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 Fe2+ 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 pro-inflammatory 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.
Highlights
Primary intracerebral hemorrhage (ICH) is the most devastating type of stroke [1]
Transmission electron microscopy images showed that PCa4C12 micelles (PM) were uniformly spherical in shape and homogeneous in size (Fig. 1c), while size distribution of DPM micelles became larger after loaded with DRC (Fig. 1d), in line with the DLS data
Our results suggest that DPM can alleviate primary and secondary brain injury driven by apoptosis and ferroptosis
Summary
Primary intracerebral hemorrhage (ICH) is the most devastating type of stroke [1]. It affects 2 million people worldwide each year and is associated with high disability and mortality rates, which have not changed substantially for decades. Individuals who suffer ICH have poor prognosis mainly because of secondary brain injuries after the stroke, including hematoma toxicity, oxidative. A neuroprotective agent that may help mitigate secondary stroke injury is the isoquinoline alkaloid dauricine. The micelles release dauricine in response to abundant F e2+ at sites of primary and secondary brain injury. DRC on its own shows poor oral absorption, high rate of metabolism and rapid systemic elimination, which means its actual concentration at hemorrhagic sites is very low [9]
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