Metal ion-responsive nanocarrier derived from phosphonated calix[4]arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage

Abstract

Primary intracerebral hemorrhage (ICH) is a leading cause of long-term disability and death worldwide. Drug delivery vehicles to treat ICH are less than satisfactory because of their short circulation lives, lack of specific targeting to the hemorrhagic site, and poor control of drug release. To exploit the fact that metal ions such as Fe 2+ are more abundant in peri-hematomal tissue than in healthy tissue because of red blood cell lysis, we developed a metal ion-responsive nanocarrier based on a phosphonated calix[4]arene derivative in order to deliver the neuroprotective agent dauricine (DRC) specifically to sites of primary and secondary brain injury. The potential of the dauricine-loaded nanocarriers for ICH therapy was systematically evaluated in vitro and in mouse models of autologous whole blood double infusion. The nanocarriers significantly reduced brain water content, restored blood-brain barrier integrity and attenuated neurological deficits by inhibiting the activation of glial cells, infiltration by neutrophils as well as production of proinflammatory factors (IL-1β, IL-6, TNF-α) and matrix-metalloprotease-9. These results suggest that our dauricine-loaded nanocarriers can improve neurological outcomes in an animal model of ICH by reducing inflammatory injury and inhibiting apoptosis and ferroptosis.

Paeonol inhibits the progression of intracerebral haemorrhage by mediating the HOTAIR/UPF1/ACSL4 axis

“…In addition, it has been previously confirmed that ferroptosis is involved in the progression of ICH (Z. Li et al., 2020 ; Mohammed Thangameeran et al., 2020 ), and this background indicates that ferroptosis is a key process in ICH-induced neuronal injury. A previous report showed that PAN inhibited the progression of inflammation and cancer (M. Cai et al., 2020 ; Shi et al., 2020 ; J. J.…”

“… Zhang et al., 2020 ). Li M et al indicated that inhibition of ferroptosis can attenuate the progression of ICH (M. Li et al., 2020 ). Based on this background, we speculated that activation of ferroptosis can lead to progression of ICH.…”

Cepharanthine Attenuates Early Brain Injury after Subarachnoid Hemorrhage in Mice via Inhibiting 15-Lipoxygenase-1-Mediated Microglia and Endothelial Cell Ferroptosis

“…The amphipathic nature of CEP facilitates its permeability through the cell membrane and interaction with lipophilic compounds [ 25 ]. More recently, another BBIQ, dauricine, was reported to inhibit ferroptosis after ICH by loading with a nanocarrier [ 28 ]. Accordingly, we assume that CEP is another potential drug to alleviate ferroptosis and provide neuroprotection via the inhibition of ALOX15 expression.…”

Zinc Sulfide-Based Hybrid Exosome-Coated Nanoplatform for Targeted Treatment of Glioblastoma in an Orthotopic Mouse Glioblastoma Model

“…After completion of the SDS PAGE, the gel was transferred to PVDF membrane for the transfer of protein by the Western-blot method as described in our recent publications. [24] PVDF membrane was treated with primary antibodies β-Actin and CD9, CD63, hsp 70, LC3-I and II, SQSTM1/p62, GADPH (Santa Cruz) along with HRP conjugated anti-mouse IgG secondary antibody (Cell signaling). The membrane was further developed using Signal Fire ECL TM Reagent and immediately imaged for chemiluminescence by Bio-imager (Kodak).…”