Multivalent fusion protein targeting VEGFR2 and DR5 receptors: assessing the antiangiogenic and antitumor effects via multimodal microangiography

Druzhkova, I.N.; Orlova, A.G.; Fedulova, A.S.; Avakiants, A.V.; Isakova, A.A.; Kukovyakina, E.V.; Zijian, Y.; Plotnikova, E.A.; Trunova, G.V.; Pankratov, A.A.; Plekhanov, A.A.; Kurnikov, A.A.; Subochev, P.V.; Shaytan, A.K.; Gasparian, M.E.; Kirpichnikov, M.P.; Dolgikh, D.A.; Razansky, D.; Yagolovich, A.V.

Авторы: Druzhkova Irina N., Orlova Anna G., Fedulova Anastasiia S., Avakiants Arina V., Isakova Alina A., Kukovyakina Ekaterina V., Zijian Yuan, Plotnikova Ekaterina A., Trunova Galina V., Pankratov Andrey A., Plekhanov Anton A., Kurnikov Alexey A., Subochev Pavel V., Shaytan Alexey K., Gasparian Marine E., Kirpichnikov Mikhail P., Dolgikh Dmitry A., Razansky Daniel, Yagolovich Anne V.
Журнал: Journal of Translational Medicine
Том: 23
Номер: 1
Год издания: 2025
Издательство: BioMed Central
Местоположение издательства: London
Номер статьи: 949
DOI: 10.1186/s12967-025-06859-8
Аннотация: BackgroundAnti-angiogenic therapy is a clinically validated method for cancer treatment. It was previously revealed that concurrent targeting of angiogenic and death receptor signaling pathways by a multivalent DR5-specific cytokine TRAIL variant DR5-B genetically fused with the effector peptides, SRH-DR5-B-iRGD, enhances solid tumor suppression and prolongs survival. The SRH peptide is aimed at blocking the tumor neoangiogenesis by preventing activation of the VEGFR2 receptor, while the iRGD peptide interferes with the activation of integrin αvβ3, and enhances the tumor penetration. Here, we investigated how the antiangiogenic activity of the SRH-DR5-B-iRGD fusion protein contributes to its antitumor effects.MethodsAn integrated approach has been applied involving molecular modeling of SRH-DR5-B-iRGD binding to DR5 receptor, optoacoustic (OA) and optical coherence tomography-based microangiography (OCT-MA) imaging of the vessel networks in xenografts of human glioblastoma and pancreatic adenocarcinoma in nude mice, supported by immunohistochemical (IHC) staining for vascularization marker CD31, and in vitro and in vivo bioactivity studies.ResultsMolecular modeling has demonstrated that genetic fusion of DR5-B with the SRH and iRGD peptides not only enables the engagement of additional tumor targets VEGFR2 and integrin αvβ3/NRP-1, but also improves the interaction with DR5 receptor. OA imaging of the vessel network in xenograft tumor nodes of human glioblastoma and pancreatic adenocarcinoma displayed a decrease in the vessel fraction in DR5-B-treated xenograft tumors, with the effect being even more pronounced in SRH-DR5-B-iRGD-treated tumor nodes. This data was consistent with the reduction in the number of perfused vessels in DR5-B and SRH-DR5-B-iRGD-treated tumors as quantified by OCT-MA, and also correlate well with the data obtained by IHC staining and tumor growth inhibition.ConclusionAmeliorated interaction with the DR5 receptor and imparting antiangiogenic properties to the multivalent fusion protein SRH-DR5-B-iRGD resulted in improved antitumor activity compared to DR5-B. Thereby, SRH-DR5-B-iRGD can be considered as a promising candidate for the treatment of vascularized solid tumors.
Добавил в систему: Яголович Анна Валерьевна

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