidence: 99%

Bax-derived membrane-active peptides act as potent and direct inducers of apoptosis in cancer cells

Valero

Sancey

Kucharczak

et al. 2011

Journal of Cell Science

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SummaryAlthough many cancer cells are primed for apoptosis, they usually develop resistance to cell death at several levels. Permeabilization of the outer mitochondrial membrane, which is mediated by proapoptotic Bcl-2 family members such as Bax, is considered as a point of no return for initiating apoptotic cell death. This crucial role has placed Bcl-2 family proteins as recurrent targets for anticancer drug development. Here, we propose and demonstrate a new concept based on minimal active versions of Bax to induce cell death independently of endogenous Bcl-2 proteins. We show that membrane-active segments of Bax can directly induce the release of mitochondria-residing apoptogenic factors and commit tumor cells promptly and irreversibly to caspase-dependent apoptosis. On this basis, we designed a peptide encompassing part of the Bax pore-forming domain, which can target mitochondria, induce cytochrome c release and trigger caspase-dependent apoptosis. Moreover, this Bax-derived 'poropeptide' produced effective tumor regression after peritumoral injection in a nude mouse xenograft model. Thus, peptides derived from proteins that form pores in the mitochondrial outer membrane represent novel templates for anticancer agents.

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“…Note that we did not evaluate the absence of targeting with the RAFTc(RAD) 4 peptide because we have already tested this in many different tumor models, 27,29,34 including melanoma. 74 Tumor size was monitored every day, and tumor volume was calculated using the formula (short diameter)2 Â long diameter/2. The procedures for human cells were approved by the French Blood Service's Institutional Review Board.…”

Section: Biodistribution and Tumor Targeting In Vivomentioning

confidence: 99%

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

et al. 2017

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Melanoma is a highly metastatic and deadly form of cancer. Invasive melanoma cells overexpress integrin a v b 3 , which is a well-known target for Arg-Gly-Asp-based (RGD) peptides. We developed a sophisticated method to synthetize milligram amounts of a targeted vector that allows the RGD-mediated targeting, internalization, and release of a mitochondria-disruptive peptide derived from the pro-apoptotic Bax protein. We found that 2.5 mM Bax[109-127] was sufficient to destabilize the mitochondria in ten different tumor cell lines, even in the presence of the anti-apoptotic Bcl2 protein, which is often involved in tumor resistance. This pore-forming peptide displayed antitumor activity when it was covalently linked by a disulfide bridge to the tetrameric RAFT-c[RGD] 4 -platform and after intravenous injection in a human melanoma tumor model established in humanized immuno-competent mice. In addition to its direct toxic effect, treatment with this combination induced the release of the immuno-stimulating factor monocyte chimoattractant protein 1 (MCP1) in the blood and a decrease in the level of the pro-angiogenic factor FGF2. Our novel multifunctional, apoptosis-inducing agent could be further customized and assayed for potential use in tumortargeted therapy.

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In vivo imaging of tumour angiogenesis in mice with the αvβ3 integrin-targeted tracer 99mTc-RAFT-RGD

Abstract: (99m)Tc-RAFT-RGD allowed the in vivo imaging of alpha(v)beta(3) integrin tumour expression.

Cited by 57 publications

References 42 publications

Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts

Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts

Bax-derived membrane-active peptides act as potent and direct inducers of apoptosis in cancer cells

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

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In vivo imaging of tumour angiogenesis in mice with the αvβ3 integrin-targeted tracer 99mTc-RAFT-RGD

Abstract: (99m)Tc-RAFT-RGD allowed the in vivo imaging of alpha(v)beta(3) integrin tumour expression.

Cited by 57 publications

References 42 publications

Imaging Integrin αvβ3 on Blood Vessels with 111In-RGD2 in Head and Neck Tumor Xenografts

Imaging Integrin αvβ3 on Blood Vessels with 111In-RGD2 in Head and Neck Tumor Xenografts

Bax-derived membrane-active peptides act as potent and direct inducers of apoptosis in cancer cells

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

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Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts

Imaging Integrin α_vβ₃ on Blood Vessels with ¹¹¹In-RGD₂ in Head and Neck Tumor Xenografts