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Novel targeted mtLivin nanoparticles treatment for disseminated diffuse large B-cell lymphoma.
- Source :
-
Oncogene [Oncogene] 2021 Jan; Vol. 40 (2), pp. 334-344. Date of Electronic Publication: 2020 Oct 30. - Publication Year :
- 2021
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 40
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 33128043
- Full Text :
- https://doi.org/10.1038/s41388-020-01529-z