Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Int J Nanomedicine. 2011;6:1719-32. doi: 10.2147/IJN.S17995. Epub 2011 Aug 18.
One of the most attractive properties of quantum dots is their potential to extend the opportunities for fluorescent and multimodal imaging in vivo. The aim of the present study was to clarify whether the composition and structure of organic coating of nanoparticles are crucial for their application in vivo.
We compared quantum dots coated with non-crosslinked amino-functionalized polyamidoamine (PAMAM) dendrimers, quantum dots encapsulated in crosslinked carboxyl-functionalized PAMAM dendrimers, and silica-shelled amino-functionalized quantum dots. A multimodal fluorescent and paramagnetic quantum dot probe was also developed and analyzed. The probes were applied intravenously in anesthetized animals for visualization of brain vasculature using two-photon excited fluorescent microscopy and visualization of tumors using fluorescent IVIS(®) imaging (Caliper Life Sciences, Hopkinton, MA) and magnetic resonance imaging.
Quantum dots coated with non-crosslinked dendrimers were cytotoxic. They induced side effects in vivo, including vasodilatation with a decrease in mean arterial blood pressure and heart rate. The quantum dots penetrated the vessels, which caused the quality of fluorescent imaging to deteriorate. Quantum dots encapsulated in crosslinked dendrimers had low cytotoxicity and were biocompatible. In concentrations <0.3 nmol quantum dots/kg bodyweight, these nanoparticles did not affect blood pressure and heart rate, and did not induce vasodilatation or vasoconstriction. PEGylation (PEG [polyethylene glycol]) was an indispensable step in development of a quantum dot probe for in vivo imaging, based on silica-shelled quantum dots. The non-PEGylated silica-shelled quantum dots possessed low colloidal stability in high-salt physiological fluids, accompanied by rapid aggregation in vivo. The conjugation of silica-shelled quantum dots with PEG1100 increased their stability and half-life in the circulation without significant enhancement of their size. In concentrations <2.5 nmol/kg bodyweight, these quantum dots did not affect the main physiological variables. It was possible to visualize capillaries, which makes this quantum dot probe appropriate for investigation of mediators of vasoconstriction, vasodilatation, and brain circulation in intact animals in vivo. The multimodal silica-shelled quantum dots allowed visualization of tumor tissue in an early stage of its development, using magnetic resonance imaging.
THE PRESENT STUDY SHOWS THAT THE TYPE AND STRUCTURE OF ORGANIC/BIOORGANIC SHELLS OF QUANTUM DOTS DETERMINE THEIR BIOCOMPATIBILITY AND ARE CRUCIAL FOR THEIR APPLICATION IN IMAGING IN VIVO, DUE TO THE EFFECTS OF THE SHELL ON THE FOLLOWING PROPERTIES: colloidal stability, solubility in physiological fluids, influence of the basic physiological parameters, and cytotoxicity.
量子点最吸引人的特性之一是它们有可能在体内扩展荧光和多模态成像的机会。本研究的目的是阐明纳米粒子的有机涂层的组成和结构是否对其在体内的应用至关重要。
我们比较了用非交联的氨基官能化聚酰胺胺（PAMAM）树状大分子涂覆的量子点、包封在交联的羧基官能化 PAMAM 树状大分子中的量子点和用硅壳官能化的量子点。还开发和分析了一种多模态荧光顺磁量子点探针。将探针静脉内应用于麻醉动物，使用双光子激发荧光显微镜可视化脑脉管系统，使用荧光 IVIS（®）成像（Caliper Life Sciences，Hopkinton，MA）和磁共振成像可视化肿瘤。
用非交联树状大分子涂覆的量子点具有细胞毒性。它们在体内引起副作用，包括血管舒张，导致平均动脉血压和心率下降。量子点穿透血管，导致荧光成像质量恶化。包封在交联树状大分子中的量子点具有低细胞毒性和生物相容性。在<0.3 nmol 量子点/kg 体重的浓度下，这些纳米粒子不影响血压和心率，也不引起血管舒张或血管收缩。基于硅壳量子点，PEG（聚乙二醇）化是开发用于体内成像的量子点探针的不可或缺的步骤。未 PEG 化的硅壳量子点在高盐生理流体中具有低胶体稳定性，体内迅速聚集。硅壳量子点与 PEG1100 的缀合增加了它们在循环中的稳定性和半衰期，而没有明显增加它们的尺寸。在<2.5 nmol/kg 体重的浓度下，这些量子点不影响主要生理变量。可以可视化毛细血管，这使得这种量子点探针适合于在体内研究完整动物的血管收缩、血管舒张和脑循环的介质。多模态硅壳量子点允许使用磁共振成像在肿瘤组织发育的早期阶段进行可视化。
本研究表明，量子点的有机/生物壳的类型和结构决定了它们的生物相容性，并且对其在体内成像中的应用至关重要，这是因为壳对以下性质有影响：胶体稳定性、在生理流体中的溶解度、基本生理参数的影响和细胞毒性。
