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首页> 外文学位 >Indocyanine green-encapsulating calcium phosphosilicate nanoparticles: Bifunctional theranostic vectors for near infrared diagnostic imaging and photodynamic therapy.
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Indocyanine green-encapsulating calcium phosphosilicate nanoparticles: Bifunctional theranostic vectors for near infrared diagnostic imaging and photodynamic therapy.

机译：吲哚菁绿封装的磷酸硅钙纳米颗粒：用于近红外诊断成像和光动力疗法的双功能治疗药物载体。

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摘要

The synthesis, laundering, and properties of calcium phosphosilicate nanoparticles (CPSNPs) that encapsulate the NIR fluorophore indocyanine green (ICG) related to multifunctional fluorescent photosensitization is presented. Imaging with transmission electron microscopy (TEM) revealed the well dispersed state of the nanoparticles, the spherical morphology, and the log normal mean particle diameter of 16 nm. Electron energy loss spectroscopy (EELS) mapping identified a Ca:P:Si ratio of 1:1.72:0.41 and a homogeneous composition without evidence of an element rich or deficient architecture. Zeta potential of the as-synthesized, citrate-functionalized CPSNPs was -29 +/-3 mV. A theoretical solids loading of 1.9 x 1013 CPSNP/mL was calculated for a standard suspension. The mean ICG content per suspension is 2 x 10 -6 M, which equates to approximately 63 fluorophore molecules encapsulated per CPSNP.;For imaging and diagnostic considerations, the doped CPSNPs exhibited significantly greater intensity at the maximum emission wavelength relative to the free constituent fluorophore. The quantum efficiency of the fluorescent agent is 200% greater at 0.053+/-0.003 over the free fluorophore in PBS. Also, photostability based on fluorescence half-life of encapsulated ICG in PBS is 500% longer under typical clinical imaging conditions relative to the free dye. These performance enhancements are attributed to the matrix shielding effect of the NP around the internalized fluorophore molecules.;The in vivo emission signal stability from ICG-CPSNPs was compared to the free fluorophore by whole animal NIR imaging. The duration of fluorescent signal from the ICG-CPSPNPs was extended to up to four days post-injection, highlighting the potential for long-term imaging and sensitive tracking applications using ICG when encapsulated within the protective matrix of CPSNPs. The surfaces of the ICG-CPSNPs were covalently bound with polyethylene glycol (PEG). The pharmacokinetic behavior of the PEGylated ICG-CPSNPs revealed that ICG-CPSNP-PEG passively localize within solid tumor xenografts within 24 hours of systemic administration via the enhanced permeation and retention (EPR) effect.;To impart tissue specificity, the ICG-CPSNP-PEGs were bioconjugated with gastrin-10 with the intention of targeting BxPC-3 pancreatic cancer cells by specifically binding the over expressed receptors for this hormone. In vitro assessment acknowledged the faculty of this functionalization to preferentially target the cells of interest; fluorescence microscopy visually revealed this targeting capacity, while flow cell cytometry explicitly characterized the preferential cellular uptake of the ICG-CPSNP-PEG-Gastrin-10 by BxPC-3 cancer cells. An NIR whole animal imaging study further verified that gastrin functionalization provides a direct means for targeting orthotopic pancreatic tumors in vivo, with emission signal intensities from excised tumors measuring higher relative to the controls. This result highlights the ability of targeted ICG-CPSNPs to provide the high in vivo selectivity needed for the most effective diagnostics imaging.;Initial in vitro toxicity trials were conducted in four distinct cell lines to identify an ICG-CPSNP-PEG dosing limit. It was revealed that acute toxicity is subject to the particle number concentration (LD 50 of 2 x108 CPSNP/cell) and not the dose of encapsulated ICG. Next, cell viability was examined as a function of photodynamic therapy (PDT) dose. An unmistakable drop in cell viability in vitro relative to the control was observed for all cell lines. The significance of these results rests in the drastically low applied fluence (1 J/cm 2), which suggests a plausibly greater efficacy in cell lethality at significantly higher, more customary laser powers.;This enhancement in photodynamic response was supplemented by the exceptional in vivo PDT effect on tumor growth. ICG-CPSNP-PEGs arrested human breast adenocarcinoma tumor growth over 36 days after only a single, low dose systemic administration (44 nM) and laser activation (12.5 J/cm2). Such heightened photodynamic cell lethality with ICG-CPSNPs emphasizes the tremendous potential this composite nanovector has for low dose PDT applications, particularly considering the non-optimized nature of the preliminary experimentation. (Abstract shortened by UMI.)
机译：介绍了封装与多功能荧光光敏化相关的NIR荧光团吲哚菁绿（ICG）的磷酸硅钙纳米粒子（CPSNP）的合成，洗涤和性能。用透射电子显微镜（TEM）成像显示纳米粒子的良好分散状态，球形形态和对数正态平均粒径为16 nm。电子能量损失谱（EELS）映射确定Ca：P：Si比为1：1.72：0.41，并且组成均匀，没有元素富集或缺乏结构的迹象。合成后的柠檬酸盐官能化的CPSNP的Zeta电位为-29 +/- 3 mV。对于标准悬浮液，计算得出的理论固含量为1.9 x 1013 CPSNP / mL。每个悬浮液的平均ICG含量为2 x 10 -6 M，相当于每个CPSNP封装的大约63个荧光团分子;出于成像和诊断考虑，相对于游离组分荧光团，掺杂的CPSNP在最大发射波长处表现出明显更高的强度。荧光剂的量子效率在0.053 +/- 0.003处比PBS中的游离荧光团高200％。同样，在典型的临床成像条件下，基于PBS中封装的ICG荧光半衰期的光稳定性比游离染料长500％。这些性能的提高归因于内化荧光团分子周围NP的基质屏蔽作用。通过全动物NIR成像将ICG-CPSNPs的体内发射信号稳定性与游离荧光团进行了比较。从ICG-CPSPNPs发出的荧光信号的持续时间延长至注射后四天，这突出显示了将ICG封装在CPSNPs的保护性基质中后，其长期成像和敏感跟踪应用的潜力。 ICG-CPSNP的表面与聚乙二醇（PEG）共价结合。 PEG化ICG-CPSNPs的药代动力学行为表明，ICG-CPSNP-PEG在全身给药后的24小时内可通过增强的渗透和保留（EPR）效果被动定位在实体肿瘤异种移植物中。为赋予组织特异性，ICG-CPSNP- PEG与gastrin-10生物缀合，旨在通过特异性结合该激素的过度表达受体来靶向BxPC-3胰腺癌细胞。体外评估认识到这种功能化的功能是优先靶向目标细胞。荧光显微镜可视地揭示了这种靶向能力，而流式细胞术则明确表征了BxPC-3癌细胞优先摄取ICG-CPSNP-PEG-Gastrin-10。 NIR全动物影像学研究进一步证实，胃泌素功能化为体内靶向原位胰腺肿瘤提供了直接手段，来自切除肿瘤的发射信号强度相对于对照更高。该结果强调了靶向ICG-CPSNPs提供最有效的诊断成像所需的高体内选择性的能力。在四个不同的细胞系中进行了初始体外毒性试验，以确定ICG-CPSNP-PEG的剂量限制。揭示了急性毒性取决于颗粒数浓度（2×108 CPSNP /细胞的LD 50）而不是胶囊化ICG的剂量。接下来，检查细胞活力与光动力疗法（PDT）剂量的关系。对于所有细胞系，均观察到相对于对照，体外细胞存活率无明显下降。这些结果的重要意义在于应用通量（1 J / cm 2）极低，这表明在更高，更常规的激光功率下，细胞致死性的功效似乎更高。体内PDT对肿瘤生长的影响。仅单次，低剂量全身性给药（44 nM）和激光激活（12.5 J / cm2）后，ICG-CPSNP-PEG抑制了人类乳腺腺癌肿瘤生长超过36天。使用ICG-CPSNPs增强的光动力细胞杀伤力强调了这种复合纳米载体在低剂量PDT应用中的巨大潜力，特别是考虑到初步实验的非优化性质。 （摘要由UMI缩短。）

著录项

  • 作者

    Altinoglu, Erhan I.;

  • 作者单位

    The Pennsylvania State University.;

  • 授予单位 The Pennsylvania State University.;
  • 学科 Engineering General.;Nanoscience.;Engineering Materials Science.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 179 p.
  • 总页数 179
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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