Probing the drug delivery strategies in ischemic stroke therapy

Figures & data

Figure 1. Therapeutic approaches for ischemic stroke.

Table 1. This table summarizes clinical therapeutic approaches for treating ischemic stroke.

Drug category	Medicines	Time window	Ref
Thrombolytics	Reteplase (r-tPA)	3–6 h after symptom onset	(Qureshi et al., 2005)
	Tenecteplase (TNK)		(Parsons et al., 2012)
Anticoagulants	Heparin	24 h after symptom onset	(Shrestha et al., 2017)
	warfarin
Fibrin-Modulators	Defibrase	3–6 h after symptom onset	(Wei et al., 2006)
	Batroxobin
Antiplatelets	Aspirin	24 h after symptom onset	(Su et al., 2015)
	Clopidogrel
Neuroprotectants	Edaravone	24 h after symptom onset	(Kikuchi et al., 2013)
	Lovastatin		(Elkind et al., 2008)

Figure 2. Brain reactions in different phase after stroke onset.

Figure 3. The structure of the blood-brain barrier (BBB).

Figure 4. Transporters expressed in the BBB and they facilitate key nutrient molecules exchange between brain and blood.

Figure 5. Overview of different strategies for drug delivery targeting ischemic stroke.

Table 2. Pharmaceutical methods for drug delivery to ischemic stroke.

Drugs applied	Highlights	Effects	Ref
Liposomes
Cytidine-5′-diphosphocholine	Increased BBB permeability and preferentially accumulated in the ischemic area	Improved the local effective delivered and enhanced neuroprotective effects	(Liu et al., 2016)
Withania somnifera, fasudil, tacrolimus, ethylacetate fraction	Increased BBB permeability	Enhanced brain delivery efficiency and neuroprotective effects	(Fukuta et al., 2015; Ahmad et al., 2016; Fukuta et al., 2016; Singh et al., 2018)
Fasudil, tPA	Increased BBB permeability and combination therapy	Reduce tPA-induced cerebral hemorrhage, prolong the therapeutic time window of Tpa and enhanced neuroprotection	(Fukuta et al., 2017)
Acetate	Improved circulation time, weaken toxicity and increased BBB permeability	Significant neuroprotective action through anti-inflammation	(So et al., 2019)
sPirB	long circulation time and improved BBB permeability	enhanced motor recovery post-stroke	(Wang et al., 2018)
DiR	Significantly enhanced signal intensities in ischemic hemispheres	Targeted imaging of ischemic tissue	(Wang et al., 2018)
Lipid nanoparticles
Resveratrol	LDL-mediated across BBB	Enhanced neuroprotection	(Neves et al., 2016)
Ferulic acid	Improved bioavailability and minimized oxidative stress	Fewer neurobehavioural deficits	(Hassanzadeh et al., 2018)
Polymer nanoparticles
NEP1-40	MMP-2-targeted and promoted autocatalysis action of BBB permeability	Improved nerve regeneration after hypoxic-ischemic brain injury	(Han et al., 2016)
Ginsenoside Rg1	TfR-targeted and increased drug delivery into the brain	Enhanced angiogenesis and nerve protection	(Shen et al., 2019)
Rapamycin	CREKA as the targeted head and ROS-responsive drug release	Restored damaged blood-brain barrier and ultimately improved microvascular perfusion	(Lu et al., 2019)
Metal nanoparticles
Cerium oxide nanoparticles	ROS scavenging and targeting ability to the ischemic brain tissue	Enhanced neuroprotection	(Bao et al., 2018)
Gold nanoparticles	TfR-targeted and ROS scavenging	remarkable neuroprotective effect	(Amani et al., 2019)
Prodrugs
Valproic acid	Phospholipid (PL) prodrug and reduced the side effect	Enhanced neuroprotection	(Labiner, 2002)
Ketoprofen	Diacetyl glyceride-like structure; Increased oral bioavailability and BBB permeability	Reduced neuroinflammation	(Deguchi et al., 2000)
Engineered platelets
ZL006e and rtPA	Thrombus targetability	Combination of thrombolysis and neuroprotection	(Xu, Wang, et al., 2019)
Exosomes
Curcumin	Targeted accumulation without toxicity to the liver or lung	Enhanced anti-inflammation effect	(Zheng et al., 2019)
mir-133b	Efficient delivery and long retention time	nerve remodeling and functional recovery	(Xin et al., 2017)

Figure 6. Schematic diagrams of a smart drug delivery system targeting ischemic stroke.

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