Engineered nanoconjugates for simultaneous detection and degradation of stroke-associated microthrombi

Area of Science:

• Biomedical Engineering
• Nanomedicine
• Neuroscience

Background:

• Microthrombi in acute ischemic stroke (AIS) pose significant treatment and imaging challenges.
• Current methods struggle to visualize and effectively treat these microvascular occlusions.

Purpose of the Study:

• To develop and evaluate a novel theranostic agent, IO@PDA@tPA, for simultaneous imaging and treatment of AIS microthrombi.
• To assess the efficacy and safety of IO@PDA@tPA in preclinical models, including diabetic mice.

Main Methods:

• Developed IO@PDA@tPA by conjugating recombinant tissue-type plasminogen activator (r-tPA) onto iron oxide nanoparticles coated with polydopamine.
• Assessed in vitro fibrinolytic activity and in vivo efficacy in a mouse model of ischemic stroke.
• Utilized T2*-weighted MRI for microthrombi visualization and assessed lesion size, recanalization, and hemorrhagic transformation at 24 hours post-stroke.

Main Results:

• IO@PDA@tPA successfully visualized and degraded microthrombi in vivo at one-quarter the standard r-tPA dose, confirmed by T2*-weighted MRI.
• Treatment significantly reduced lesion size, promoted recanalization, and demonstrated efficacy comparable to r-tPA in diabetic mice without increasing hemorrhagic risk.
• Full functional recovery was observed within five days, and the agent mitigated inflammatory processes.

Conclusions:

• IO@PDA@tPA is a promising theranostic agent for targeting microthrombi in AIS.
• The agent enables dose reduction of r-tPA and minimizes associated side effects, offering a potential advancement in stroke treatment.
• This theranostic approach holds potential for improved diagnosis and therapy of ischemic stroke.