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- Title
Targeted Silencing of NRF2 by rituximab-conjugated nanoparticles increases the sensitivity of chronic lymphoblastic leukemia cells to Cyclophosphamide.
- Authors
Khodakarami, Atefeh; Kashani, Mahsa Afsari; Nazer, Atefeh; Kheshti, Armin Mahmoudsalehi; Rashidi, Bentolhoda; Karpisheh, Vahid; Masjedi, Ali; Abolhasani, Shiva; Izadi, Sepideh; Bagherifar, Rafieh; Hejazian, Seyyed Sina; Mohammadi, Hamed; Movassaghpour, AliAkbar; Feizi, Abbas Ali Hosseinpour; Hojjat-Farsangi, Mohammad; Jadidi-Niaragh, Farhad
- Abstract
Background: Targeting influential factors in resistance to chemotherapy is one way to increase the effectiveness of chemotherapeutics. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway overexpresses in chronic lymphocytic leukemia (CLL) cells and appears to have a significant part in their survival and chemotherapy resistance. Here we produced novel nanoparticles (NPs) specific for CD20-expressing CLL cells with simultaneous anti-Nrf2 and cytotoxic properties. Methods: Chitosan lactate (CL) was used to produce the primary NPs which were then respectively loaded with rituximab (RTX), anti-Nrf2 Small interfering RNA (siRNAs) and Cyclophosphamide (CP) to prepare the final version of the NPs (NP-Nrf2_siRNA-CP). All interventions were done on both peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMNCs). Results: NP-Nrf2_siRNA-CP had satisfying physicochemical properties, showed controlled anti-Nrf2 siRNA/CP release, and were efficiently transfected into CLL primary cells (both PBMCs and BMNCs). NP-Nrf2_siRNA-CP were significantly capable of cell apoptosis induction and proliferation prevention marked by respectively decreased and increased anti-apoptotic and pro-apoptotic factors. Furthermore, use of anti-Nrf2 siRNA was corresponding to elevated sensitivity of CLL cells to CP. Conclusion: Our findings imply that the combination therapy of malignant CLL cells with RTX, CP and anti-Nrf2 siRNA is a novel and efficient therapeutic strategy that was capable of destroying malignant cells. Furthermore, the use of NPs as a multiple drug delivery method showed fulfilling properties; however, the need for further future studies is undeniable. BBVrWc4UysbSA-bTREcqrz Video Abstract
- Subjects
FLUDARABINE; NUCLEAR factor E2 related factor; CHRONIC leukemia; LYMPHOBLASTIC leukemia; NANOMEDICINE; MONONUCLEAR leukocytes; CHRONIC lymphocytic leukemia
- Publication
Cell Communication & Signaling, 2023, Vol 21, Issue 1, p1
- ISSN
1478-811X
- Publication type
Article
- DOI
10.1186/s12964-023-01213-1