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Novel targeted mtLivin nanoparticles treatment for disseminated diffuse large B-cell lymphoma

Oncogene volume 40, pages 334–344 (2021)Cite this article

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Abstract

We previously showed that Livin, an inhibitor of apoptosis protein, is specifically cleaved to produce a truncated protein, tLivin, and demonstrated its paradoxical proapoptotic activity. We further demonstrated that mini-tLivin (MTV), a 70 amino acids derivative of tLivin, is a proapoptotic protein as potent as tLivin. Based on these findings, in this study we aimed to develop a venue to target MTV for the treatment of diffuse large B-cell lymphoma (DLBCL). MTV was conjugated to poly (lactide-co-glycolic acid) surface-activated nanoparticles (NPs). In order to target MTV-NPs we also conjugated CD40 ligand (CD40L) to the surface of the NPs and evaluated the efficacy of the bifunctional CD40L-MTV-NPs. In vitro, CD40L-MTV-NPs elicited significant apoptosis of DLBCL cells. In a disseminated mouse model of DLBCL, 37.5% of MTV-NPs treated mice survived at the end of the experiment. Targeting MTV-NPs using CD40L greatly improved survival and 71.4% of these mice survived. CD40L-MTV-NPs also greatly reduced CNS involvement of DLBCL. Only 20% of these mice presented infiltration of lymphoma to the brain in comparison to 77% of the MTV-NPs treated mice. In a subcutaneous mouse model, CD40L-MTV-NPs significantly reduced tumor volume in correlation with significant increased caspase-3 activity. Thus, targeted MTV-NPs suggest a novel approach to overcome apoptosis resistance in cancer.

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Fig. 1: MTV-NPs induce apoptosis of OCI-LY19 DLBCL cells in vitro.
Fig. 2: Targeted CD40L-MTV-NPs induce apoptosis of OCI-LY19 DLBCL cells in vitro.
Fig. 3: In a xenograft mouse model, human OCI-LY19-GLuc DLBCL cells disseminate mainly to the brain and bone marrow.
Fig. 4: MTV-NPs with and without CD40L inhibit tumor growth in the in vivo disseminated DLBCL mouse model.
Fig. 5: CD40L-MTV-NPs inhibit dissemination of OCI-LY19-GLuc tumor cells to the BM and brain.
Fig. 6: CD40L-MTV-NPs induce apoptotic tumor cell death and improve survival of mice with DLBCL subcutaneous tumors.

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Acknowledgements

We thank Galina Skarzinski for immunohistochemistry. This work was supported by Kamin Incentive Program, Israel Innovation Authority (DBY and SB), Dorot foundation (DBY), Eleanor Fox (DBY), and Aleen and David M. Epstein Fund for Hematology/oncology research (DBY).

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Authors and Affiliations

  1. Department of Hematology, Hadassah Medical Organization, Jerusalem, Israel

    Ihab Abd-Elrahman, Noha Khairi, Riki Perlman & Dina Ben Yehuda

  2. The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    Taher Nassar & Simon Benita

  3. Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    Dina Ben Yehuda

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Abd-Elrahman, I., Nassar, T., Khairi, N. et al. Novel targeted mtLivin nanoparticles treatment for disseminated diffuse large B-cell lymphoma. Oncogene 40, 334–344 (2021). https://doi.org/10.1038/s41388-020-01529-z

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