PLGA nanoparticle formulation of RK-33: an RNA helicase inhibitor against DDX3

Abstract

Background The DDX3 helicase inhibitor RK-33 is a newly developed anticancer agent that showed promising results in preclinical research (Bol et al. EMBO Mol Med, 7(5):648–649, 2015). However, due to the physicochemical and pharmacological characteristics of RK-33, we initiated development of alternative formulations of RK-33 by preparing sustained release nanoparticles that can be administered intravenously. Methods In this study, RK-33 was encapsulated in poly(lactic-co-glycolic acid) (PLGA), one of the most well-developed biodegradable polymers, using the emulsion solvent evaporation method. Results Hydrodynamic diameter of RK-33-PLGA nanoparticles was about 245 nm with a negative charge, and RK-33-PLGA nanoparticles had a payload of 1.4 % RK-33. RK-33 was released from the PLGA nanoparticles over 7 days (90 ± 5.7 % released by day 7) and exhibited cytotoxicity to human breast carcinoma MCF-7 cells in a time-dependent manner. Moreover, RK-33-PLGA nanoparticles were well tolerated, and systemic retention of RK-33 was markedly improved in normal mice. Conclusions PLGA nanoparticles have a potential as a parenteral formulation of RK-33.

A double-edged function of DDX3, as an oncogene or tumor suppressor, in cancer progression (Review)

“…PLGA nanoparticles loading with RK-33 may facilitate to overcome chemical hydrophobicity of RK-33. RK-33-PLGA nanoparticles exhibit cytotoxicity to human breast carcinoma MCF-7 cells in vitro, and a systemic retention of RK-33 is markedly improved in mice (79).…”

“…It is difficult for FE-15 to selectively recognize DDX3 due to the high homology between other similar RNA helicases. NZ51, one of ring-expanded nucleosides (REN), has been identified as a potential DDX3 inhibitor by abrogating the (32,35) DDX3 and block its helicase activity preferentially cytotoxic to to illustrate the direct interaction (40,45) cancer cells; act as a radio-of RK-33 with DDX3 (46,79) sensitizer; highly feasible unwinding activity of DDX3 helicase (74). NZ51 significantly inhibits cell motility and viability of breast cancer cells by targeting the ATP binding pocket domain of DDX3 (31).…”

“…Another small molecular inhibitor RK-33 has been demonstrated to bind with the ATP-binding domain of DDX3 to block its helicase activity in Ewing sarcoma, breast, colorectal, prostate and lung cancer cells (32,35,40,45,46,79). RK-33 causes cell cycle G1 arrest and cell apoptosis in DDX3-overexpressing cancer cells.…”

“…In contrast, DDX3 inhibitor RK-33 has been tried to be modify into a novel nanoparticle reagent for cancer. The poly (lactic-co-glycolic acid) (PLGA) encapsulated RK-33 nanoparticles are suitable for intravenous injection (79), which is a systemic delivery and controlled-release drug delivery (80). PLGA nanoparticles loading with RK-33 may facilitate to overcome chemical hydrophobicity of RK-33.…”

RNA Helicases as Shadow Modulators of Cell Cycle Progression

“…Most of the RNA helicases discussed here have become [ 133 ] or may become promising biomarkers or targets for the diagnosis, prognosis and treatment of viral diseases and cancers [ 134 , 135 ]. Small molecule inhibitors have already been developed and validated for the canonical translation initiation factor eIF4A: hypericin [ 136 ], hippuristanol [ 137 ], pateamine A [ 138 ], rocaglamides [ 139 ] and DDX3 (RK-33 [ 140 ]) and DDX5 (RX-5902 [ 141 ]) helicases. Among them, we want to highlight DDX3 as a confirmed target for cancer and antiviral therapy [ 142 ], while others, like DDX46, DHX9 and DDX5, are still poorly studied in this context.…”