Nanoparticle Delivery of CD147 Antagonistic Peptide-9 Protects against Acute Ischemic Brain Injury and tPA-Induced Intracerebral Hemorrhage in Mice

Abstract

CD147 has emerged as a potential therapeutic target in many human diseases. We have demonstrated that inhibition of CD147 using its function-blocking antibody ameliorates acute ischemic brain injury and promotes long-term functional recovery in mice. Recently, peptide–nanoparticle conjugates have emerged as powerful tools for biomedical applications. The present study aimed to investigate the therapeutic potential of CD147 antagonist peptide-9 (AP9) in acute ischemic stroke in mice using nanomaterial as the drug delivery vehicles. AP9-conjugated nanoparticles (APN), with an average size of about 40 nm, were fabricated by maleimide linkage and characterized using dynamic light scattering and transmission electron microscopy. We found that APN specifically bound to CD147 in cultured mouse brain endothelial cells (bEnd.3) and to ischemia-induced CD147 in mouse cerebral microvessels. Using a mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated, for the first time, that systemic delivery of APN (2.5 mg/kg, I.V.) initiated at 1 h after tMCAO significantly reduced brain infarct size, improved functional outcome, and attenuated delayed (5 h after tMCAO) tPA-induced intracerebral hemorrhage in acute ischemic stroke. These protective effects were associated with profound inhibition of MMP-9 and MMP-3 in both ischemic brain and plasma. In conclusion, the CD147 antagonist peptide-9 represents a potentially promising therapeutic candidate for the treatment of ischemic stroke.

Neuroinflammation and anti-inflammatory therapy for ischemic stroke

“… The administration of APN via intravenous injection at a dose of 2.5 mg/kg led to an improvement in acute stroke outcome on the third day. [ 145 ] αCD147 mice, tMCAO once daily i.v. Injection for 3 days beginning 4 h after ischemia onset.…”

Extracellular matrix metalloproteinase inducer in brain ischemia and intracerebral hemorrhage

“…AP9 can target EMMPRIN to prevent cancer invasion and metastasis ( 87 , 88 ). A recent study showed that AP9, likely through inhibition of EMMPRIN-mediated MMP-2/-9 activation and ECM degradation, attenuates ischemia/reperfusion injury in an experimental model of acute myocardial infarction ( 89 ), and inhibits MMP-9 and MMP-3 in the ischemic brain and plasma ( 90 ).…”

Therapeutic Nanoparticles for the Different Phases of Ischemic Stroke

“…It is known that MMP-9 is able to induce BBB leakage by interfering with brain endothelial cell tight junctions [101]. Thus, MMP-9 silencing and/or its direct inhibition could result in an interesting treatment for hyperacute stroke [69][70][71]. In this regard, NPs conjugated or loaded with an MMP-9 inhibiting peptide [69], tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) [70], or CD147 antagonist peptide-9 [71] were able to cross the BBB and inhibit MMP-9 [69].…”