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Fabrication of Red Blood Cell-Based Multimodal Theranostic Probes for Second Near-Infrared Window Fluorescence Imaging-Guided Tumor Surgery and Photodynamic Therapy.

ABSTRACT: The therapeutic efficacy of fluorescence image-guided tumor surgery and photodynamic therapy (PDT) is impaired by the penetration depth limitation, low signal-to-noise ratio of traditional first near-infrared window (NIR I) fluorescence and the hypoxic tumor microenvironment. Here, a "red blood cell-based multimodal probe" was proposed to achieve enhanced tumor targeting and retention of fluorescent probes after an intravenous injection, so that second near-infrared window (NIR II) fluorescence bioimaging-guided complete tumor resection and high-efficiency photodynamic therapy could then be realized. Methods: The hexanoic acid ester-modified rose bengal (RB-HA), RGD (Arginine-Glycine-Aspartic) peptide and avidin were covalently coupled onto amine-modified upconversion nanoparticles (UCNPs) via EDC/NHS reaction (UCNPs@RB@RGD@avidin). Afterwards, the complex of ICG with bovine serum albumin (BSA) was loaded into RBCs through hypotonic dialysis (RBC@ICG). Then, the membrane proteins of RBC@ICG were biotinylated by biotin-modified phospholipids (RBC@ICG@biotin). Finally, the RBCp (Red Blood Cell based probe) was obtained by crosslinking UCNPs@RB@RGD@avidin to RBC@ICG@biotin through the interaction of avidin and biotin. The obtained multimodal RBCp was extensively characterized, both in vitro and in vivo, including analysis of chemical, physical and fluorescent features, O₂ delivery ability, tumor accumulation, NIR II fluorescence bioimaging ability, photodynamic therapeutic efficiency, and biosafety. Results: The RBCp experienced efficient tumor targeting and long tumor retention for almost 4 h after intravenous injection, and the superior signal-to-noise ratio at the optimal time window can be used for guiding precise tumor resection under an 808-nm laser irradiation to facilitate lymph popliteal metastasis surgical delineation. Meanwhile, the RBCp can provide laser-responsive O₂ release to enhance the PDT efficiency of popliteal lymph node metastasis under NIR II fluorescence bioimaging guidance. These excellent performances obviously lead to remarkably enhanced synergistic therapeutic effects of tumor surgery and metastatic inhibition. Conclusion: The proposed strategy will develop a new platform to increase surgical resection completeness and improve PDT efficiency, resulting in the successful and complete inhibition of tumor and metastasis, which could offer a promising approach for the clinical translation of malignant tumor treatment.

SUBMITTER: Wang P

PROVIDER: S-EPMC6376196 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Fabrication of Red Blood Cell-Based Multimodal Theranostic Probes for Second Near-Infrared Window Fluorescence Imaging-Guided Tumor Surgery and Photodynamic Therapy.

Wang Peiyuan P Wang Xuandong X Luo Qiang Q Li Yang Y Lin Xiaoxiao X Fan Lingling L Zhang Yun Y Liu Jingfeng J Liu Xiaolong X

Theranostics 20190101 2

The therapeutic efficacy of fluorescence image-guided tumor surgery and photodynamic therapy (PDT) is impaired by the penetration depth limitation, low signal-to-noise ratio of traditional first near-infrared window (NIR I) fluorescence and the hypoxic tumor microenvironment. Here, a "red blood cell-based multimodal probe" was proposed to achieve enhanced tumor targeting and retention of fluorescent probes after an intravenous injection, so that second near-infrared window (NIR II) fluorescence ...[more]

PMID: 30809280

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Project description:IntroductionFluorescence-guided surgery has emerged as a powerful tool to detect, localize and resect tumors in the operative setting. Our laboratory has pioneered a novel way to administer an FDA-approved near-infrared (NIR) contrast agent to help surgeons with this task. This technique, coined Second Window ICG, exploits the natural permeability of tumor vasculature and its poor clearance to deliver high doses of indocyanine green (ICG) to tumors. This technique differs substantially from established ICG video angiography techniques that visualize ICG within minutes of injection. We hypothesized that Second Window ICG can provide NIR optical contrast with good signal characteristics in intracranial brain tumors over a longer period of time than previously appreciated with ICG video angiography alone. We tested this hypothesis in an intracranial mouse glioblastoma model, and corroborated this in a human clinical trial.MethodsIntracranial tumors were established in 20 mice using the U251-Luc-GFP cell line. Successful grafts were confirmed with bioluminescence. Intravenous tail vein injections of 5.0 mg/kg (high dose) or 2.5 mg/kg (low dose) ICG were performed. The Perkin Elmer IVIS Spectrum (closed field) was used to visualize NIR fluorescence signal at seven delayed time points following ICG injection. NIR signals were quantified using LivingImage software. Based on the success of our results, human subjects were recruited to a clinical trial and intravenously injected with high dose 5.0 mg/kg. Imaging was performed with the VisionSense Iridium (open field) during surgery one day after ICG injection.ResultsIn the murine model, the NIR signal-to-background ratio (SBR) in gliomas peaks at one hour after infusion, then plateaus and remains strong and stable for at least 48 hours. Higher dose 5.0 mg/kg improves NIR signal as compared to lower dose at 2.5 mg/kg (SBR = 3.5 vs. 2.8; P = 0.0624). Although early (? 6 hrs) visualization of the Second Window ICG accumulation in gliomas is stronger than late (?24 hrs) visualization (SBR = 3.94 vs. 2.32; p<0.05) there appears to be a long plateau period of stable ICG NIR signal accumulation within tumors in the murine model. We call this long plateau period the "Second Window" of ICG. In glioblastoma patients, the delayed visualization of intratumoral NIR signal was strong (SBR 7.50 ± 0.74), without any significant difference within the 19 to 30 hour visualization window (R2 = 0.019).ConclusionThe Second Window ICG technique allows neurosurgeons to deliver NIR optical contrast agent to human glioblastoma patients, thus providing real-time tumor identification in the operating room. This nonspecific tumor accumulation of ICG within the tumor provides strong signal to background contrast, and is not significantly time dependent between 6 hours to 48 hours, providing a broad plateau for stable visualization. This finding suggests that optimal imaging of the "Second Window of ICG" may be within this plateau period, thus providing signal uniformity across subjects.

Dataset Information

Fabrication of Red Blood Cell-Based Multimodal Theranostic Probes for Second Near-Infrared Window Fluorescence Imaging-Guided Tumor Surgery and Photodynamic Therapy.

Publications

Fabrication of Red Blood Cell-Based Multimodal Theranostic Probes for Second Near-Infrared Window Fluorescence Imaging-Guided Tumor Surgery and Photodynamic Therapy.

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