1. Novel targeted mtLivin nanoparticles treatment for disseminated diffuse large B-cell lymphoma.
- Author
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Abd-Elrahman I, Nassar T, Khairi N, Perlman R, Benita S, and Ben Yehuda D
- Subjects
- Adaptor Proteins, Signal Transducing chemistry, Adaptor Proteins, Signal Transducing metabolism, Animals, Apoptosis, Cell Proliferation, Humans, Inhibitor of Apoptosis Proteins chemistry, Inhibitor of Apoptosis Proteins metabolism, Lymphoma, Large B-Cell, Diffuse metabolism, Lymphoma, Large B-Cell, Diffuse pathology, Male, Mice, Mice, Inbred NOD, Mice, SCID, Nanoparticles chemistry, Neoplasm Proteins chemistry, Neoplasm Proteins metabolism, Tumor Burden, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Adaptor Proteins, Signal Transducing administration & dosage, Gene Expression Regulation, Neoplastic, Inhibitor of Apoptosis Proteins administration & dosage, Lymphoma, Large B-Cell, Diffuse therapy, Nanoparticles administration & dosage, Neoplasm Proteins administration & dosage
- 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.
- Published
- 2021
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