期刊
ACS NANO
卷 12, 期 8, 页码 8723-8732出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.8b04787
关键词
drug delivery; ischemic stroke; CXCR4; glyburide; protease-responsive
类别
资金
- NIH [NS095817, NS095147]
- AHA grant [15GRNT25290018, 18TPA34170180]
- State of Connecticut
- NSFC [51603172, 81471415]
- Projects of International Cooperation and Exchanges Natural Science Foundation of Shannxi Province of China [2018KW-038]
Current treatments for ischemic stroke are insufficient. The lack of effective pharmacological approaches can be mainly attributed to the difficulty in overcoming the blood brain barrier. Here, we report a simple strategy to synthesize protease-responsive, brain-targeting nanoparticles for the improved treatment of stroke. The resulting nanoparticles respond to proteases enriched in the ischemic microenvironment, including thrombin or matrix metalloproteinase-9, by shrinking or expanding their size. Targeted delivery was achieved using surface conjugation of ligands that bind to proteins that were identified to enrich in the ischemic brain using protein arrays. By screening a variety of formulations, we found that AMD3100-conjugated, size-shrinkable nanoparticles (ASNPs) exhibited the greatest delivery efficiency. The brain targeting effect is mainly mediated by AMD3100, which interacts with CXCR4 that is enriched in the ischemic brain tissue. We showed that ASNPs significantly enhanced the efficacy of glyburide, a promising stroke therapeutic drug whose efficacy is limited by its toxicity. Due to their high efficiency in penetrating the ischemic brain and low toxicity, we anticipate that ASNPs have the potential to be translated into clinical applications for the improved treatment of stroke patients.
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