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首页> 外文学位 >Development of indocyanine green loaded long circulating and folate-receptor-targeted PLGA nanoparticles for photodynamic therapy of breast cancer.
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Development of indocyanine green loaded long circulating and folate-receptor-targeted PLGA nanoparticles for photodynamic therapy of breast cancer.

机译：吲哚菁绿负载长循环和叶酸受体靶向PLGA纳米粒子的开发，用于乳腺癌的光动力治疗。

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摘要

Purpose. The purpose of this study was to develop a long-circulating and folate-receptor (FR) targeted indocyanine green (ICG) nanoparticles with sustained-release properties, to enhance tumor uptake. We have hypothesized that dual surface modification with mPEG and folic acid (FA) in the nanoparticles may increase the particles' blood circulation time and may result in specific recognition toward tumors with over-expression of FR. Methods. The following co-polymers were synthesized: mPEG-PLGA, FA-PLGA, and FA-mPEG-PLGA. Nanoparticles were prepared with PLGA, mPEG-PLGA, FA-PLGA, FA-mPEG-PLGA or blends of FA-PLGA and mPEG-PLGA with molar ratio 1:3 and 5:3 (Blend 1 and 2 respectively). The specificity of FR-targeting nanoparticles was demonstrated by comparative intracellular uptake of these nanoparticles using human breast cancer cells, MDA-MB-231 (with high FR density) and MCF-7 (with low FR density), and a normal cell line, HEK-293 (with low FR density). The specific targeting was further confirmed by a competitive inhibition assay, in which MDA-MB-231 cells were cultured in a media with or without FA and by evaluating the effect of low temperature (4°C) on ICG uptake. In vitro photodynamic antiproliferation was studied at three activation energy densities, 0.045, 0.9 and 0.135 J/mm². Biodistribution of ICG solution and nanoparticles was studied in MDA-MB-231-bearing athymic mice by measuring the fluorescence intensity of ICG in dorsal and ventral regions using an imaging system. In vivo photodynamic anti-cancer activity of the FR-targeted nanoparticles was investigated on athymic mice bearing MDA-MB-231. Results. Characterization of these nanoparticles showed that Blend 1 and 2 nanoparticles exhibited desired properties: dual surface modification with PEG and FA, sustained release (39.66 +/- 4.91 % and 43.7 +/- 7.96 % release over 24 hr, respectively), suitable particle size (233 nm and 240 nm, respectively), satisfied entrapment efficiency (51.37 +/- 4.28 % and 50.26 +/- 0.72 %, respectively) and stable for 3 months at -20°C (0.36 +/- 0.01 % and 0.94 +/- 0.01 %). FA-PLGA and Blend nanoparticles enhanced the in vitro uptake by the MDA-MB-231 cells than the other nanoparticles by 3--26 times (p0.05) after 24 h incubation. FA-PLGA and Blend nanoparticles exhibited 30--70% higher (p0.05) in antiproliferation against the MDA-MB-231 cells than the other two cells while mPEG-PLGA nanoparticles showed similar antiproliferation against the three cells. All the photodynamic antiproliferation activities were increased with the increase of the irradiation energy. There existed a correlation between the cellular uptake of ICG and the antiproliferation effect. The cellular uptake of FA-tagged nanoparticles was suppressed in presence of 12 nM FA in the media by 1.2 to 3 times and at 4°C by 1.2 to 4.5 times supporting the role of folate receptor-mediated endocytosis. The maximum growth inhibition for MDA-MB-231 cells was 64.43 +/- 2.78 % by Blend 2 nanoparticles at 786 nm with 0.135 J/mm² energy density and 0.15 mW/mm² fluency. The uptake of FA-PLGA and Blend nanoparticles by MDA-MB-231 cells was 43--51 times higher (p0.05) than that by MCF-7 and HEK-293 cells demonstrating the targeting ability toward cancer cells with overexpression of FR through surface modification with FA. After i.v. injection, high accumulation of Blend nanoparticles in tumor region was observed, followed by FA-PLGA nanoparticles. Blend nanoparticles had a steady ICG fluorescent intensity in tumor region till the 7th day of the treatment while the intensity due to FA-PLGA nanoparticles or mPEG-PLGA nanoparticles reduced after 4 days or sooner. The ratios of sum of the ICG intensities in the tumor region by Blend nanoparticles vs. to other nanoparticles were in the range of 1.21 to 2.82 during the 7 days photodynamic treatment. All the nanoparticle formulations and ICG solution had similar fluorescence intensity in the middle region of dorsal side during the 7 days treatment. Compared to the control group without any treatment Blend 2 nanoparticles resulted in 73% reduction in tumor weight (p0.001), while the treatment of FA-PLGA nanoparticles and m-PEG nanoparticles resulted in 47% and 46% reduction (p>0.05), respectively. The reduction in tumor weight by Blend 2 nanoparticles was also significantly higher (p0.05) than the FA-PLGA or mPEG-PLGA nanoparticles, demonstrating the higher efficiency against the FR over-expressed tumor and by the dual surface modification of nanoparticles with FA and mPEG than the single surface modification with either FA or mPEG. Conclusion. Thus, an ICG-loaded folate-targeted mPEG-PLGA nanoparticles with high cellular uptake efficiency of ICG and high photodynamic anti-cancer activity against FR over-expressing tumor cells was developed through the dual surface modification of PLGA nanoparticles with both FA and mPEG. (Abstract shortened by UMI.)
机译：目的。这项研究的目的是开发具有持续释放特性的长循环叶酸受体（FR）吲哚菁绿（ICG）纳米粒子，以增强肿瘤吸收。我们假设纳米颗粒中的mPEG和叶酸（FA）进行双重表面修饰可能会增加颗粒的血液循环时间，并可能导致对FR过度表达的肿瘤的特异性识别。方法。合成了以下共聚物：mPEG-PLGA，FA-PLGA和FA-mPEG-PLGA。用PLGA，mPEG-PLGA，FA-PLGA，FA-mPEG-PLGA或FA-PLGA和mPEG-PLGA的混合物以摩尔比1：3和5：3（分别混合1和2）制备纳米颗粒。通过使用人乳腺癌细胞，MDA-MB-231（高FR密度）和MCF-7（低FR密度）和正常细胞系比较比较地将这些纳米颗粒摄取到细胞内，可以证明FR靶向纳米颗粒的特异性， HEK-293（低FR密度）。通过竞争抑制试验进一步证实了特异性靶向，其中在有或没有FA的培养基中培养MDA-MB-231细胞，并评估低温（4°C）对ICG摄取的影响。在三种活化能密度为0.045、0.9和0.135 J /mm²的条件下研究了体外光动力扩散。通过使用成像系统测量背侧和腹侧区域中ICG的荧光强度，在带有MDA-MB-231的无胸腺小鼠中研究了ICG溶液和纳米颗粒的生物分布。在携带MDA-MB-231的无胸腺小鼠上研究了FR靶向纳米颗粒的体内光动力学抗癌活性。结果。这些纳米粒子的表征表明，掺合物1和2纳米粒子表现出所需的特性：用PEG和FA进行双重表面改性，持续释放（分别在24小时内释放39.66 +/- 4.91％和43.7 +/- 7.96％），合适的粒径（分别为233 nm和240 nm），令人满意的包封效率（分别为51.37 +/- 4.28％和50.26 +/- 0.72％）并在-20°C下稳定3个月（0.36 +/- 0.01％和0.94 + /-0.01％）。孵育24小时后，FA-PLGA和Blend纳米颗粒比其他纳米颗粒提高了MDA-MB-231细胞的体外摄取3--26倍（p <0.05）。 FA-PLGA和Blend纳米颗粒对MDA-MB-231细胞的抗增殖能力比其他两个细胞高30--70％（p <0.05），而mPEG-PLGA纳米颗粒对三个细胞的抗增殖能力相似。随着照射能量的增加，所有的光动力学抗增殖活性都增加。 ICG的细胞摄取与抗增殖作用之间存在相关性。在培养基中存在12 nM FA时，FA标记的纳米颗粒的细胞摄取被抑制了1.2至3倍，在4°C时被抑制了1.2至4.5倍，从而支持了叶酸受体介导的内吞作用。在786 nm处，掺混2个纳米粒子对MDA-MB-231细胞的最大生长抑制为64.43 +/- 2.78％，能量密度为0.135 J /mm²，流利度为0.15 mW /mm²。 MDA-MB-231细胞对FA-PLGA和Blend纳米颗粒的摄取比MCF-7和HEK-293细胞高43--51倍（p <0.05），这证明了FR过度表达对癌细胞的靶向能力通过用FA进行表面改性。在i.v.之后注射后，观察到Blend纳米颗粒在肿瘤区域的高积累，其次是FA-PLGA纳米颗粒。直到治疗的第7天，共混纳米颗粒在肿瘤区域的ICG荧光强度一直稳定，而FA-PLGA纳米颗粒或mPEG-PLGA纳米颗粒引起的强度在4天或更早后降低。在7天的光动力治疗期间，Blend纳米颗粒相对于其他纳米颗粒在肿瘤区域的ICG强度总和之比在1.21至2.82的范围内。在7天的处理中，所有纳米颗粒制剂和ICG溶液在背侧的中间区域具有相似的荧光强度。与未进行任何治疗的对照组相比，Blend 2纳米颗粒的肿瘤重量减少了73％（p <0.001），而FA-PLGA纳米颗粒和m-PEG纳米颗粒的治疗导致肿瘤重量减少了47％（p> 0.05） ）， 分别。 Blend 2纳米颗粒的肿瘤重量降低也显着高于FA-PLGA或mPEG-PLGA纳米颗粒（p <0.05），表明抗FR过表达的肿瘤效率更高，并且纳米颗粒经FA双重修饰与用FA或mPEG进行的单表面修饰相比，mPEG的效果更好。结论。因此，通过用FA和mPEG对PLGA纳米颗粒进行双重表面修饰，开发了具有ICG的高叶酸靶向mPEG-PLGA纳米颗粒，具有ICG的高细胞摄取效率和对FR超表达的肿瘤细胞的高光动力抗癌活性。 （摘要由UMI缩短。）

著录项

  • 作者

    Tikekar, Shilpa.;

  • 作者单位

    St. John's University (New York), School of Pharmacy.;

  • 授予单位 St. John's University (New York), School of Pharmacy.;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 197 p.
  • 总页数 197
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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