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Theranostics 2018; 8(18):4870-4883. doi:10.7150/thno.27466 This issue Cite

Research Paper

Platelet bio-nanobubbles as microvascular recanalization nanoformulation for acute ischemic stroke lesion theranostics

Mingxi Li^1,2, Yang Liu^1,2, Jinpeng Chen³, Taotao Liu¹, Zhuxiao Gu², Jianqiong Zhang³, Xiaochun Gu⁴, Gaojun Teng⁴, Fang Yang^1,2✉, Ning Gu^1,2✉

1. State key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences & Medical Engineering, Southeast University, Nanjing, 210096, China
2. Collaborative Innovation Center of Suzhou Nano-Science and Technology, Southeast University, Suzhou 215123, China
3. Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing 210009, China
4. Jiangsu Key Laboratory of Molecule and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical Schoool, Southeast University, Nanjing 210009, PR China

✉ Corresponding authors: F. Y. (Email: yangfang2080edu.cn) and N. G. (Email: guningedu.cn).

Abstract

Since the expected therapeutic results of ischemic stroke are strictly time dependent, early and accurate diagnosis as well as short intervals between diagnosis and treatment are key factors for the survival of stroke patients. In this study, we fabricated platelet (PLT) membrane-derived biomimetic nanobubbles (PNBs) for timely perfusion intervention and ultrasound imaging of acute ischemic stroke.

Methods: The PNBs are fabricated by sonication-assisted reassembly of repeatedly freeze-thawed live platelet-derived PLT membrane vesicles (PMVs). The TEM, SEM, EDS and DLS were used to analyze the morphology and physicochemical properties of PNBs. The HPLC and LC-MS/MS were applied to confirm the lipid and protein compositions of PNBs. The in vitro macrophage uptake and platelet aggregation of PNBs were designed to examine the immune escape and thrombotic response characteristics. Furthermore, based on a photothrombotic ischemic stroke mouse model, the biodistribution, stroke microvascular network change, as well as cerebral blood flow of PNBs were studied by using near-infrared fluorescence imaging, multimodal optical imaging, and full-field laser perfusion imager. Finally, we assessed the brain ultrasound imaging of PNBs with a high-resolution micro-imaging system using both B-mode and contrast mode.

Results: The natural lipid and protein components isolated from PLT membrane endow the PNBs with accurate lesion-targeting ability. The preferentially accumulated PNBs exhibit microvascular bio-remodeling ability of the stroke lesion, which is critical for recanalization of the obstructed vessels to protect the neural cells around the ischemic region of the stroke. Furthermore, with the increased accumulation of PNBs clusters in the lesion, PNBs in the lesion can be monitored by real-time contrast-enhanced ultrasound imaging to indicate the severity and dynamic development of the stroke.

Conclusions: In summary, platelet membrane-based nanobubbles for targeting acute ischemic lesions were developed as microvascular recanalization nanoformulation for acute ischemic stroke lesion theranostics. This biomimetic PNBs theranostic strategy will be valuable for ischemic stroke patients in the future.

Keywords: Platelet membrane, nanobubbles, stroke targeting, neuroprotection, ultrasound imaging

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