Fernandez-Fernandez Alicia, Manchanda Romila, Carvajal Denny A, Lei Tingjun, Srinivasan Supriya, McGoron Anthony J
Biomedical Engineering Department, Florida International University, Miami, FL, USA ; Physical Therapy Department, Nova Southeastern University, Fort Lauderdale, FL, USA.
Biomedical Engineering Department, Florida International University, Miami, FL, USA ; Chemistry Department, Galgotias University, Greater Noida, UP, India.
Int J Nanomedicine. 2014 Oct 6;9:4631-48. doi: 10.2147/IJN.S69550. eCollection 2014.
Near-infrared dyes can be used as theranostic agents in cancer management, based on their optical imaging and localized hyperthermia capabilities. However, their clinical translatability is limited by issues such as photobleaching, short circulation times, and nonspecific biodistribution. Nanoconjugate formulations of cyanine dyes, such as IR820, may be able to overcome some of these limitations. We covalently conjugated IR820 with 6 kDa polyethylene glycol (PEG)-diamine to create a nanoconjugate (IRPDcov) with potential for in vivo applications. The conjugation process resulted in nearly spherical, uniformly distributed nanoparticles of approximately 150 nm diameter and zeta potential -0.4±0.3 mV. The IRPDcov formulation retained the ability to fluoresce and to cause hyperthermia-mediated cell-growth inhibition, with enhanced internalization and significantly enhanced cytotoxic hyperthermia effects in cancer cells compared with free dye. Additionally, IRPDcov demonstrated a significantly longer (P<0.05) plasma half-life, elimination half-life, and area under the curve (AUC) value compared with IR820, indicating larger overall exposure to the theranostic agent in mice. The IRPDcov conjugate had different organ localization than did free IR820, with potential reduced accumulation in the kidneys and significantly lower (P<0.05) accumulation in the lungs. Some potential advantages of IR820-PEG-diamine nanoconjugates may include passive targeting of tumor tissue through the enhanced permeability and retention effect, prolonged circulation times resulting in increased windows for combined diagnosis and therapy, and further opportunities for functionalization, targeting, and customization. The conjugation of PEG-diamine with a near-infrared dye provides a multifunctional delivery vector whose localization can be monitored with noninvasive techniques and that may also serve for guided hyperthermia cancer treatments.
基于其光学成像和局部热疗能力，近红外染料可作为癌症治疗诊断剂用于癌症管理。然而，它们的临床可转化性受到诸如光漂白、循环时间短和非特异性生物分布等问题的限制。花青染料的纳米共轭制剂，如IR820，可能能够克服其中一些限制。我们将IR820与6 kDa聚乙二醇（PEG）-二胺共价共轭，以制备具有体内应用潜力的纳米共轭物（IRPDcov）。共轭过程产生了直径约150 nm、zeta电位为-0.4±0.3 mV的近球形、均匀分布的纳米颗粒。IRPDcov制剂保留了荧光能力和引起热疗介导的细胞生长抑制的能力，与游离染料相比，其内化增强，在癌细胞中的细胞毒性热疗效果显著增强。此外，与IR820相比，IRPDcov的血浆半衰期、消除半衰期和曲线下面积（AUC）值显著更长（P<0.05），表明小鼠体内对治疗诊断剂的总体暴露量更大。IRPDcov共轭物与游离IR820的器官定位不同，在肾脏中的蓄积可能减少，在肺部中的蓄积显著更低（P<0.05）。IR820-PEG-二胺纳米共轭物的一些潜在优势可能包括通过增强的渗透和滞留效应被动靶向肿瘤组织、延长循环时间从而增加联合诊断和治疗的时间窗，以及进一步的功能化、靶向和定制机会。PEG-二胺与近红外染料的共轭提供了一种多功能递送载体，其定位可以通过非侵入性技术进行监测，并且还可用于引导性热疗癌症治疗。
