Neuroprotection against cerebral ischemia/reperfusion injury by intravenous administration of liposomal fasudil

Fukuta, Tatsuya; Asai, Tomohiro; Sato, Akihiko; Namba, Mio; Yanagida, Yosuke; Kikuchi, Takashi; Koide, Hiroyuki; Shimizu, Kosuke; Oku, Naoto

doi:10.1016/j.ijpharm.2016.04.046

Cited by 60 publications

(50 citation statements)

References 35 publications

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“…Whereas the reduction in the level of these vesicles in the time between 4h and 24h after stroke is behind the minimal accumulation of liposomes observed at those time points. This agrees with previous studies that reported limited liposomal translocation or therapeutic effect from delivery systems administered around those times [41,42]. Our data also reveals a second window for liposomal entry into the brain (~48h after stroke) in which both transcellular and paracellular pathways contribute to the selective localisation of liposomes.…”

Section: Discussionsupporting

confidence: 92%

“…Recent studies using nanoparticles-based delivery systems demonstrated the possibility to selectively target the lesion area after experimental stroke. This effect was only demonstrated when those nanoparticles injected I.V just before reperfusion or 1-3 h afterward [41,42]. Although these studies suggested that the increase in the permeability of the BECs is the drive for this selective accumulation, no direct correlation to BBB damage was reported.…”

Section: Discussionmentioning

confidence: 96%

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Selective Liposomal Transport Through Blood Brain Barrier Disruption in Ischaemic Stroke Reveals Two Distinct Therapeutic Opportunities

Al-Ahmady¹,

Jasim²,

Ahmad³

et al. 2019

Preprint

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The development of new therapies for stroke continues to face repeated translational failures. Brain endothelial cells form paracellular and transcellular barriers to many blood-borne therapies and the development of efficient delivery strategies is highly warranted. Here, in a mouse model of stroke, we show selective recruitment of clinically used liposomes into the ischaemic brain that correlates with biphasic blood brain barrier (BBB) breakdown. Intravenous administration of liposomes into mice exposed to transient middle cerebral artery occlusion took place at early (0.5h and 4h) and delayed (24h and 48h) timepoints, covering different phases of BBB disruption after stroke. Using a combination of in vivo real-time imaging and histological analysis we show that selective liposomal brain accumulation coincides with biphasic enhancement in transcellular transport followed by a delayed impairment to the paracellular barrier. This process precedes neurological damage in the acute phase and maintains long-term liposomal co-localisation within the neurovascular unit, which could have great potential for neuroprotection. Levels of liposomal uptake by glial cells are similarly selectively enhanced in the ischaemic region late after experimental stroke (2-3 days), highlighting their potential for blocking delayed inflammatory responses or shifting the polarization of microglia/macrophages towards brain repair.These findings demonstrate the capability of liposomes to maximise selective translocation into the brain after stroke and identify for the first time two windows for therapeutic manipulation. This emphasizes the benefits of selective drug delivery for efficient tailoring of new stroke treatments.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 96%

Selective Liposomal Transport Through Blood Brain Barrier Disruption in Ischaemic Stroke Reveals Two Distinct Therapeutic Opportunities

Al-Ahmady¹,

Jasim²,

Ahmad³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…75,76) Moreover, liposomes approximately 100 nm in size accumulated to a greater extent than those about 200 nm in size; and those about 800 nm in size did not accumulate in the ischemic brain. 77) Figure 3 also shows that once accumulated the liposomes resided there for a long period of time.…”

Section: Liposomal Traffic In the Brainmentioning

confidence: 89%

“…Similarly, we entrapped fasudil hydrochloride, a Rho-associated kinase (ROCK) inhibitor, into liposomes 77) (Fig. 5A).…”

Section: Treatment For Ischemic Stroke With Liposomal Neuroprotenctantsmentioning

confidence: 99%

Innovations in Liposomal DDS Technology and Its Application for the Treatment of Various Diseases

Oku

2017

Biological & Pharmaceutical Bulletin

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Liposomes have been widely used as drug carriers in the field of drug delivery systems (DDS), and they are thought to be ideal nano-capsules for targeting DDS after being injected into the bloodstream. In general, DDS drugs meet the needs of aged and super-aged societies, since the administration route of drugs can be changed, the medication frequency reduced, the adverse effects of drugs suppressed, and so on. In fact, a number of liposomal drugs have been launched and used worldwide including liposomal anticancer drugs, and these drugs have appeared on the market owing to various innovations in liposomal DDS technologies. The accumulation of long-circulating liposomes in cancer tissue is driven by the enhanced permeability and retention (EPR) effect. In this review, liposome-based targeting DDS for cancer therapy is briefly discussed. Since cancer angiogenic vessels are the ideal target of drug carriers after their injection and are critical for cancer growth, damaging of these neovessels has been an approach for eradicating cancer cells. Also, the usage of liposomal DDS for the treatment of ischemic stroke is possible, since we observed that PEGylated liposomes accumulate in the site of cerebral ischemia in transient middle cerebral artery occlusion (t-MCAO) model rats. Interestingly, liposomes carrying neuroprotectants partly suppress ischemia/reperfusion injury of these model rats, suggesting that the EPR effect also works in ischemic diseases by causing an increase in the permeability of the blood vessel endothelium. The potential of liposomal DDS against life-threatening diseases might thus be attractive for supporting long-lived societies.

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“…These results suggest that PEG-liposomes gradually reach the brain parenchyma in the I/R region due to the EPR effect, similar to the liposomal accumulation in tumor tissue. 18) We also examined the influence of particle size on liposomal accumulation in the ischemic region. The results showed that the accumulation of PEG-liposomes approximately 200 nm in diameter was less than that of 100-nm liposomes, and almost no accumulation of liposomes with an average diameter of greater than 800 nm was observed.…”

Section: Distribution Of Nano-sized Liposomes In the Brain After I/rmentioning

confidence: 99%

Applications of Liposomal Drug Delivery Systems to Develop Neuroprotective Agents for the Treatment of Ischemic Stroke

Fukuta

Ishii

Asai

et al. 2019

Biological & Pharmaceutical Bulletin

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Ischemic stroke is one of the leading causes of severe disability and death. In clinical settings, tissue plasminogen activator (t-PA) for thrombolytic therapy is the only globally approved drug for the treatment of ischemic stroke. However, the proportion of patients who receive t-PA therapy is extremely limited due to its narrow therapeutic time window (TTW) and the risk of cerebral hemorrhage. Cerebral ischemia-reperfusion (I/R) injury is also a serious problem for patients' outcomes. Hence, the development of more effective therapies has been desired to prolong the TTW of t-PA and prevent cerebral I/R injury. For delivering drugs into the brain, the blood-brain barrier (BBB) must be overcome since it limits drug penetration into the brain, leading to insufficient therapeutic efficacy. As a distinctive pathology after an ischemic stroke, it was reported that the vascular permeability of the BBB is increased around the ischemic region. We found that nano-sized liposomes can pass through the disrupted BBB and accumulate in the I/R region, and that delivery of neuroprotective agents using a liposomal drug delivery system (DDS) is effective for the treatment of cerebral I/R injury. Moreover, we have recently demonstrated that combination therapy with liposomal drugs and t-PA can suppress the deleterious effects of t-PA and extend its TTW in a rat ischemic stroke model. These findings indicate that applications of nanoparticle DDS technology could be a hopeful approach to drug development for ischemic stroke therapy. In this review, we introduce our findings on ischemic stroke treatment using liposomal DDS and recent advances from other research groups.

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Neuroprotection against cerebral ischemia/reperfusion injury by intravenous administration of liposomal fasudil

Cited by 60 publications

References 35 publications

Selective Liposomal Transport Through Blood Brain Barrier Disruption in Ischaemic Stroke Reveals Two Distinct Therapeutic Opportunities

Selective Liposomal Transport Through Blood Brain Barrier Disruption in Ischaemic Stroke Reveals Two Distinct Therapeutic Opportunities

Innovations in Liposomal DDS Technology and Its Application for the Treatment of Various Diseases

Applications of Liposomal Drug Delivery Systems to Develop Neuroprotective Agents for the Treatment of Ischemic Stroke

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