RESUMO
Treatments for cancer that incorporate small interfering RNA (siRNA) to target iron-dependent ferroptosis are thought to be highly promising. However, creating a reliable and clinically feasible siRNA delivery system continues to be a major obstacle in the field of cancer treatment. Here, three imidazole-based ionizable lipid nanoparticles (LNPs) with pH-sensitive effects are rationally designed and synthesized for siRNA delivery. LNPs formulated with the top-performing lipid (O12-D3-I3) encapsulating FVII siRNA (FVII@O-LNP) elicited greater gene silencing than those with the benchmark Onpattro lipid DLin-MC3-DMA (MC3) due to its stronger endosomal escape. Moreover, Fc-siRNA@O-LNPs encapsulated with ferrocene (Fc) and SLC7A11/Nrf2-targeted siRNA is formulated. The outcomes demonstrate optimal safety profiles and a significant anti-tumor effect by inducing long-lasting and efficient ferroptosis through a synergistic action in vivo. In summary, this work shows that imidazolyl lipid-prepared LNPs are efficient delivery vehicles for cancer therapy and ferroptosis-targeting siRNA administration, both of which have extensive clinical application potential.
RESUMO
Hexadimethrine bromide (HB), a synthetic polycationic species, was introduced to clinical practice as a heparin antidote and recently used in gene therapy. However, HB causes various complications such as severe red blood cells (RBCs) aggregation and tissue damage. Herein, we have synthesized a water-soluble quaterphen[3]arene containing multiple sulfonate moieties (SQP3) as a novel macrocyclic neutralizer to reverse HB via direct host-guest complexation. SQP3 exhibited a robust binding affinity toward HB with a considerably high association constant of (4.73 ± 0.61) × 107 M-1. Co-dosed with 1 equiv of SQP3, HB-induced RBCs aggregation and blood coagulation could be effectively reversed. In vitro cellular assay verified that complexation of HB with SQP3 significantly decreased reactive oxygen species production, thereby suppressing cell apoptosis. In vivo neutralization efficacy studies demonstrated that HB/SQP3 was capable of alleviating related organic damage caused by HB and improving the survival rate of HB-treated mice from 20 to 100%.